RESISTANCE TO CHEMOTHERAPEUTIC ANTIMETABOLITES - A FUNCTION OF SALVAGE PATHWAY INVOLVEMENT AND CELLULAR-RESPONSE TO DNA-DAMAGE

The inherent or acquired (induced) resistance of certain tumours to cy totoxic drug therapy is a major clinical problem. There are many categ ories of cytotoxic agent: the antimetabolites, e.g. methotrexate (MTX) , N-phosphonacetyl-L-aspartate (PALA), 5-fluorouracil (5-FU), 6-mercap topurine (6-TG), hydroxyurea (HU) and 1-beta-D-arabinofuranosylcytosin e (AraC); the alkylating agents, e.g, the nitrogen mustards and nitros oureas; the antibiotics, e.g. doxorubicin and mitomycin C; the plant a lkaloids, e.g. vincristine and vinblastine; and miscellaneous compound s, such as cisplatin. There are also many mechanisms of drug resistanc e elucidated principally from in vitro studies. These include mutation of target genes, amplification of target and mutated genes, differenc es in repair capacity, altered drug transport and differences in nucle oside and nucleobase salvage pathways (Fox et al, 1991). The aim of th e present review is to evaluate in detail the mechanisms of response o f both normal and tumour cells to three chemotherapeutic antimetabolit es, MTX, PALA and 5-FU, which are routinely used in the clinic either alone or in combination to treat some of the commonest solid tumours, e.g, breast, colon, gastric and head and neck. The normal and tumour c ell response to these agents will be discussed in relation to the oper ation of the known alternative 'salvage pathways' of DNA synthesis and current theories of DNA damage response.