Alkylating Agents

The oxazaphosphorine alkylating agents cyclophosphamide (CTX) and ifosfamide (IFX) are prodrugs that undergo extensive P450-catalyzed metabolism to yield both active (4-hydroxylated, i.e., 4-hydroxy-CTX/IFX and ifo/phosphoramide mustard) and thera-peutically inactive but neurotoxic N-dechloroethylated metabolites (i.e., dechloroethyl-CTX/IFX and chloroacetaldehyde). Metabolism studies using cDNA-expressed CYP isoforms have shown that the production of active cytotoxic metabolites mainly depends on the activity of, in decreasing order of importance, CYP2B6 ^ 3A4 for CTX and CYP3A4 ^ 2B6 for IFX, whereas the production of neurotoxic metabolites almost exclusively occurs through the CYP3A4 isozyme for CTX and CYP3A4 > 2B6 for IFX (58). Overexpression of the type 1 (cytosolic) isoform of aldehyde dehydrogenase (ALDH1), which irreversibly oxidizes aldophosphamide, the major circulating metabolite of CTX, to the inactive metabolite carboxyphosphamide may be associated with drug resistance. Indeed, a retrospective analysis has shown that cellular levels of ALDH1A1 were significantly higher in metastatic tumor cells that (i) had survived exposure to CTX and (ii) did not respond to subsequent treatment with CTX-based chemotherapeutic regimens than in those that did respond to such regimens. The therapeutic outcome of CTX-based chemotherapy corresponded to cellular ALDH1A1 levels in 77% of the cases, and partial or complete responses to CTX-based chemotherapy occurred 2.3 times more often when the ALDH1A1 level was low than when it was high (59). Finally, variability in CYP2B6 activity (60) could be responsible for severe neurological toxicities induced by IFX, because of the overproduction of dechloroethyl-IFX and chloroacetalde-hyde, although this is yet to be shown.

The glutathione-S-transferase (GST) gene locus is located on chromosome 11q13 and encodes the A, M, P, and T isozymes. The GST enzymes conjugate electrophilic groups of toxic compounds, including chemotherapeutic agents, with glutathione. Amplification of the GSTP gene locus is a common event in head and neck squamous cell cancer; indeed, tumors with a normal GSTP copy number responded completely to cisplatin-based neoadjuvant chemotherapy, whereas patients showing GSTP gene amplification did not respond and died within nine months of the diagnosis (61). The GSTP1 gene product shows a Ile104Val polymorphism; survival of patients with advanced colorectal cancer when given 5-FU/oxaliplatin therapy varied according to the GSTP1 genotype and was 24.9 months (homozygous 105Val/105Val), 13.3 months (heterozygous 105Ile/ 105Val), and 7.9 months (homozygous 105Ile/105Ile) (62). A second GSTP1 variant (Ala113Val) displays higher activity (from 2.5- to 15-fold) with chlorambucil than other variants of GSTP1 (Ile104/Val113, Val104/Ala113, and Val104/Val113) (63). Finally, a promoter region polymorphism in the GSTA1*B gene is associated with reduced expression of the enzyme with respect to the wild-type allele. Breast cancer patients given cyclophosphamide-containing chemotherapy showed a 5-year survival rate of 66% (0 or 1 GSTA1*B) or 86% (GSTA1 *B/*B), the risk of death during the first five years after diagnosis being significantly reduced in GSTA1*B/*B subjects (64).

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