Alkylating Agents

Cisplatin and related drugs, including carboplatin and oxaliplatin, inhibit cell proliferation by irreversibly damaging DNA through the formation of intra- and interstrand cross-links. Drug resistance occurs because of poor cisplatin accumulation, detoxification, or efficient repair of damaged DNA by the nucleotide excision repair (NER) system. The NER super-family is composed of numerous members, including ERCC1, XPA, XPB, XPC, XPD, and XPF, which display different functions (helicases, 3'- and 5'-endonucleases, and ligases)

(81). Among those factors, the ERCC1 (excision repair cross complementing 1) gene product forms a heterodimer with XPF, and the complex is responsible for the endonuclease activity required to repair the DNA damage (Fig. 14). In vitro studies have demonstrated that upregulation of ERCC1-XPF is associated with cisplatin resistance

(82). However, in another study, DNA repair activity was not correlated with cytotoxicity of cisplatin and melphalan in ovary and colon cancer cells (83).

ERCC1 gene expression affects the clinical outcome of patients with NSCLC and colorectal cancer treated with cisplatin and oxaliplatin, with response and survival being improved in the presence of low ERCC1 expression (84,85). The survival of patients with relapsed colorectal cancer treated with oxaliplatin/5-FU was 17.4 months in subjects with the wild-type 751Lys/Lys XPD, whereas survival of patients with 751Lys/Gln and 751Gln/Gln polymorphism was reduced to 12.8 and 3.3 months, respectively (86). The O6-alkyl(methyl)guanine-DNA alkyl(methyl)transferase (AGAT/MGMT) is capable of protecting cells from the mutagenic effect of DNA alkylation and, therefore, from the cytotoxicity induced by chemotherapeutic drugs, such as BCNU (87,88). Correlation between pretreatment expression of AGAT/MGMT and response to treatment has so far been established in primary brain tumors only. Patients with malignant astrocytoma treated with BCNU had a better objective response when the AGAT/MGMT expression levels were low (89). Furthermore, low AGAT/MGMT activity, due to promoter methyl-ation, was associated with statistically significant prolongation of survival and improved

Figure 14 Members of the NER system. XPA, XPC, and XPE are involved in DNA damage recognition by alkylating agents; ERCC1/XPF have 5'-endonuclease activity, XPG has 3'-endonu-clease activity, while XPB and XPD have helicase activity (109). Abbreviation: NER, nucleotide excision repair.

disease-free survival in patients with gliomas treated with the combination of BCNU and cisplatin (90). Similar results were observed in patients with astrocytomas and glioblastomas; a 60% response rate to temozolomide was obtained if tumor expression of AGAT/ MGMT was low, but the response rate was only 9% in those with high enzyme activity; tumor MMR status was less predictive of response than AGAT/MGMT (91).

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