Cancer pharmacogenetics: polymorphisms, pathways and beyond (original) (raw)

Abstract

... Baggott, JE, Vaughn, WH & Hudson, BB Inhibition of 5-aminoimidazole-4-carboxamide ribotide transformylase, adenosine deaminase and 5´-adenylate deaminase by polyglutamates of methotrexate and oxidized folates and by 5-aminoimidazole-4-carboxamide riboside and ...

Figures (4)

Figure 1 | Folate metabolism and related pathways. This simplified figure illustrates the interconnectedness of folate metabolism and proteins for which functional polymorphisms have been identified. Polymorphisms have been found that are associated with pharmacogenetic outcomes in three key proteins in these pathways: the drug transporter protein reduced folate carrier (RFC); the regulatory enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR); and the drug target thymidylate synthase. Key enzymes are denoted as ovals, substrates as rectangles. Red ovals denote enzymes with genetic polymorphisms that have been investigated in pharmacogenetic studies. Orange ovals denote enzymes for which functional genetic polymorphisms have been described. 5-FU, 5-fluorouracil; AICAR, 5-aminoimidazole-4-carboxamine ribonucleotide; AICARFT, AICAR formyltransferase; CBS, cystathionine-B-synthase; DHF, dihydrofolate; DHFR, DHF reductase; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; GAR, glycinamide ribonucleotide; GART, phosphoribosylglycinamide formyltransferase; hFR, human folate receptor; MTX, methotrexate; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate; X, various substrates for methylation.

Figure 1 | Folate metabolism and related pathways. This simplified figure illustrates the interconnectedness of folate metabolism and proteins for which functional polymorphisms have been identified. Polymorphisms have been found that are associated with pharmacogenetic outcomes in three key proteins in these pathways: the drug transporter protein reduced folate carrier (RFC); the regulatory enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR); and the drug target thymidylate synthase. Key enzymes are denoted as ovals, substrates as rectangles. Red ovals denote enzymes with genetic polymorphisms that have been investigated in pharmacogenetic studies. Orange ovals denote enzymes for which functional genetic polymorphisms have been described. 5-FU, 5-fluorouracil; AICAR, 5-aminoimidazole-4-carboxamine ribonucleotide; AICARFT, AICAR formyltransferase; CBS, cystathionine-B-synthase; DHF, dihydrofolate; DHFR, DHF reductase; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; GAR, glycinamide ribonucleotide; GART, phosphoribosylglycinamide formyltransferase; hFR, human folate receptor; MTX, methotrexate; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate; X, various substrates for methylation.

SML, chronic myeloid leukaemia; MTHFR, 5,10-methylenetetrahydrofolate reductase; NCI-CTC, National Cancer Institute Commo Toxicity Criteria; rpt, repeat; TSER, thymidylate-synthase enhancer region; WHO, World Health Organization.

SML, chronic myeloid leukaemia; MTHFR, 5,10-methylenetetrahydrofolate reductase; NCI-CTC, National Cancer Institute Commo Toxicity Criteria; rpt, repeat; TSER, thymidylate-synthase enhancer region; WHO, World Health Organization.

Figure 2 | Possible pathways of irinotecan metabolism. Irinotecan (CPT-11) can be converted into the active metabolite SN-38 by carboxylesterases (CES) outside or inside the cell. CPT-11 and SN-38 are both substrates for the ATP-binding cassette (ABC) transport proteins — P-glycoprotein (ABCB), ABCC and ABCG — which transport the drug out of the cell. Alternatively, CPT-11 and SN-38 can be inactivated by cytochrome P450 enzymes (CYP) or uridine diphosphate glycosyltransferase (UGT), respectively. If SN-38 persists, it binds to its target topoisomerase I (TOP1), interfering with DNA synthesis and repair processes, culminating in cell death. ADPRT, ADP -ribosyltransferase; APC, inactive metabolite of SN-38; CDC45L, cell-division cycle 45L; NPC, inactive metabolite of SN-38; SN-38G, SN-38 glucuronide; TDP, tyrosyl-DNA phosphodiesterase; XRCC1, X-ray-repair cross-complementing defective-1.

Figure 2 | Possible pathways of irinotecan metabolism. Irinotecan (CPT-11) can be converted into the active metabolite SN-38 by carboxylesterases (CES) outside or inside the cell. CPT-11 and SN-38 are both substrates for the ATP-binding cassette (ABC) transport proteins — P-glycoprotein (ABCB), ABCC and ABCG — which transport the drug out of the cell. Alternatively, CPT-11 and SN-38 can be inactivated by cytochrome P450 enzymes (CYP) or uridine diphosphate glycosyltransferase (UGT), respectively. If SN-38 persists, it binds to its target topoisomerase I (TOP1), interfering with DNA synthesis and repair processes, culminating in cell death. ADPRT, ADP -ribosyltransferase; APC, inactive metabolite of SN-38; CDC45L, cell-division cycle 45L; NPC, inactive metabolite of SN-38; SN-38G, SN-38 glucuronide; TDP, tyrosyl-DNA phosphodiesterase; XRCC1, X-ray-repair cross-complementing defective-1.

Table 2 | Various approaches to analyzing pharmacogenetic variation

Table 2 | Various approaches to analyzing pharmacogenetic variation

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