Antimetabolites

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Damage to DNA induced by antimetabolites is recognized by the cell and generates a signal that blocks proliferation in order to repair the alteration and allows the proliferation to either resume or depending on the extent of the damage, triggers cell death by apoptosis. The regulation of this machinery is finely regulated by proapoptotic factors, such as p53, Bax, and related proteins, and antiapoptotic factors, which are mainly members of the Bcl-2 superfamily (71).

Defects in the ability of tumor cells to undergo apoptosis may result in drug resistance and poor clinical outcome. The TP53 gene product is characterized by a 3'-5' exonuclease activity (72) and controls the transactivation of proapoptotic factors (i.e., Bax, Bak) and the repression of antiapoptotic pathways (i.e., Bcl-2, Bcl-XL), hence favoring the death of cells with irrepairable DNA damage (Fig. 13). Given that TP53 is a tumor suppressor gene, a defective TP53 pathway will allow cell proliferation to proceed in the presence of damaged DNA, thereby causing accumulation of DNA mutations (73). Reduced sensitivity of tumor cells to antimetabolites, such as 5-FU, may thus be due to TP53 gene mutations (74), which is unable to upregulate Bax and downregulate Bcl-2.

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Figure 13 Schematic representation of apoptosis pathways triggered by antimetabolites, alkylating, and antimicrotubule agents. Proapototic factors (Bax and Bak) are activated by p53, which is in turn suppressed by MDM2; Bcl-2 inhibits caspase-dependent and -independent apoptosis initiated by the release of cytochrome c and ROS, respectively. Abbreviations: PARP, poly (ADP-ribose) polymerase; BH3, Bcl-2 homology 3 domain; APAF-1, apoptosis protease activating factor 1; -, inhibition; +, induction; ROS, reactive oxygen species.

Figure 13 Schematic representation of apoptosis pathways triggered by antimetabolites, alkylating, and antimicrotubule agents. Proapototic factors (Bax and Bak) are activated by p53, which is in turn suppressed by MDM2; Bcl-2 inhibits caspase-dependent and -independent apoptosis initiated by the release of cytochrome c and ROS, respectively. Abbreviations: PARP, poly (ADP-ribose) polymerase; BH3, Bcl-2 homology 3 domain; APAF-1, apoptosis protease activating factor 1; -, inhibition; +, induction; ROS, reactive oxygen species.

Similar findings have been obtained in ovarian cancer, where p53 overexpression or missense mutations were associated with resistance to platinum compounds, early relapse, and shortened overall survival (75). Indeed, the ratio between Bcl-xL and Bax is significantly associated with 5-FU chemosensitivity in colorectal carcinoma cell lines (76), whereas Bax overexpression in gliomas is sufficient to render the cells more sensitive to apoptosis even in the presence of a deficient TP53 pathway (77). Finally, the mismatch repair (MMR) system is the crucial mutation avoidance machinery that recognizes and repairs mismatched and unpaired bases that arise from replication errors and DNA-damaging agents. In MMR-proficient cells, inability to repair sublethal damage to the DNA results in cell cycle arrest and apoptosis; conversely, MMR-deficient cells are not deleted and accumulate mutations that may result in aberrant biological behavior and potentially cancerogenesis. The expression of two important MMR members, hMLHl and hMSH2, is significantly correlated with response to the chemotherapy regimen comprising cyclophosphamide, methotrexate, and 5-FU (CMF) in patients with advanced ductal breast cancer and lymph node metastasis. Patients with low hMLH1 immunoreac-tivity have a significantly higher failure rate with the CMF regimen than those with high hMLHl expression (78). MMR-deficient tumor cells are resistant to the cytotoxic effects of 5-FU, and demethylation of the hMLH1 promoter in hypermethylated colorectal cancer cells restores MMR proficiency and drug sensitivity to 5-FU (79). Finally, loss of chemosensitivity to gemcitabine may arise as a consequence of cisplatin-mediated selection of

MMR-deficient cells, and the presence of such cells in a tumor may predispose to drug resistance and treatment failure (80).

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