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Are we there yet
I got it maybe the Moon is to far away how about the Pizza store down the street.LOL
Are we going to the Moon yet
Dnap more than just a fling
Good things are coming
GOODS AND/OR SERVICES
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computer services, namely, access to a database containing components of a person's genetic architecture with respect to a complex multigenic phenotype for determining predisposition to certain diseases via a global computer network
International Class: 042
First Use Date: (DATE NOT AVAILABLE)
First Use in Commerce Date: (DATE NOT AVAILABLE)
GOODS AND/OR SERVICES
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computer services, namely, access to a database containing components of a person's genetic architecture with respect to a complex multigenic phenotype for determining predisposition to certain diseases via a global computer network
International Class: 042
Providing an on-line electronic database on global computer networks in the field of patients' genotype profiles or a collection of a set of individuals's genotype profiles which can show a predisposition for certain medical conditions
International Class: 042
Whats up with that all Abandoned !!! ????
And another one - Thank you for your request. Here are the latest results from the TARR web server.
This page was generated by the TARR system on 2004-03-06 13:05:21 ET
Serial Number: 75924118
Registration Number: (NOT AVAILABLE)
Mark (words only): DNAPRINT
Standard Character claim: No
Current Status: Abandoned: No Statement of Use filed after Notice of Allowance was issued.
Date of Status: 2003-02-08
Filing Date: 2000-02-22
Transformed into a National Application: No
Registration Date: (DATE NOT AVAILABLE)
Register: Principal
Law Office Assigned: LAW OFFICE 105
If you are the applicant or applicant's attorney and have questions about this file, please contact the Trademark Assistance Center at TrademarkAssistanceCenter@uspto.gov
Current Location: 900 -Warehouse (Newington)
Date In Location: 2003-10-16
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LAST APPLICANT(S)/OWNER(S) OF RECORD
--------------------------------------------------------------------------------
1. Pacific Atlantic Corporation
Address:
Pacific Atlantic Corporation
1748 Independence Blvd., Suite D1
Sarasota, FL 34234
United States
Legal Entity Type: Corporation
State or Country of Incorporation: Florida
--------------------------------------------------------------------------------
GOODS AND/OR SERVICES
--------------------------------------------------------------------------------
Providing an on-line electronic database on global computer networks in the field of patients' genotype profiles or a collection of a set of individuals's genotype profiles which can show a predisposition for certain medical conditions
International Class: 042
First Use Date: (DATE NOT AVAILABLE)
First Use in Commerce Date: (DATE NOT AVAILABLE)
Basis: 1(b)
--------------------------------------------------------------------------------
ADDITIONAL INFORMATION
--------------------------------------------------------------------------------
(NOT AVAILABLE)
--------------------------------------------------------------------------------
MADRID PROTOCOL INFORMATION
--------------------------------------------------------------------------------
(NOT AVAILABLE)
--------------------------------------------------------------------------------
PROSECUTION HISTORY
--------------------------------------------------------------------------------
2003-10-15 - Abandonment - No use statement filed
2003-01-22 - Extension 2 granted
2002-08-05 - Extension 2 filed
2002-12-31 - PAPER RECEIVED
2002-07-30 - PAPER RECEIVED
2002-08-05 - TEAS Extension Received
2002-08-01 - TEAS Change of Correspondence Received
2002-03-04 - Extension 1 granted
2002-02-07 - Extension 1 filed
2001-08-07 - Notice of allowance - mailed
2001-05-15 - Published for opposition
2001-05-02 - Notice of publication
2000-12-27 - Approved for Pub - Principal Register (Initial exam)
2000-08-28 - Communication received from applicant
2000-07-27 - Non-final action mailed
2000-07-26 - Case file assigned to examining attorney
2000-07-25 - Case file assigned to examining attorney
2000-07-25 - Case file assigned to examining attorney
--------------------------------------------------------------------------------
CONTACT INFORMATION
--------------------------------------------------------------------------------
Correspondent (Owner)
Mary B. Scott (Attorney of record)
Tony Frudakis
DNAPrint genomics, Inc.
900 Cocoanut Avenue
Sarasota FL 34236
Phone Number: 941-366-3400
Fax Number: 941-952-9770
And another one - Thank you for your request. Here are the latest results from the TARR web server.
This page was generated by the TARR system on 2004-03-06 13:04:08 ET
Serial Number: 75927822
Registration Number: (NOT AVAILABLE)
Mark (words only): PHENOME
Standard Character claim: No
Current Status: Abandoned: Applicant failed to respond to an Office action.
Date of Status: 2001-05-07
Filing Date: 2000-02-25
Transformed into a National Application: No
Registration Date: (DATE NOT AVAILABLE)
Register: Principal
Law Office Assigned: TMO Law Office 115
If you are the applicant or applicant's attorney and have questions about this file, please contact the Trademark Assistance Center at TrademarkAssistanceCenter@uspto.gov
Current Location: 900 -Warehouse (Newington)
Date In Location: 2002-09-12
--------------------------------------------------------------------------------
LAST APPLICANT(S)/OWNER(S) OF RECORD
--------------------------------------------------------------------------------
1. Pacific Atlantic Corporation
Address:
Pacific Atlantic Corporation
1748 Independence Blvd., Suite D1
Sarasota, FL 34234
United States
Legal Entity Type: Corporation
State or Country of Incorporation: Florida
--------------------------------------------------------------------------------
GOODS AND/OR SERVICES
--------------------------------------------------------------------------------
computer services, namely, access to a database containing components of a person's genetic architecture with respect to a complex multigenic phenotype for determining predisposition to certain diseases via a global computer network
International Class: 042
First Use Date: (DATE NOT AVAILABLE)
First Use in Commerce Date: (DATE NOT AVAILABLE)
Basis: 1(b)
--------------------------------------------------------------------------------
ADDITIONAL INFORMATION
--------------------------------------------------------------------------------
(NOT AVAILABLE)
--------------------------------------------------------------------------------
MADRID PROTOCOL INFORMATION
--------------------------------------------------------------------------------
(NOT AVAILABLE)
--------------------------------------------------------------------------------
PROSECUTION HISTORY
--------------------------------------------------------------------------------
2001-05-07 - Abandonment - Failure to respond
2000-08-23 - Non-final action mailed
2000-08-16 - Case file assigned to examining attorney
2000-08-11 - Case file assigned to examining attorney
2000-07-27 - Case file assigned to examining attorney
--------------------------------------------------------------------------------
CONTACT INFORMATION
--------------------------------------------------------------------------------
Correspondent (Owner)
Mary B. Scott (Attorney of record)
MARY B. SCOTT
GRAY CARY WARE & FREIDENRICH
401 B ST STE 1700
SAN DIEGO CA 92101-4297
United States
Here's another one - Thank you for your request. Here are the latest results from the TARR web server.
This page was generated by the TARR system on 2004-03-06 13:02:41 ET
Serial Number: 75924316
Registration Number: (NOT AVAILABLE)
Mark (words only): TRUSPIN
Standard Character claim: No
Current Status: Abandoned: No Statement of Use filed after Notice of Allowance was issued.
Date of Status: 2001-07-10
Filing Date: 2000-02-22
Transformed into a National Application: No
Registration Date: (DATE NOT AVAILABLE)
Register: Principal
Law Office Assigned: TMO Law Office 114
If you are the applicant or applicant's attorney and have questions about this file, please contact the Trademark Assistance Center at TrademarkAssistanceCenter@uspto.gov
Current Location: 900 -Warehouse (Newington)
Date In Location: 2002-09-11
--------------------------------------------------------------------------------
LAST APPLICANT(S)/OWNER(S) OF RECORD
--------------------------------------------------------------------------------
1. Pacific Atlantic Corporation
Address:
Pacific Atlantic Corporation
1748 Independence Blvd., Suite D1
Sarasota, FL 34234
United States
Legal Entity Type: Corporation
State or Country of Incorporation: Florida
--------------------------------------------------------------------------------
GOODS AND/OR SERVICES
--------------------------------------------------------------------------------
reusable novel spin column separation device for biomedical products
International Class: 010
First Use Date: (DATE NOT AVAILABLE)
First Use in Commerce Date: (DATE NOT AVAILABLE)
Basis: 1(b)
--------------------------------------------------------------------------------
ADDITIONAL INFORMATION
--------------------------------------------------------------------------------
(NOT AVAILABLE)
--------------------------------------------------------------------------------
MADRID PROTOCOL INFORMATION
--------------------------------------------------------------------------------
(NOT AVAILABLE)
--------------------------------------------------------------------------------
PROSECUTION HISTORY
--------------------------------------------------------------------------------
2001-10-23 - Abandonment - No use statement filed
2001-01-09 - Notice of allowance - mailed
2000-10-17 - Published for opposition
2000-09-15 - Notice of publication
2000-07-26 - Approved for Pub - Principal Register (Initial exam)
2000-07-18 - Examiner's amendment mailed
2000-07-13 - Case file assigned to examining attorney
--------------------------------------------------------------------------------
CONTACT INFORMATION
--------------------------------------------------------------------------------
Correspondent (Owner)
Mary B. Scott (Attorney of record)
MARY B. SCOTT
GRAY CARY WARE & FREIDENRLCH
401 B STREET., SUITE 1700
SAN DIEGO, CALIFORNIA 92101-4297
United States
Another Trade Mark abandoned - All of them are !!!!!
Thank you for your request. Here are the latest results from the TARR web server.
This page was generated by the TARR system on 2004-03-06 12:59:54 ET
Serial Number: 75924117
Registration Number: (NOT AVAILABLE)
Mark (words only): SNIPDOC
Standard Character claim: No
Current Status: Abandoned: No Statement of Use filed after Notice of Allowance was issued.
Date of Status: 2002-04-24
Filing Date: 2000-02-22
Transformed into a National Application: No
Registration Date: (DATE NOT AVAILABLE)
Register: Principal
Law Office Assigned: TMEG Law Office 105
If you are the applicant or applicant's attorney and have questions about this file, please contact the Trademark Assistance Center at TrademarkAssistanceCenter@uspto.gov
Current Location: 900 -Warehouse (Newington)
Date In Location: 2002-10-30
--------------------------------------------------------------------------------
LAST APPLICANT(S)/OWNER(S) OF RECORD
--------------------------------------------------------------------------------
1. Pacific Atlantic Corporation
Address:
Pacific Atlantic Corporation
1748 Independence Blvd., Suite D1
Sarasota, FL 34234
United States
Legal Entity Type: Corporation
State or Country of Incorporation: Florida
--------------------------------------------------------------------------------
GOODS AND/OR SERVICES
--------------------------------------------------------------------------------
Providing an on-line electronic database on global computer networks in the field of patients' genotype
International Class: 042
First Use Date: (DATE NOT AVAILABLE)
First Use in Commerce Date: (DATE NOT AVAILABLE)
Basis: 1(b)
--------------------------------------------------------------------------------
ADDITIONAL INFORMATION
--------------------------------------------------------------------------------
(NOT AVAILABLE)
--------------------------------------------------------------------------------
MADRID PROTOCOL INFORMATION
--------------------------------------------------------------------------------
(NOT AVAILABLE)
--------------------------------------------------------------------------------
PROSECUTION HISTORY
--------------------------------------------------------------------------------
2002-10-02 - Abandonment - No use statement filed
2001-10-23 - Notice of allowance - mailed
2001-07-31 - Published for opposition
2001-07-18 - Notice of publication
2001-02-25 - Approved for Pub - Principal Register (Initial exam)
2000-09-21 - Communication received from applicant
2000-07-27 - Non-final action mailed
2000-07-26 - Case file assigned to examining attorney
2000-07-25 - Case file assigned to examining attorney
2000-07-25 - Case file assigned to examining attorney
--------------------------------------------------------------------------------
CONTACT INFORMATION
--------------------------------------------------------------------------------
Correspondent (Owner)
Mary B. Scott (Attorney of record)
MARY B. SCOTT
GRAY CARY WARE & FREIDENRICH
401 B STREET, SUITE 1700
SAN DIEGO, CALIFORNIA 92101-4297
United States
Thank you for your request. Here are the latest results from the TARR web server.
This page was generated by the TARR system on 2004-03-06 12:39:42 ET
Serial Number: 75924316
Registration Number: (NOT AVAILABLE)
Mark (words only): TRUSPIN
Standard Character claim: No
Current Status: Abandoned: No Statement of Use filed after Notice of Allowance was issued.
Date of Status: 2001-07-10
Filing Date: 2000-02-22
Transformed into a National Application: No
Registration Date: (DATE NOT AVAILABLE)
Register: Principal
Law Office Assigned: TMO Law Office 114
If you are the applicant or applicant's attorney and have questions about this file, please contact the Trademark Assistance Center at TrademarkAssistanceCenter@uspto.gov
Current Location: 900 -Warehouse (Newington)
Date In Location: 2002-09-11
--------------------------------------------------------------------------------
LAST APPLICANT(S)/OWNER(S) OF RECORD
--------------------------------------------------------------------------------
1. Pacific Atlantic Corporation
Address:
Pacific Atlantic Corporation
1748 Independence Blvd., Suite D1
Sarasota, FL 34234
United States
Legal Entity Type: Corporation
State or Country of Incorporation: Florida
--------------------------------------------------------------------------------
GOODS AND/OR SERVICES
--------------------------------------------------------------------------------
reusable novel spin column separation device for biomedical products
International Class: 010
First Use Date: (DATE NOT AVAILABLE)
First Use in Commerce Date: (DATE NOT AVAILABLE)
Basis: 1(b)
--------------------------------------------------------------------------------
ADDITIONAL INFORMATION
--------------------------------------------------------------------------------
(NOT AVAILABLE)
--------------------------------------------------------------------------------
MADRID PROTOCOL INFORMATION
--------------------------------------------------------------------------------
(NOT AVAILABLE)
--------------------------------------------------------------------------------
PROSECUTION HISTORY
--------------------------------------------------------------------------------
2001-10-23 - Abandonment - No use statement filed
2001-01-09 - Notice of allowance - mailed
2000-10-17 - Published for opposition
2000-09-15 - Notice of publication
2000-07-26 - Approved for Pub - Principal Register (Initial exam)
2000-07-18 - Examiner's amendment mailed
2000-07-13 - Case file assigned to examining attorney
--------------------------------------------------------------------------------
CONTACT INFORMATION
--------------------------------------------------------------------------------
Correspondent (Owner)
Mary B. Scott (Attorney of record)
MARY B. SCOTT
GRAY CARY WARE & FREIDENRLCH
401 B STREET., SUITE 1700
SAN DIEGO, CALIFORNIA 92101-4297
United States
Tony look I'll make a deal with ya. You come out with approval on the "SINGLE NUCLEOTIDE POLYMORPHISMS AND COMBINATIONS THEREOF PREDICTIVE FOR PACLITAXEL RESPONSIVENESS" Patent This Month, the month of March 2004 and I will not be mad at you AND AND my wife and chrilden will not be either. LOL
Dear Tony,Shame on you !! What ever happen to the "SINGLE NUCLEOTIDE POLYMORPHISMS AND COMBINATIONS THEREOF PREDICTIVE FOR PACLITAXEL RESPONSIVENESS" info. at the US patent office. Are you hiding it from us ? Is it ready to Blow ? Cant say,hay.Oh Tony your holding out on us, when do we getto have it ? Soon, like very soon. Why would you place a Black out on this little baby ? Why ? if you were not going to come out with it soon.Come on Tony you can tell me I wont say a word to anyone - Crosseee pay double I promise.
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(11) WO 03/045227
REVISED VERSION
(13) A3
(21) PCT/US02/38345
(22) 26 November 2002 (26.11.2002)
(25) English
(26) English
(30) 60/334,310 28 November 2001
(28.11.2001) US
(30) 60/410,363 11 September 2002
(11.09.2002) US
(43) 05 June 2003 (05.06.2003)
(51)7 C12Q 1/68, C12P 19/34, C12M 1/34, C07H 21/04
(54) SINGLE NUCLEOTIDE POLYMORPHISMS AND COMBINATIONS THEREOF PREDICTIVE FOR PACLITAXEL RESPONSIVENESS
(71) DNAPRINT GENOMICS, INC. [US/US]; 900 Cocoanut Avenue, Sarasota, FL 34236 (US).
(72)
(75) FRUDAKIS, Tony, N. [US/US]; 3707 Plumosa Terrace, Bradenton, FL 34210 (US).
(74) HAILE, Lisa, A.; Gary Cary Ware & Friedenrich LLP, Suite 1100, 4365 Executive Drive, San Diego, CA 92121-2133 (US).
(81) AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SC, SD, SE, SG, SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW
(84) ARIPO patent (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG)
For information on time limits for entry into the national phase please click here
Published
-- with international search report
-- before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments
(88) 21 August 2003 (21.08.2003)
(57) Single nucleotide polymorphisms (SNPs) and combinations of SNPs that allow an inference as to whether a cancer patient is likely to respond or not respond to paclitaxel (Taxol®) are provided. Also provided are methods of determining a whether a cancer patient should be treated with paclitaxel.
A Little more Statnome info. - http://l2.espacenet.com/espacenet/viewer?PN=WO03002721&CY=gb&LG=en&DB=EPD
Drug interactions due to cytochrome P450
CHRIS C. OGU, PHARMD, AND JAN L. MAXA, RPH
From the Department of Pharmacy Services, Baylor University Medical Center, Dallas, Texas.
Corresponding author: Jan L. Maxa, RPh, Department of Pharmacy Services, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, Texas 75246.
Cytochrome P450 is a family of isozymes responsible for the biotransformation of several drugs. Drug metabolism via the cytochrome P450 system has emerged as an important determinant in the occurrence of several drug interactions that can result in drug toxicities, reduced pharmacological effect, and adverse drug reactions. Recognizing whether the drugs involved act as enzyme substrates, inducers, or inhibitors can prevent clinically significant interactions from occurring. Avoiding coadministration or anticipating potential problems and adjusting a patient's drug regimen early in the course of therapy can provide optimal response with minimal adverse effects.
rug metabolism via the cytochrome P450 system has emerged as an important determinant in the occurrence of several drug-drug interactions. A greater degree of interaction predictability has been achieved through the identification of P450 isozymes and some of the drugs that share them. Six different P450 isozymes--CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP2E1, and CYP3A4--that play important roles in drug metabolism have been identified (1, 2). Of these 6 isozymes, shared metabolism by the CYP3A4 isozyme has resulted in several clinically significant drug-drug interactions. More information about the effects of certain drugs on enzyme-mediated biotransformation has led to identification of enzyme inducers and inhibitors, providing even greater insight into the nature of the interactions.
Cytochrome P450 represents a family of isozymes responsible for biotransformation of many drugs via oxidation. The enzymes are heme-containing membrane proteins, which are located in the smooth endoplasmic reticulum of several tissues. Although a majority of the isozymes are located in the liver, extrahepatic metabolism also occurs in the kidneys, skin, gastrointestinal tract, and lungs. Significant inactivation of some orally administered drugs is due to the extensive first-pass metabolism in the gastrointestinal tract by the CYP3A4 isozyme (3).
FACTORS AFFECTING BIOTANSFORMATION
Numerous factors affect drug biotransformation. Enzyme induction is the process by which exposure to certain substrates (e.g., drugs, environmental pollutants) results in accelerated biotransformation with a corresponding reduction in unmetabolized drug. Most drugs can exhibit decreased efficacy due to rapid metabolism, but drugs with active metabolites can display increased drug effect and/or toxicity due to enzyme induction. Enzyme inhibition occurs when 2 drugs sharing metabolism via the same isozyme compete for the same enzyme receptor site. The more potent inhibitor will predominate, resulting in decreased metabolism of the competing drug. For most drugs, this can lead to increased serum levels of the unmetabolized entity, leading to a greater potential for toxicity. For drugs whose pharmacological activity requires biotransformation from a pro-drug form, inhibition can lead to decreased efficacy.
Factors contributing to interpatient variability in biotransformation include genetic polymorphism, disease, age, and gender. The 2 isozymes most affected by genetic control are CYP2C19 and CYP2D6 (4). Individuals lacking the gene for these isozymes are poor metabolizers; those possessing it are capable of normal drug metabolism and are considered extensive metabolizers (1). Disease states affecting metabolism are hepatic disease, which affects organ function, and congestive heart failure, which causes decreased blood flow to the liver. The cytochrome P450 monooxygenase system is more affected by aging than any other metabolic pathway (3). Decreased biotransformation occurs in newborns due to underdevelopment of hepatic microsomal components (5). In the elderly, decreases in hepatic blood flow, enzyme activity, and liver mass result in reduced metabolic activity.
CYP3A4 ISOZYME INTERACTIONS
Studies on the CYP3A4 isozyme and drug-drug/drug-food interactions are becoming an integral part of drug research. Recent case reports of serious, sometimes fatal reactions due to concomitant administration of certain drugs require careful consideration. Drug prescribing for patients on multidrug regimens warrants thorough review of the patient's current therapy with respect to drug biotransformation.
For CYP3A4-metabolized drugs that require periodic monitoring of serum levels, the interaction of another CYP3A4-metabolized drug can be controlled by dosage adjustments to maintain appropriate levels of the monitored drug. Cyclosporine (CYA), tacrolimus, and carbamazepine are all substrates of CYP3A4. Coadministration of cyclosporine with a CYP3A4 inhibitor decreases an individual's CYA dosage requirement. Drinking grapefruit juice may be an inexpensive way to reduce cyclosporine dosages, but the unpredictable nature of the inhibition of CYA metabolism has not vindicated this practice. Ketoconazole and diltiazem, purer entities of CYP3A4 inhibitors, have been used successfully in this respect. Patients unable to obtain therapeutic CYA levels with orally administered cyclosporine due to inadequate absorption can been placed on either of these agents to achieve this goal.
The real problem with prescribing drugs that share the CYP3A4 pathway has been seen with drugs whose levels are not measured. When the serum levels of these drugs reach a toxic state, the toxicity can manifest itself with serious medical consequences. The pro-arrhythmic effects from high serum levels of the nonsedating antihistamines terfenadine and astemizole have severely limited their usefulness and led to the development of newer agents to take their place. Mibefradil (Posicor), a potent inhibitor of CYP3A4, was withdrawn from the market after numerous reports of serious drug-drug interactions.
Another drug class of note in this category is the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors. High serum concentrations of some of these agents are strongly linked to the development of rhabdomyolysis. Adding a CYP3A4 inhibitor to a drug regimen that includes certain HMG CoA reductase inhibitors greatly increases the patient's risk of developing rhabdomyolysis. One advantage of recognizing this drug interaction has been the subsequent studies conducted to identify which agents can be used safely in multidrug combinations. Research focusing on CYP3A4 inhibitors and HMG CoA reductase inhibitors has found that pravastatin and fluvastatin can be coadministered with itraconazole, a potent CYP3A4 inhibitor, without significant changes in maximum serum concentrations (6, 7).
CONCLUSION
The Table has been provided to identify those drugs that share the CYP3A4 isozyme. Some drugs are metabolized by more than one isozyme, and because they possess a dual pathway of metabolism, their use may not be precluded after risk/benefit analysis. Further studies on cytochrome P450 metabolism will continue to provide clinicians with guidelines for appropriate agents to use when circumstances arise warranting the use of multiple-drug regimens.
Do you know what P450 stands for you should it will one day make us all rich.
HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis
W W-L Wong1,2, J Dimitroulakos1, M D Minden1,2 and L Z Penn1,2
1Department of Cellular and Molecular Biology, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Canada
2Department of Medical Biophysics, University of Toronto, Toronto, Canada
Correspondence to: L Z Penn, Division of Cellular and Molecular Biology, Ontario Cancer Institute, University Health Network, 610 University Ave, Rm 9-628, Toronto, Ontario, Canada M5G 2M9; Fax: 416-946-2840
Abstract
The statin family of drugs target HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, and have been used successfully in the treatment of hypercholesterolemia for the past 15 years. Experimental evidence suggests this key biochemical pathway holds an important role in the carcinogenic process. Moreover, statin administration in vivo can provide an oncoprotective effect. Indeed, in vitro studies have shown the statins can trigger cells of certain tumor types, such as acute myelogenous leukemia, to undergo apoptosis in a sensitive and specific manner. Mechanistic studies show bcl-2 expression is down-regulated in transformed cells undergoing apoptosis in response to statin exposure. In addition, the apoptotic response is in part due to the depletion of the downstream product geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or other products of the mevalonate pathway including cholesterol. Clinically, preliminary phase I clinical trials have shown the achievable plasma concentration corresponds to the dose range that can trigger apoptosis of tumor types in vitro. Moreover, little toxicity was evident in vivo even at high concentrations. Clearly, additional clinical trials are warranted to further assess the safety and efficacy of statins as novel and immediately available anti-cancer agents. In this article, the experimental evidence supporting a role for the statin family of drugs to this new application will be reviewed.
Leukemia (2002) 16, 508-519. DOI: 10.1038/sj/leu/2402476
Keywords
HMG-CoA reductase; statins; apoptosis; geranylgeranylation; bcl-2
Introduction
A new opportunity for the development of novel anti-cancer therapeutic agents has recently been realized with the discovery that cells are programmed with the potential to commit suicide through the molecular mechanism of apoptosis (for recent reviews see Refs 1-4). This apoptotic process is highly regulated at the cellular level by a multiplicity of independent and interdependent pathways.5,6,7,8,9,10,11 Deregulation within the apoptotic network contributes to tumor development by allowing cells to evade signals to commit suicide,12 yet paradoxically, transformed cells often retain the ability to undergo apoptosis. Proof of concept is provided by traditional chemotherapeutic agents that inhibit DNA synthesis or cellular replication, often leading to irreparable DNA breaks, cell cycle arrest and ultimately apoptosis of the tumor cells.13 However, application of such agents is often limited by significant toxicity and a lack of specificity. Traditional cytotoxic agents affect both normal as well as tumor cells, and can result in toxic side-effects that significantly impact patient quality of life.13 Taken together, cancer eradication by chemotherapy is achieved by triggering tumor cells to undergo apoptosis; however, the stimuli need to be radically modified to target tumor cells in a more specific, less toxic manner (Figure 1). New approaches through molecular targeted therapies promise to fill this gap and provide the novel anti-cancer agents urgently required.
A novel molecular target with strong potential for rapid application to the clinic is the rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.14 The end products of the mevalonate (MVA) pathway are required for a number of essential cellular functions (Figure 2). These include sterols, such as cholesterol, involved in membrane integrity and steroid production; ubiquinone (coenzyme Q), involved in electron transport and cell respiration; farnesyl and geranylgeranyl isoprenoids involved in covalent binding of proteins such as the Ras family to membranes; dolichol, which is required for glycoprotein synthesis; and isopentenyladenine, essential for certain tRNA function and protein synthesis.14,15,16,17,18 Importantly, inhibitors of this key enzyme, collectively known as statins, are well established and effective agents used in the treatment of hypercholesterolemia.19,20,21,22 Thus, HMG-CoA reductase is a unique molecular target for anti-cancer therapy; it holds a pivotal role in the well-defined MVA pathway, and a specific family of inhibitors is available for immediate application in the cancer clinic.
Recent evidence strongly suggests the MVA pathway holds an important regulatory role in cellular proliferation and transformation. For example, malignant cells appear highly dependent on the sustained availability of the end products of the MVA pathway.23,24,25 Deregulated or elevated activity of HMG-CoA reductase has been shown in a range of different tumors including hepatocellular carcinoma, leukemia, lymphoma, colorectal and lung adenocarcinoma.26,27,28,29,30,31 Moreover, large retrospective analyses for drug safety and efficacy trials of statins in coronary artery disease have shown, that not only are these agents able to reduce cardiac disease-related mortality, but cancer incidence is also reduced by 28-33%.32,33 These data further suggest these agents may have a role in cancer prophylaxis as well as therapy.19,32,33,34,35 Indeed, recent analyses have demonstrated that inhibitors of HMG-CoA reductase can directly block tumor cell growth both in vitro and in vivo. In this review, we will focus on the antiproliferative activity of the statins, the mechanism of statin-induced apoptosis, and the application of statin therapy as an anti-cancer agent.
The statin family of drugs
The statin family is composed of eight unique compounds that are naturally derived or chemically synthesized (Figure 3).22,36,37,38,39 Statins derived from fungal fermentation include pravastatin, simvastatin, and lovastatin, whereas fluvastatin, atorvastatin, cerivastatin, rosuvastatin and pitavastatin are synthetic compounds.40,41,42,43,44,45,46,47 The common structural characteristic of all statins is a side chain that exists either in a closed ring (inactive, lactone) or an open ring (active, acid) form (Figure 2).48,49 The former undergoes activation in vivo by carboxyesterases in plasma and liver.50,51 The open ring conformation of this drug blocks catalytically active HMG-CoA reductase by functioning as a molecular mimic of a reaction intermediate formed within the active site of this enzyme.49 Statins are effective competitive inhibitors as they bind HMG-CoA reductase approximately1000-fold more effectively than the natural substrate.36,49
Each member of the statin family of drugs functions by a similar mechanism of action but maintains unique binding affinities, pharmacokinetics and dosing levels (Table 1). A detailed overview of these features is beyond the scope of this article, and the reader is referred to several reviews of this subject.36,39,40,46,47,52,53,54,55 In brief, the binding affinities of the inhibitors (Ki) range from 0.1 to 2.3 nM,36,45,46,47 whereas the Km of the natural substrate, HMG-CoA is 4 M.56 The pharmacokinetics are disparate and largely dictated by their lipophilic nature, acid or lactone form, and mechanism of cytochrome P450 metabolism in the liver, which is the primary site of action for cholesterol control.57,58 Briefly, statin action for hypercholesterolemia leads to a decrease in intracellular hepatic cholesterol levels which then induces expression of cell surface low-density lipoprotein receptors, enabling cholesterol to be removed from the circulation and replenish intracellular cholesterol stores.59 The safety of this family of drugs has been documented extensively and they are remarkably well tolerated.21,22,39,55 Reports of minor adverse side-effects include constipation, flatulence, dyspepsia, nausea, gastrointestinal pain, and elevated serum transaminase levels.22,59 The most serious adverse effect is myotoxicity including rhabdomyolysis which can be diminished with co-administration of ubiquinone.55,59 Patients with hepatic insufficiency, cholestasis, or hepatic or renal diseases warrant careful monitoring when treated with statins.57,59 In addition, drug:drug interactions must be thoroughly considered to ensure systemic concentrations are controlled. This is of particular importance with agents that are also metabolized by cytochrome P450 3A4 such as gemfibrozil.33,37,55,60,61,62,63,64,65,66 Thus, the statins are functionally equivalent and the choice of drug is largely determined by individual patient needs and tolerability.
Antiproliferative activities of statins
Growth arrest
It is well established that exposure of certain transformed cells to statins in vitro can lead to growth arrest at the G1/S phase boundary of the cell cycle.67,68 Indeed, lovastatin is used routinely as an experimental tool to block G1 to S phase transition and to synchronize cells in vitro, by reversing the block with the addition of mevalonate.67 This characteristic has been primarily exploited and studied in cell lines derived from mammary carcinomas but is also evident in other cell types.67,69,70,71,72 At the molecular level, this p53-independent growth arrest response, is mediated by a down-regulation of cyclin dependent kinase (CDK) 2 activity with an associated up-regulation of CDK inhibitors p21Cip1 and/or p27Kip1.69,71,72,73 It has been recently suggested that this cytostatic activity can be mediated by the closed ring, pro-form of lovastatin or simvastatin by affecting proteasome function.74,75 The precise inhibitory mechanism of statins on the proteasome function requires further clarification. Interestingly, these effects are reversible with mevalonate74,75,76 and a role for the pro-form of lovastatin is not consistent with other results in the field. For example, cerivastatin, an active open ring statin, can induce the classical G1/S phase growth arrest with an associated increase in p21Cip1 in malignant breast cells.77 Moreover, we and others, have shown that the lactone ring is hydrolyzed to its active form when exposed to aqueous solution, including cell growth medium, strongly suggesting the pro-drug was activated in these in vitro studies.60,78,79 Taken together, statins can growth arrest certain tumor sub-types by activating a well defined cell cycle checkpoint at the G1/S phase border by a mechanism that remains ill defined, but involves inhibition of HMG-CoA reductase.
Apoptosis
In recent years it has become clear that inhibitors of HMG-CoA reductase can trigger a subset of tumor-derived cells to undergo apoptosis (Table 2). Tumor cell types that undergo apoptosis upon exposure to lovastatin include acute myelogenous leukemia (AML), juvenile monomyelocytic leukemia, rhabdomyosarcoma, squamous cell carcinoma of the cervix and of the head and neck; medulloblastoma, mesothelioma, pancreatic carcinoma, neuroblastoma and astrocytoma.79,80,81,82,83,84,85,86,87 Clearly, this list is not yet comprehensive. Further investigation is essential to fully evaluate which additional tumor types are sensitive to statin-induced apoptosis.72,88,89,90 Sensitive tumor types show a consistent pronounced apoptotic response following statin exposure in vitro, suggesting these cancers may have a high-probability of sensitivity in vivo. The molecular features conferring sensitivity to statin-induced apoptosis remain unclear. Experimental evidence show cells must be proliferating to be sensitive to statin-induced apoptosis.91,92,93,94 However, being engaged in the cell cycle is essential but not sufficient for statins to trigger an apoptotic response.73,79,82 For example, proliferating tumor-derived cell lines that are not sensitive to statin-induced apoptosis in vitro include breast and prostate.79 Further work delineating the molecular features conferring sensitivity to statin-induced apoptosis is a subject of intense investigation because of the therapeutic potential of statins to trigger tumor cells to undergo apoptosis in vivo (discussed below). Statin-induced apoptosis occurs due to the open-ring active drug blocking HMG-CoA reductase.79,95,96 Cell lines that have been rendered resistant to lovastatin-induced apoptosis by exposure to increasing doses of statins show drug-resistance is due to amplification of the gene encoding HMG-CoA reductase.97,98 In addition, the apoptotic response is abrogated by the addition of excess mevalonate to the sensitive cells.88,99,100,101,102,103,104 Thus, cells of certain malignant transformations are sensitive to statin-induced apoptosis as a direct result of blocking HMG-CoA reductase and the mevalonate pathway.
Most importantly, statins can trigger apoptosis in a tumor-specific manner. The majority of both primary and established tumor cells derived from AML undergo apoptosis in response to lovastatin.81,82,105,106. By contrast, myeloid progenitor cells derived from normal bone marrow or cord blood do not undergo apoptosis and retain their full proliferative potential.82,106 Further evidence that non-transformed cells of hematopoietic origin are not damaged by exposure to statins originates from animal studies as well as both low- and high-dose human clinical trials (discussed below).19,36,57,81,105,106,107,108,109,110,111 Thus, despite the prevalence of HMG-CoA reductase in all cells, data to date suggests statins will possess a high therapeutic index (efficacy/toxicity) when used to target apoptosis-sensitive tumor sub-types in vivo.
Molecular mechanism of statin-induced apoptosis
Understanding the mechanism of statin-induced apoptosis of tumor cells is at its infancy and further investigation is required to delineate the key features that dictate statin sensitivity. One of the distinguishing molecular characteristics of statin-sensitive AML and colon cells is the down-regulation of bcl-2 mRNA and protein, respectively.112,113 Although basal bcl-2 mRNA levels are not associated with sensitivity to lovastatin-induced apoptosis, down-regulation of bcl-2 is a consistent feature of the lovastatin-sensitive AML cell lines.112 Indeed, this molecular event contributes to the sensitivity of the apoptotic response as ectopic expression of bcl-2 can inhibit lovastatin-induced apoptosis.112,114 The mechanism of bcl-2 down-regulation following exposure to lovastatin is unknown but is associated with a pronounced differentiation response in AML cells. For example, elevated expression of differentiation-specific cell surface antigens, CD11b and CD18 was detected in response to lovastatin. Interestingly, retinoic acid, a potent cell differentiating and growth inhibitory agent, regulated bcl-2 as well as CD11b and CD18 in a similar manner to lovastatin in the apoptosis-sensitive AML cell lines.112 The relationship between lovastatin-induced differentiation and apoptosis are provocative and require further investigation. Statin regulation of Bcl-2 expression and function is consistent with statin-induced apoptosis employing the intrinsic mitochondrial pathway to effect cell death. Apoptosis in response to lovastatin is associated with release of cytochrome c, activation of caspase-3, and PARP cleavage in AML.115
The depletion of mevalonate is responsible for statin-induced apoptosis in sensitive tumor cells, suggesting that blocking the production of specific mevalonate metabolites is involved in this process. To determine which downstream product(s) of the mevalonate pathway could suppress this apoptotic response, add-back experiments were conducted. Of the many diverse downstream products of the mevalonate pathway, only geranylgeranyl pyrophosphate (GGPP) was able to inhibit apoptosis.88,102,104 No effect was evident with other products including cholesterol, ubiquinone, isopentenyladenine and dolichol phosphate. Interestingly, farnesyl pyrophosphate (FPP), a molecule similar to GGPP, had little to no effect on statin-triggered apoptosis in a variety of cell systems.88,102,104 GGPP and FPP serve as substrates for geranylgeranyl transferases (GGTase) and farnesyl transferase (FTase), respectively, which isoprenylate proteins to ensure proper localization within the cell.17 The importance of geranylgeranylation in statin-induced apoptosis of AML cells was confirmed with inhibitors of geranylgeranyl transferase (GGTI-298) and farnesyl transferase (FTI-277).104 GGTI-298 was as potent as lovastatin in triggering apoptosis, whereas FTI-277 showed little apoptotic activity.104 Therefore, one possible model is that exposure to statins depletes GGPP causing improper localization and function of proteins which ultimately triggers the cell to commit suicide (Figure 4).
It remains unclear whether global loss of protein geranylgeranylation is key to apoptosis or whether loss of a restricted substrate(s) is responsible for the apoptotic response to statin exposure. Approximately 0.5 to 1% of cellular proteins are geranylgeranylated yet only a small number of substrates have been identified.116 Known target proteins include small GTP-binding proteins including K-Ras and N-Ras as well as the Rho family of proteins. Interestingly, statins have been shown to block metastasis at the level of cell attachment, migration and invasion in solid tumors.77,117,118,119,120,121,122 Mechanistic studies strongly suggest geranylgeranylation is also key to the anti-metastatic properties of statins, and a pivotal role for RhoA in these activities.77,122 It will be fascinating to delineate whether similar or different target proteins are responsible for the pro-apoptotic and antimetastatic properties of the statin family of drugs. To this end, direct analysis of the geranylgeranylated proteins in both apoptosis-sensitive and -resistant cells should begin to address the issue of target specificity and apoptotic response. Moreover, by this approach molecular markers to identify tumor cells that will undergo apoptosis in response to statin therapy may be achieved.
Analysis in three additional areas of research will further identify distinguishing features of tumor cells that are sensitive to statin-induced apoptosis. First, the nature and number of transforming events that contribute to the statin-induced apoptotic response remains relatively unknown.123,124,125 Indeed, it has become clear in recent years that certain transforming events can significantly affect cellular apoptotic response. For example, cytostatic agents block proliferation of non-transformed cells, yet will trigger apoptosis in cells expressing an activated allele of the c-myc oncogene.126 It will be instructive to learn which specific transforming events contribute to statin sensitivity. Secondly, cells of sensitive tumor types expressing P-glycoprotein (P-gp) have been shown to be further sensitized to the cytotoxic effects of lovastatin.86,127,128,129 The mechanism of this remarkable characteristic has only recently been explored and requires additional investigation.62,63 Finally, an important and often overlooked concept of apoptosis regulation, is the cell type-dependent response. For example, irradiation of T lymphocytes and fibroblasts leads to an induction of p53 expression that is similar at the molecular level in both cell types, but only the lymphocytes undergo apoptosis.130 Cell type differences clearly contribute to the multifunctional properties of statins. For example, statins can function as anti-inflammatory agents, antioxidants, immunomodulators, and angiogenic agents depending on the non-transformed cell type.131,132,133,134,135,136,137,138,139 In addition, statins can block vascular smooth muscle cell proliferation as well as signal endothelial cell survival and progenitor cell expansion.140,141,142,143,144 These results underscore the cell type-dependent effects of statins as well as the pleiotropic effects of these agents. Thus, the parameters that confer sensitivity to certain tumor cells to undergo statin-induced apoptosis require further investigation.
Complete mechanistic knowledge is key to optimal utilization of statins in the clinical management of cancer in combination with other anti-neoplastic agents. For example, insulin growth factor-1 (IGF-1) and nerve growth factor exposure of mouse colon cancer cells and neuronal cells, respectively, delayed the cytotoxic effects of lovastatin.94,145 Similarly, growth factors, estradiol and IGF-1 have been shown to reverse the growth arrest phenotype triggered by lovastatin in breast and melanoma cells, respectively.146,147,148 These data suggest that growth and survival pathways triggered by these factors can overcome the anti-cancer effects of statins. Identifying the modulators of statin activity within these signaling pathways may shed light on the mechanism of statin-directed cytotoxicity. This knowledge may provide an opportunity to further potentiate statin efficacy by combining inhibitors of these modulators with statin therapy in vivo.
Preclinical evaluation of statins as anti-cancer agents
Analyses of cell culture and animal models of carcinogenesis have shown that statins can decrease tumor cell number alone and in combination with other anti-cancer agents. When administered as the sole agent in animal models statins can decrease tumor load of AML, melanoma, hepatoma, pancreatic, lung and neuroblastoma.107,117,149,150,151,152 Importantly, there was little overt toxicity. However, it is unlikely that an agent will be effective in eradicating disease when administered by itself, hence multiagent cancer therapy is practised. In particular, lovastatin has been shown to potentiate antitumor activity of doxorubicin, TNF-, carmustine (BCNU; N, N'-bis(2-chloroethyl)-N-nitrosourea) in mouse tumor models of lung, colon carcinoma, melanoma and astrocytoma, respectively.153,154,155,156,157 Other statins, including lovastatin have been shown to potentiate apoptotic effects of cytosine arabinoside, phenylacetate, cisplatin, 5-fluorouracil, butyrate and non-steroidal anti-inflammatory drugs (NSAIDs) such as sulindac in AML, glioblastoma, and colon cancer cells.71,102,113,158,159,160 Identifying agents that synergize with statins will aid in their proper application in the clinic and may also help elucidate the mechanism of statin-induced apoptosis.
Clinical trials
Clinical trials investigating the possible value of the statins as chemotherapeutic agents have been recently conducted and suggest dosing and scheduling are important (Table 3). In the first phase I clinical trial lovastatin was administered at a dose of 25 mg/kg/day in four divided doses by the usual oral route for 1 week followed by 3 weeks off statin administration. Dose-related toxicities were minimal and consisted of gastrointestinal dysfunction, and musculoskeletal system complaints including mylagias and muscle weakness.109 Supplementation with ubiquinone reduced the severity but did not decrease the incidence of musculoskeletal toxicity or affect drug activity as a cholesterol agent.109 Interestingly, at doses higher than 25 mg/kg/day, no direct correlation between the incidence of myotoxicity and the dose of lovastatin administered was evident.109 Most importantly, the trial established the achievable plasma concentration at 0.10 to 3.92 M at a dose of 25 mg/kg/day, which corresponds to the dose range that can trigger apoptosis of sensitive tumor types in vitro.79,82 Interpatient variability in achievable plasma concentration was evident and no direct relationship to the dose administered was noted.109 In this phase I clinical trial, one minor response was seen at 30-35 mg/kg/day in a patient diagnosed with anaplastic astrocytoma.109 There was no evidence of efficacy in patients with other tumor types including breast, prostate, ovarian and other primary central nervous system malignancies. However, the lack of efficacy in this trial may be because the tumor types under study did not correspond to those that are sensitive to lovastatin-induced apoptosis.
Two additional high-dose anti-cancer lovastatin trials have been recently reported. Using the same dosing schedule, a phase I-II trial targeted anaplastic astrocytoma and glioblastoma multiforme with lovastatin (20-30 mg/kg/day orally) alone or in combination with radiation treatment.110 Of the nine patients treated with lovastatin alone, there was one stable, one minor and one partial response. Of the nine patients that were treated with both lovastatin and radiation, there were two minor and two partial responses as determined by standard clinical trial response criteria.110 A phase II study of high-dose lovastatin (35 mg/kg/day orally) was conducted in patients with gastric adenocarcinoma.111 Patients were treated for 1 week on and then were off drug for 3 weeks which resulted in one out of 14 patients with stable response.111 In all three trials reported to date, the high dose was well tolerated with no neurological, hematological, liver or renal toxicity observed; however, tumor response was limited.
To evaluate the safety and efficacy of lovastatin in the control of AML blast counts, we initiated a trial of lovastatin in high-count, drug-refractory AML patients and administered an oral dose of 10-20 mg/kg/day for a 2 week dosing period followed by 2 weeks off. However, due to drug-related toxicities in these patients, including nausea and elevated levels of creatine phosphokinase, the full regimen could not be administered. An alternative approach to diminish these toxicity issues and to allow for an assessment of efficacy, was to administer a lower dose of lovastatin for a prolonged period of time. An elderly female presenting with relapsed AML, whose blast cells were sensitive to lovastatin-induced apoptosis in vitro,82 was treated with twice the maximal recommended cholesterol dose of lovastatin 160 mg/day (~2 mg/kg/day) for 54 days.161 This regimen was effective in managing blast counts during the period of drug administration.161 Remarkably, despite halting the administration of drug, the decreased blast counts persisted for an additional 3 months.161 Indeed, recent results of a clinical trial showed that administration of pravastatin to patients with hepatocellular carcinoma at the recommended cholesterol dose 40 mg/day (~0.5 mg/kg/day) in conjunction with 5-fluorouracil, doubled the median time of survival for these patients.108 This suggests that the statins may be of value in disease control when combined with standard therapeutic approaches.162,163,164 Moreover, efficacy may be improved when statins are administered in a low-dose regimen over an extended period of time. Further investigation is required to determine the best regimen of treatment for each tumor type whether it be administration of a low dose of statins over an extended period of time or a high dose of statins which is well-tolerated for shorter periods. Another approach may be to administer a statin with high specific activity in driving tumor cell death. Indeed, cerivastatin fulfills this criteria95,96 and although it has been recently recalled from the market,66 evaluating its efficacy as an anti-cancer agent in vivo may warrant its reinstatement. Taken together, further testing of the statins to fully evaluate their efficacy as a novel therapeutic agent alone and in combination with other agents is merited.
Future considerations
Clearly, understanding the molecular mechanism of statin's anti-cancer action remains outstanding. This knowledge is fundamental as it is critical to the clinical management of patients. To date, the depletion of GGPP is the pivotal signal that triggers sensitive tumor cell types to undergo apoptosis following statin exposure. Delineating whether specific transforming events contribute to tumor sensitivity as well as identifying the geranylgeranylated substrate(s) and their downstream pathways essential for the cytotoxic effects of statins will mark a key advance. Moreover, further work to unravel the contribution of P-gp to tumor sensitivity and the mechanistic association of lovastatin-induced apoptosis and differentiation is essential. The outcome of such investigations will provide mechanistic insight into the growth arrest and apoptotic response upon exposure to statins and may uncover a novel molecular target for therapeutic intervention. In addition, molecular predictors of response may be identified allowing for more effective stratification of patients. Finally, with the mechanism well understood, a synergistic combination of agents can be designed to maximize statin efficacy in vivo.
Another major area of investigation in this field, is to evaluate and optimize the clinical utility of statins as anti-cancer agents. The tumor types that are sensitive to statin-induced apoptosis, as opposed to growth arrest, will probably represent the most attractive therapeutic targets for tumor eradication. Furthermore, as statins possess low cytotoxicity toward non-transformed cells and high tumoricidal activity, the net result will be the recovery and survival of normal cells while transformed cells are eliminated. In comparison to other molecular targeted therapies that require local delivery, this agent can be delivered systemically to the patient, due to its tumor-specific apoptotic properties and minimal general toxicities.3 The clinically achievable plasma concentration corresponds to the dose range that can trigger tumor-specific apoptosis in vitro. Experimental evidence suggests the exposure to statin therapy in vivo may be maximized by administering statins at a low dose for extended treatment times or at high doses for a limited period. Synergistic effects of statins in combination with traditional chemotherapeutic agents have been shown, warranting the addition of lovastatin to drug cocktails. This synergy may be due to statin down-regulation of bcl-2 expression which has been shown to potentiate therapeutic response with other agents that repress bcl-2 such as anti-sense bcl-2 and retinoic acid. Tracking this and other distinguishing features of statin-induced apoptosis in vivo will be mechanistically instructive. Finally, statins may be effective in cancer prevention and this aspect needs to be directly addressed. Taken together, HMG-CoA reductase inhibitors have a proven track record as safe and effective drugs and are readily available for application to the cancer clinic. Clearly, the efficacy of these well established inhibitors as novel anti-cancer therapeutic agents requires immediate evaluation through additional clinical trials.
INTERNATIONAL APPLICATION on Statin PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(11) WO 03/002721
(13) A2
(21) PCT/US02/20847
(22) 01 July 2002 (01.07.2002)
(25) English
(26) English
(30) 60/301,867 29 June 2001
(29.06.2001) US
(30) 60/310,783 07 August 2001
(07.08.2001) US
(30) 60/322,478 13 September 2001
(13.09.2001) US
(43) 09 January 2003 (09.01.2003)
(51)7 C12N
(54) COMPOSITIONS AND METHODS FOR INFERRING A RESPONSE TO A STATIN
(71) DNAPRINT GENOMICS, INC. [US/US]; 900 Cocoanut Avenue, Sarasota, FL 34236 (US).
(72)
(75) FRUDAKIS, Tony [US/US]; 3707 Plumosa Terrace, Bradenton, FL 34210 (US).
(74) HAILE, Lisa, A.; Gary Cary Ware & Friedenrich LLP, Suite 1100, 4365 Executive Drive, San Diego, CA 92121-2133 (US).
(81) AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZM, ZW
(84) ARIPO patent (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG)
For information on time limits for entry into the national phase please click here
Published
-- without international search report and to be republished upon receipt of that report
(57) Methods for inferring a statin response of a human subject from a nucleic acid sample of the suject are provided, as are reagents such as oligonucleotide probes, primers, and primer pairs, which can be used to practice such methods. A method of inferring a statin response can be performed, for example, by identifying in a nucleic acid sample from a subject, a nucleotide occurrence of at least one statin response related single nucleotide polymorphism (SNP) and/or at least one statin response-related haplotype in a cytochrome P450 gene and/or and HMG Co-A reductase gene.
Here,s a question to ponder - If Gmed will have nothing to do with Dnap in the furture {and i think it will} Than For God's sake why do they have a Thumb print logo "as in finger printing" on the front page of their web site ????? Hmmmmm
Outstanding Shares = 161,452,849
Restricted Shares = 57,642,849
Float = 103.8 Million as of 3-4-04
Standard Register & Transfer
(801) 571-8844
Gandolf3, Yes i agree.EOM
Ot-Gmed 103.8 Million Float ; Dnap = 486.5 Million Float;
bahl,Thanks and i can relate to that my Br. has done the same as well and is younger than me he did not go to college where i did for 8 years. Well i cant get him to invest one dime into Dnap but I have. LOL And oh yes i've had to help him out with home projects as well and had the same thought go through my mine. Well like you say our day will come and so will a New House all payed for, retire early i cant wait.LOL God Bless
dmceng,It seems we have all the right things in all the right places,yet we still have to wait.Everytime I look at Gmed at .12 cents and look back at Dnap it makes me sick.Evertime i get another Bill,everytime i see another friend of mine get his first house and i still in the same old apt. with no backyard for the kids,it makes me sick cause i know as sure as the sun will rise the next day Dnap will one day rise in the PPS.Some times its hard to just sit and watch life go by knowing we could be just days away or weeks or Months from receiving our just reward.For my self i could care less but i have a family that depends on me and i would like it to be just a little better for them, than it is.If Dnap took off I could offer to them a "SAFER PLACE" to live, a better place,with better schools,playgrounds, and friends.Some time soon it will happen I pray
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What does that mean for the entrepreneur? It means you don’t just get one attorney’s contacts or just one attorney’s fundraising expertise. With more than 420 attorneys in eight offices throughout the country, clients are now able to access the collective knowledge and contacts within Gray Cary. It means that the Venture Pipeline Group connects you to the right advisors, the right market influencers, and the right funding sources. It means your potential for successfully raising capital, particularly in tough economic times, is greatly enhanced.
The Venture Pipeline Group adds further value through its entrepreneurial industry teams. Consisting of experts knowledgeable in specific verticals - such as telecommunications, information technology, software, Internet, semiconductors and life sciences - these teams have specific knowledge of industry leaders, the competitive landscape, and the venture capitalists that invest in those verticals.
Our industry teams are also designed to bring a variety of transaction expertise to the table, in venture capital financings, licensing, intellectual property, mergers & acquisitions and strategic alliances. For entrepreneurs, this all equates to an efficient way to access the most specialized knowledge within the firm effectively and efficiently - regardless of where it resides.
Value Proposition
The bar for raising funds is high, and the Venture Pipeline chooses its start-up clients selectively. We maintain strong relationships with more than 400 of the world’s leading venture capitalists, and we foster those relationships by referring them companies of a consistent high quality that match their funding criteria. Our purpose is simple - to fit great companies with great venture capital firms.
The Venture Pipeline Group is a value proposition where everyone wins. The client wins by getting dedicated business counsel and support. The venture community wins by getting a higher caliber of target-specific deal flow. And Gray Cary wins leveraging our information, working efficiently, and having successful and grateful clients.
It’s a relatively simple concept - but one that’s unique to Gray Cary.
For more information, please contact the Gray Cary Venture Pipeline, at venturepipeline@graycary.com, or through your Gray Cary attorney.
I would also like to see us merg with Johnson Matthey so I'll keep it in my prayers.
lauty1981,I think it will be a few Mo.'s before we see eye color come out. After that nothing till Mid 2005.Dear God I hope i'm wrong.
oh for God's sake
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(11) WO 03/045227
REVISED VERSION
(13) A3
(21) PCT/US02/38345
(22) 26 November 2002 (26.11.2002)
(25) English
(26) English
(30) 60/334,310 28 November 2001
(28.11.2001) US
(30) 60/410,363 11 September 2002
(11.09.2002) US
(43) 05 June 2003 (05.06.2003)
(51)7 C12Q 1/68, C12P 19/34, C12M 1/34, C07H 21/04
(54) SINGLE NUCLEOTIDE POLYMORPHISMS AND COMBINATIONS THEREOF PREDICTIVE FOR PACLITAXEL RESPONSIVENESS
(71) DNAPRINT GENOMICS, INC. [US/US]; 900 Cocoanut Avenue, Sarasota, FL 34236 (US).
(72)
(75) FRUDAKIS, Tony, N. [US/US]; 3707 Plumosa Terrace, Bradenton, FL 34210 (US).
(74) HAILE, Lisa, A.; Gary Cary Ware & Friedenrich LLP, Suite 1100, 4365 Executive Drive, San Diego, CA 92121-2133 (US).
(81) AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SC, SD, SE, SG, SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW
(84) ARIPO patent (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG)
For information on time limits for entry into the national phase please click here
Published
-- with international search report
-- before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments
(88) 21 August 2003 (21.08.2003)
(57) Single nucleotide polymorphisms (SNPs) and combinations of SNPs that allow an inference as to whether a cancer patient is likely to respond or not respond to paclitaxel (Taxol®) are provided. Also provided are methods of determining a whether a cancer patient should be treated with paclitaxel.
With all that Dnap has on the Table you think something more would have happen by now with thwe PPS and or IP's
I just wish something would happen Now.
Gcbr,ok "what will happen will happen" we shall see. LOL
ann441j, thanks have a nice day