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John D. Schuetz - One of the best experts on this subject based on the ideXlab platform.
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Substrate Overlap between Mrp4 and Abcg2/Bcrp Affects Purine Analogue Drug Cytotoxicity and Tissue Distribution
Cancer research, 2007Co-Authors: Kazumasa Takenaka, Jessica A. Morgan, George L. Scheffer, Masashi Adachi, Clinton F. Stewart, Daxi Sun, Markos Leggas, Karin F.k. Ejendal, Christine A. Hrycyna, John D. SchuetzAbstract:The use of probe substrates and combinations of ATP-binding cassette (ABC) transporter knockout (KO) animals may facilitate the identification of common substrates between apparently unrelated ABC transporters. An unexpectedly low concentration of the purine nucleotide analogue, 9-(2-(phosphonomethoxy)ethyl)-adenine (PMEA), and up-regulation of Abcg2 in some tissues of the Mrp4 KO mouse prompted us to evaluate the possibility that Abcg2 might transport purine-derived Drugs. Abcg2 transported and conferred resistance to PMEA. Moreover, a specific Abcg2 inhibitor, fumitremorgin C, both increased PMEA accumulation and reversed Abcg2-mediated PMEA resistance. We developed Mrp4 and Abcg2 double KO mice and used both single KOs of Abcg2 and Mrp4 mice to assess the role of these transporters in vivo . Abcg2 contributed to PMEA accumulation in a variety of tissues, but in some tissues, this contribution was only revealed by the concurrent absence of Mrp4. Abcg2 also transported and conferred resistance to additional purine analogues, such as the antineoplastic, 2-chloro-2′-deoxyadenosine (cladribine) and puromycin, a protein synthesis inhibitor that is often used as a dominant selectable marker. Purine analogues interact with ABCG2 by a site distinct from the prazosin binding site as shown by their inability to displace the substrate analogue and photoaffinity tag [ 125 I]iodoarylazidoprazosin. These studies show that Abcg2, like Mrp4, transports and confers resistance to purine nucleoside analogues and suggest that these two transporters work in parallel to affect Drug Cytotoxicity and tissue distribution. This new knowledge will facilitate an understanding of how Abcg2 and Mrp4, separately and in combination, protect against purine analogue host toxicity as well as resistance to chemotherapy. [Cancer Res 2007;67(14):6965–72]
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substrate overlap between mrp4 and abcg2 bcrp affects purine analogue Drug Cytotoxicity and tissue distribution
Cancer Research, 2007Co-Authors: Kazumasa Takenaka, Jessica A. Morgan, George L. Scheffer, Masashi Adachi, Clinton F. Stewart, Daxi Sun, Markos Leggas, Karin F.k. Ejendal, Christine A. Hrycyna, John D. SchuetzAbstract:The use of probe substrates and combinations of ATP-binding cassette (ABC) transporter knockout (KO) animals may facilitate the identification of common substrates between apparently unrelated ABC transporters. An unexpectedly low concentration of the purine nucleotide analogue, 9-(2-(phosphonomethoxy)ethyl)-adenine (PMEA), and up-regulation of Abcg2 in some tissues of the Mrp4 KO mouse prompted us to evaluate the possibility that Abcg2 might transport purine-derived Drugs. Abcg2 transported and conferred resistance to PMEA. Moreover, a specific Abcg2 inhibitor, fumitremorgin C, both increased PMEA accumulation and reversed Abcg2-mediated PMEA resistance. We developed Mrp4 and Abcg2 double KO mice and used both single KOs of Abcg2 and Mrp4 mice to assess the role of these transporters in vivo . Abcg2 contributed to PMEA accumulation in a variety of tissues, but in some tissues, this contribution was only revealed by the concurrent absence of Mrp4. Abcg2 also transported and conferred resistance to additional purine analogues, such as the antineoplastic, 2-chloro-2′-deoxyadenosine (cladribine) and puromycin, a protein synthesis inhibitor that is often used as a dominant selectable marker. Purine analogues interact with ABCG2 by a site distinct from the prazosin binding site as shown by their inability to displace the substrate analogue and photoaffinity tag [ 125 I]iodoarylazidoprazosin. These studies show that Abcg2, like Mrp4, transports and confers resistance to purine nucleoside analogues and suggest that these two transporters work in parallel to affect Drug Cytotoxicity and tissue distribution. This new knowledge will facilitate an understanding of how Abcg2 and Mrp4, separately and in combination, protect against purine analogue host toxicity as well as resistance to chemotherapy. [Cancer Res 2007;67(14):6965–72]
Jacques Robert - One of the best experts on this subject based on the ideXlab platform.
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Abstract 1871: Role of CYP1B1 gene polymorphisms in anticancer Drug Cytotoxicity as studied on isogenic cell lines
Experimental and Molecular Therapeutics, 2012Co-Authors: Valérie Le Morvan, Ricardo Bellott, Jacques Robert, Elodie Richard, Alban Pasquies, Amélie LansiauxAbstract:Cytochrome P450 1B1 (CYP1B1) is found in tumour tissue and is suspected to play a role in oncogenesis and Drug resistance. CYP1B1 gene polymorphisms have been associated with the risk of developing lung and other cancers. We have recently shown that one of them (rs1056836, 1697C>G, L432V) was significantly associated with the Cytotoxicity of DNA-damaging anticancer Drugs in two independent panels of tumour cell lines, the NCI-60 panel and the JFCR-45 panel (Mol Cancer Ther 2010; 9: 3315-21). The present study was aimed at identifying the molecular mechanisms involved in anticancer Drug resistance associated with this polymorphic variation. We have cloned the wild-type human CYP1B1 cDNA (1697C) in a lentiviral vector pDesti-pGK and obtained the variant cDNA (1697G) by directed mutagenesis. The two polymorphic variants were then used for the generation of viruses and the infection of cell lines. The CYP1B1 viruses were produced by cotransfection of 293T cells with viral plasmid DNA and either pER51CYP1B1WT-pGK or pER51CYP1B1VAR-pGK plasmid DNA in the presence of calcium phosphate. Cell supernatants containing the virus were harvested 24 h after transfection, filtered through a 0.45 μm membrane and stored at −80°C. Five different cell lines devoid of CYP1B1 expression were infected (COS-1 [Fibroblastic cell line], SW620 [colorectal cancer cell line], CAL27, CAL33 and SQ20B [HNSCC cell lines]). We thus generated five pairs of isogenic cell lines differing only by the polymorphic status of one nucleotide in the CYP1B1 gene. mRNA and protein expression were evaluated by qRT-PCR and western blotting, respectively. The Cytotoxicity of a panel of anticancer Drugs was evaluated on these cell lines (cisplatin, oxaliplatin, gemcitabine, doxorubicin, etoposide, camptothecin, irinotecan and its active metabolite [SN38]). A systematically higher IC 50 was noticed for the cell lines harbouring the variant cDNA as compared to those harbouring the wild-type cDNA, the variant cell lines being 2-3-fold resistant to all agents. These results obtained on isogenic cell lines were in perfect agreement with what could be expected from the study of the cell line panels. The catalytic activity of the two CYP1B1 variants is being studied using ethoxyresorufine O-deethylation. A population of 125 head-and-neck cancer patients treated by chemotherapy in the palliative setting has been prospectively constituted and will be used for the clinical validation of the interest of CYP1B1 genotyping for predicting anticancer Drug activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1871. doi:1538-7445.AM2012-1871
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Impact of EGFR Gene Polymorphisms on Anticancer Drug Cytotoxicity In Vitro
Molecular diagnosis & therapy, 2008Co-Authors: Stéphane Puyo, Valérie Le Morvan, Jacques RobertAbstract:Background and objective: The epidermal growth factor receptor (EGFR) plays a major role in cell proliferation of epithelial tissues, and its alterations frequently contribute to oncogenesis. Several common polymorphisms of the EGFR gene have been described, at the level of both coding and regulatory sequences. Some of these polymorphisms are associated with alterations of EGFR expression and/or activity and may have an impact on the activity of anticancer agents. This study aims to analyze the relationships between specific EGFR functional polymorphisms and anticancer Drug activity.
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Relationships between genetic polymorphisms and anticancer Drug Cytotoxicity vis-à-vis the NCI60 panel
Cancer Research, 2006Co-Authors: Valerie Lemorvan, Ricardo Bellott, François Moisan, Simone Mathoulin-pélissier, Jacques Bonnet, Jacques RobertAbstract:Proc Amer Assoc Cancer Res, Volume 47, 2006 1317 The NCI60 panel consists of 60 human tumor cell lines which were initially used for the screening of thousands of molecules for their potential anticancer activity, with a disease-oriented strategy. This panel has been especially powerful for deciphering the relationships between the Cytotoxicity of anticancer agents and the molecular characteristics of the cell lines. We have tested the potential interest of the panel in order to establish relationships between the polymorphism of genes involved in metabolism and transport of anticancer agents or in DNA repair, and the Cytotoxicity of these agents as indicated in the NCI databases. Using a PCR-RFLP technique, three frequent single nucleotide polymorphisms (SNP) were analyzed in order to validate this approach: the Lys751Gln SNP of the Xeroderma pigmentosum complementation group D (XPD) gene, the Asp1104His SNP of the Xeroderma pigmentosum complementation group G (XPG) gene and the Ile105Val SNP of the glutathione S-transferase P1 (GSTP1) gene. The allelic frequencies of the variants were 33% for XPD, 23% for XPG and 39% for GSTP1. The XPD polymorphism appeared as a strong determinant of the in vitro Cytotoxicity of most anticancer agents, which have systematically lower IC50 values in variant homozygous lines than in common homozygous or heterozygous cell lines. Unexpectedly, the Cytotoxicity of spindle poisons appeared especially dependent upon the XPD genotype, with three-fold lower mean IC50 values in variant homozygous cell lines ( P =10-8). The XPG genotype appeared important only for the taxanes, with nearly four-fold higher IC50 values in variant homozygous cell lines ( P =10-6). The GSTP1 polymorphism was related to the Cytotoxicity of several Drug classes, especially topoisomerase I and II inhibitors and N7 alkylating agents; the mean IC50 values of these compounds was 1.4 to 2.2 times lower in variant homozygous cell lines than in common homozygous cell lines. The NCI60 panel appears as capable of providing clues and tracks for the establishment of clinically useful relationships between a given genotype and the Cytotoxicity of an anticancer agent.
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Relationships between genetic polymorphisms and anticancer Drug Cytotoxicity vis-à-vis the NCI-60 panel.
Pharmacogenomics, 2006Co-Authors: Valérie Le Morvan, Ricardo Bellott, François Moisan, Simone Mathoulin-pélissier, Jacques Bonnet, Jacques RobertAbstract:Introduction: The National Cancer Institute (NCI)-60 panel consists of 60 human tumor cell lines initially established for screening thousands of molecules for antiproliferative activity. It has been powerful for deciphering the relationships between anticancer Drug Cytotoxicity and cell molecular characteristics. We tested its potential interest for establishing relationships between the polymorphism of genes involved in Drug metabolism and transport or in DNA repair, and Drug Cytotoxicity extracted from NCI databases. Methods: Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques, three frequent single nucleotide polymorphisms (SNPs) were analyzed: Lys751Gln in the Xeroderma pigmentosum complementation group D (XPD, ERCC2) gene, Asp1104His in the Xeroderma pigmentosum complementation group G (XPG, ERCC5) gene and Ile105Val in the glutathione S-transferase P1 (GSTP1) gene. Results: The allelic frequencies of the variants were 33% for ERCC2, 23% for ERCC5 and 39% f...
Kazumasa Takenaka - One of the best experts on this subject based on the ideXlab platform.
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Substrate Overlap between Mrp4 and Abcg2/Bcrp Affects Purine Analogue Drug Cytotoxicity and Tissue Distribution
Cancer research, 2007Co-Authors: Kazumasa Takenaka, Jessica A. Morgan, George L. Scheffer, Masashi Adachi, Clinton F. Stewart, Daxi Sun, Markos Leggas, Karin F.k. Ejendal, Christine A. Hrycyna, John D. SchuetzAbstract:The use of probe substrates and combinations of ATP-binding cassette (ABC) transporter knockout (KO) animals may facilitate the identification of common substrates between apparently unrelated ABC transporters. An unexpectedly low concentration of the purine nucleotide analogue, 9-(2-(phosphonomethoxy)ethyl)-adenine (PMEA), and up-regulation of Abcg2 in some tissues of the Mrp4 KO mouse prompted us to evaluate the possibility that Abcg2 might transport purine-derived Drugs. Abcg2 transported and conferred resistance to PMEA. Moreover, a specific Abcg2 inhibitor, fumitremorgin C, both increased PMEA accumulation and reversed Abcg2-mediated PMEA resistance. We developed Mrp4 and Abcg2 double KO mice and used both single KOs of Abcg2 and Mrp4 mice to assess the role of these transporters in vivo . Abcg2 contributed to PMEA accumulation in a variety of tissues, but in some tissues, this contribution was only revealed by the concurrent absence of Mrp4. Abcg2 also transported and conferred resistance to additional purine analogues, such as the antineoplastic, 2-chloro-2′-deoxyadenosine (cladribine) and puromycin, a protein synthesis inhibitor that is often used as a dominant selectable marker. Purine analogues interact with ABCG2 by a site distinct from the prazosin binding site as shown by their inability to displace the substrate analogue and photoaffinity tag [ 125 I]iodoarylazidoprazosin. These studies show that Abcg2, like Mrp4, transports and confers resistance to purine nucleoside analogues and suggest that these two transporters work in parallel to affect Drug Cytotoxicity and tissue distribution. This new knowledge will facilitate an understanding of how Abcg2 and Mrp4, separately and in combination, protect against purine analogue host toxicity as well as resistance to chemotherapy. [Cancer Res 2007;67(14):6965–72]
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substrate overlap between mrp4 and abcg2 bcrp affects purine analogue Drug Cytotoxicity and tissue distribution
Cancer Research, 2007Co-Authors: Kazumasa Takenaka, Jessica A. Morgan, George L. Scheffer, Masashi Adachi, Clinton F. Stewart, Daxi Sun, Markos Leggas, Karin F.k. Ejendal, Christine A. Hrycyna, John D. SchuetzAbstract:The use of probe substrates and combinations of ATP-binding cassette (ABC) transporter knockout (KO) animals may facilitate the identification of common substrates between apparently unrelated ABC transporters. An unexpectedly low concentration of the purine nucleotide analogue, 9-(2-(phosphonomethoxy)ethyl)-adenine (PMEA), and up-regulation of Abcg2 in some tissues of the Mrp4 KO mouse prompted us to evaluate the possibility that Abcg2 might transport purine-derived Drugs. Abcg2 transported and conferred resistance to PMEA. Moreover, a specific Abcg2 inhibitor, fumitremorgin C, both increased PMEA accumulation and reversed Abcg2-mediated PMEA resistance. We developed Mrp4 and Abcg2 double KO mice and used both single KOs of Abcg2 and Mrp4 mice to assess the role of these transporters in vivo . Abcg2 contributed to PMEA accumulation in a variety of tissues, but in some tissues, this contribution was only revealed by the concurrent absence of Mrp4. Abcg2 also transported and conferred resistance to additional purine analogues, such as the antineoplastic, 2-chloro-2′-deoxyadenosine (cladribine) and puromycin, a protein synthesis inhibitor that is often used as a dominant selectable marker. Purine analogues interact with ABCG2 by a site distinct from the prazosin binding site as shown by their inability to displace the substrate analogue and photoaffinity tag [ 125 I]iodoarylazidoprazosin. These studies show that Abcg2, like Mrp4, transports and confers resistance to purine nucleoside analogues and suggest that these two transporters work in parallel to affect Drug Cytotoxicity and tissue distribution. This new knowledge will facilitate an understanding of how Abcg2 and Mrp4, separately and in combination, protect against purine analogue host toxicity as well as resistance to chemotherapy. [Cancer Res 2007;67(14):6965–72]
Jessica A. Morgan - One of the best experts on this subject based on the ideXlab platform.
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Substrate Overlap between Mrp4 and Abcg2/Bcrp Affects Purine Analogue Drug Cytotoxicity and Tissue Distribution
Cancer research, 2007Co-Authors: Kazumasa Takenaka, Jessica A. Morgan, George L. Scheffer, Masashi Adachi, Clinton F. Stewart, Daxi Sun, Markos Leggas, Karin F.k. Ejendal, Christine A. Hrycyna, John D. SchuetzAbstract:The use of probe substrates and combinations of ATP-binding cassette (ABC) transporter knockout (KO) animals may facilitate the identification of common substrates between apparently unrelated ABC transporters. An unexpectedly low concentration of the purine nucleotide analogue, 9-(2-(phosphonomethoxy)ethyl)-adenine (PMEA), and up-regulation of Abcg2 in some tissues of the Mrp4 KO mouse prompted us to evaluate the possibility that Abcg2 might transport purine-derived Drugs. Abcg2 transported and conferred resistance to PMEA. Moreover, a specific Abcg2 inhibitor, fumitremorgin C, both increased PMEA accumulation and reversed Abcg2-mediated PMEA resistance. We developed Mrp4 and Abcg2 double KO mice and used both single KOs of Abcg2 and Mrp4 mice to assess the role of these transporters in vivo . Abcg2 contributed to PMEA accumulation in a variety of tissues, but in some tissues, this contribution was only revealed by the concurrent absence of Mrp4. Abcg2 also transported and conferred resistance to additional purine analogues, such as the antineoplastic, 2-chloro-2′-deoxyadenosine (cladribine) and puromycin, a protein synthesis inhibitor that is often used as a dominant selectable marker. Purine analogues interact with ABCG2 by a site distinct from the prazosin binding site as shown by their inability to displace the substrate analogue and photoaffinity tag [ 125 I]iodoarylazidoprazosin. These studies show that Abcg2, like Mrp4, transports and confers resistance to purine nucleoside analogues and suggest that these two transporters work in parallel to affect Drug Cytotoxicity and tissue distribution. This new knowledge will facilitate an understanding of how Abcg2 and Mrp4, separately and in combination, protect against purine analogue host toxicity as well as resistance to chemotherapy. [Cancer Res 2007;67(14):6965–72]
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substrate overlap between mrp4 and abcg2 bcrp affects purine analogue Drug Cytotoxicity and tissue distribution
Cancer Research, 2007Co-Authors: Kazumasa Takenaka, Jessica A. Morgan, George L. Scheffer, Masashi Adachi, Clinton F. Stewart, Daxi Sun, Markos Leggas, Karin F.k. Ejendal, Christine A. Hrycyna, John D. SchuetzAbstract:The use of probe substrates and combinations of ATP-binding cassette (ABC) transporter knockout (KO) animals may facilitate the identification of common substrates between apparently unrelated ABC transporters. An unexpectedly low concentration of the purine nucleotide analogue, 9-(2-(phosphonomethoxy)ethyl)-adenine (PMEA), and up-regulation of Abcg2 in some tissues of the Mrp4 KO mouse prompted us to evaluate the possibility that Abcg2 might transport purine-derived Drugs. Abcg2 transported and conferred resistance to PMEA. Moreover, a specific Abcg2 inhibitor, fumitremorgin C, both increased PMEA accumulation and reversed Abcg2-mediated PMEA resistance. We developed Mrp4 and Abcg2 double KO mice and used both single KOs of Abcg2 and Mrp4 mice to assess the role of these transporters in vivo . Abcg2 contributed to PMEA accumulation in a variety of tissues, but in some tissues, this contribution was only revealed by the concurrent absence of Mrp4. Abcg2 also transported and conferred resistance to additional purine analogues, such as the antineoplastic, 2-chloro-2′-deoxyadenosine (cladribine) and puromycin, a protein synthesis inhibitor that is often used as a dominant selectable marker. Purine analogues interact with ABCG2 by a site distinct from the prazosin binding site as shown by their inability to displace the substrate analogue and photoaffinity tag [ 125 I]iodoarylazidoprazosin. These studies show that Abcg2, like Mrp4, transports and confers resistance to purine nucleoside analogues and suggest that these two transporters work in parallel to affect Drug Cytotoxicity and tissue distribution. This new knowledge will facilitate an understanding of how Abcg2 and Mrp4, separately and in combination, protect against purine analogue host toxicity as well as resistance to chemotherapy. [Cancer Res 2007;67(14):6965–72]
Masashi Adachi - One of the best experts on this subject based on the ideXlab platform.
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Substrate Overlap between Mrp4 and Abcg2/Bcrp Affects Purine Analogue Drug Cytotoxicity and Tissue Distribution
Cancer research, 2007Co-Authors: Kazumasa Takenaka, Jessica A. Morgan, George L. Scheffer, Masashi Adachi, Clinton F. Stewart, Daxi Sun, Markos Leggas, Karin F.k. Ejendal, Christine A. Hrycyna, John D. SchuetzAbstract:The use of probe substrates and combinations of ATP-binding cassette (ABC) transporter knockout (KO) animals may facilitate the identification of common substrates between apparently unrelated ABC transporters. An unexpectedly low concentration of the purine nucleotide analogue, 9-(2-(phosphonomethoxy)ethyl)-adenine (PMEA), and up-regulation of Abcg2 in some tissues of the Mrp4 KO mouse prompted us to evaluate the possibility that Abcg2 might transport purine-derived Drugs. Abcg2 transported and conferred resistance to PMEA. Moreover, a specific Abcg2 inhibitor, fumitremorgin C, both increased PMEA accumulation and reversed Abcg2-mediated PMEA resistance. We developed Mrp4 and Abcg2 double KO mice and used both single KOs of Abcg2 and Mrp4 mice to assess the role of these transporters in vivo . Abcg2 contributed to PMEA accumulation in a variety of tissues, but in some tissues, this contribution was only revealed by the concurrent absence of Mrp4. Abcg2 also transported and conferred resistance to additional purine analogues, such as the antineoplastic, 2-chloro-2′-deoxyadenosine (cladribine) and puromycin, a protein synthesis inhibitor that is often used as a dominant selectable marker. Purine analogues interact with ABCG2 by a site distinct from the prazosin binding site as shown by their inability to displace the substrate analogue and photoaffinity tag [ 125 I]iodoarylazidoprazosin. These studies show that Abcg2, like Mrp4, transports and confers resistance to purine nucleoside analogues and suggest that these two transporters work in parallel to affect Drug Cytotoxicity and tissue distribution. This new knowledge will facilitate an understanding of how Abcg2 and Mrp4, separately and in combination, protect against purine analogue host toxicity as well as resistance to chemotherapy. [Cancer Res 2007;67(14):6965–72]
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substrate overlap between mrp4 and abcg2 bcrp affects purine analogue Drug Cytotoxicity and tissue distribution
Cancer Research, 2007Co-Authors: Kazumasa Takenaka, Jessica A. Morgan, George L. Scheffer, Masashi Adachi, Clinton F. Stewart, Daxi Sun, Markos Leggas, Karin F.k. Ejendal, Christine A. Hrycyna, John D. SchuetzAbstract:The use of probe substrates and combinations of ATP-binding cassette (ABC) transporter knockout (KO) animals may facilitate the identification of common substrates between apparently unrelated ABC transporters. An unexpectedly low concentration of the purine nucleotide analogue, 9-(2-(phosphonomethoxy)ethyl)-adenine (PMEA), and up-regulation of Abcg2 in some tissues of the Mrp4 KO mouse prompted us to evaluate the possibility that Abcg2 might transport purine-derived Drugs. Abcg2 transported and conferred resistance to PMEA. Moreover, a specific Abcg2 inhibitor, fumitremorgin C, both increased PMEA accumulation and reversed Abcg2-mediated PMEA resistance. We developed Mrp4 and Abcg2 double KO mice and used both single KOs of Abcg2 and Mrp4 mice to assess the role of these transporters in vivo . Abcg2 contributed to PMEA accumulation in a variety of tissues, but in some tissues, this contribution was only revealed by the concurrent absence of Mrp4. Abcg2 also transported and conferred resistance to additional purine analogues, such as the antineoplastic, 2-chloro-2′-deoxyadenosine (cladribine) and puromycin, a protein synthesis inhibitor that is often used as a dominant selectable marker. Purine analogues interact with ABCG2 by a site distinct from the prazosin binding site as shown by their inability to displace the substrate analogue and photoaffinity tag [ 125 I]iodoarylazidoprazosin. These studies show that Abcg2, like Mrp4, transports and confers resistance to purine nucleoside analogues and suggest that these two transporters work in parallel to affect Drug Cytotoxicity and tissue distribution. This new knowledge will facilitate an understanding of how Abcg2 and Mrp4, separately and in combination, protect against purine analogue host toxicity as well as resistance to chemotherapy. [Cancer Res 2007;67(14):6965–72]
