Irinotecan

Irinotecan is a wide spectrum anticancer agent with a preeminent role in the therapy of colorectal cancer. Cleavage of the bispiperidine moiety of irinotecan by carboxylesterases releases the active metabolite SN-38 (Fig. 11), which is up to 1000 times more potent than the parent compound in inhibiting nuclear topoisomerase I through the formation of the SN-38-topoisomerase I-DNA ternary complex. This results in DNA fragmentation during replication (38). Gene sequencing has revealed the presence of several non-synonymous mutations, potentially associated with drug resistance and mainly involving exons 12, 13, 15, and 20. Most of them occur in the DNA-binding domain, resulting in amino acid changes (Gly717Val, Ile721Arg, Asn722Ser, Asn722Ala, Thr729Ile, and Thr729Ala); others affect exons 12 and 13 (Phe361Ser, Arg362Leu, Gly363Cys, Arg364Gly, Met370Thr, and Glu418Lys), whereas the Ala653Pro mutation in the linker domain of topoisomerase I results in a marked increase in the re-ligation rate relative to the wild-type enzyme (39-41). Therefore, it is conceivable that mutational analysis of topoisomerase I might be considered to exclude patients from receiving irinotecan chemotherapy if their genotype suggests drug resistance. Likewise, selection of patients on the basis of their risk of toxicity is an important goal of clinical pharmacogenetics. Uridine diphosphate-glucuronosyl transferase, and in particular the UGT1A1 isoform, plays a pivotal role in SN-38 detoxification, leading to the formation of the inactive metabolite SN-38 glucuronate (SN-38G) (42) (Figs. 11, 12). The rate of SN-38 glucuronidation is genetically determined and variants of uridine glucuronyl transferase (UGT) with low activity have been described, thus providing a potential reason for the severe neutropenia

Figure 11 Overview of selected molecular determinants of irinotecan activity and tolerability. Abbreviations: APC, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camp-tothecin; SN-38G, glucuronide metabolite of SN-38; CYP3A4, cytochrome P450 3A4 isoform; UGT1A1/7/9, UGT1A 1, -7, and -9 isoforms; CE, carboxylesterase; ABCB1-C1/2, ATP-binding cassette drug transporters B1-C1/2; TOPO I, topoisomerase I.

Figure 11 Overview of selected molecular determinants of irinotecan activity and tolerability. Abbreviations: APC, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camp-tothecin; SN-38G, glucuronide metabolite of SN-38; CYP3A4, cytochrome P450 3A4 isoform; UGT1A1/7/9, UGT1A 1, -7, and -9 isoforms; CE, carboxylesterase; ABCB1-C1/2, ATP-binding cassette drug transporters B1-C1/2; TOPO I, topoisomerase I.

and dose-limiting diarrhea suffered by some patients. However, the clinical relevance and utility of UGT variants in irinotecan toxicity remains to be firmly established. The most common cause of reduced glucuronidation is a polymorphism in the promoter region of UGT1A1, which consists of a variable number of TA tandem sequences (43). Individuals who have a high number of TA repeats, that is, TA7 (UGT1A1 *28) versus wild-type TA6 (UGT1A1* 1), have reduced gene expression and diminished UGT1A1 production (44). Additional nucleotide changes in the UGT1A1 gene generate a number of variants with reduced activity (UGT1A1*6, UGT1A1*7, UGT1A1*27, UGT1A1 *29, Fig. 12) (45). Other UGT isoforms involved in irinotecan metabolism also show missense mutations with moderate to profound reduction in UGT activity, including Met33Thr Asp256Asn in UGT1A9 (46,47) and Trp208Arg, Asn129Lys, and Arg131Lys in UGT1A7 (46). Finally, the influence of irinotecan oxidation to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC) and to 7-ethyl-10-(4-amino-1-piperidino)-carbonyloxy-camptothecin (NPC) by CYP3A4 and its genetic variants is an attractive field of research that awaits further investigation (48).

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