Resistance to chemotherapeutic antimetabolites: a function of salvage pathway involvement and cellular response to DNA damage

Abstract

Summary The inherent or acquired (induced) resistance of certain tumours to cytotoxic drug therapy is a major clinical problem. There are many categories of cytotoxic agent: the antimetabolites, e.g. methotrexate (MTX), N-phosphonacetyl-L-aspartate (PALA), 5-fluorouracil (5-FU), 6-mercaptopurine (6-TG), hydroxyurea (HU) and 1-pB-D-arabinofuranosylcytosine (AraC); the alkylating agents, e.g. the nitrogen mustards and nitrosoureas; the antibiotics, e.g. doxorubicin and mitomycin C; the plant alkaloids, e.g. vincristine and vinblastine; and miscellaneous compounds, such as cisplatin. There are also many mechanisms of drug resistance elucidated principally from in vitro studies. These include mutation of target genes, amplification of target and mutated genes, differences in repair capacity, altered drug transport and differences in nucleoside and nucleobase salvage pathways (Fox et al, 1991). The aim of the present review is to evaluate in detail the mechanisms of response of both normal and tumour cells to three chemotherapeutic antimetabolites, 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 cell response to these agents will be discussed in relation to the operation of the known alternative 'salvage pathways' of DNA synthesis and current theories of DNA damage response.

Expression of rTSβ as a 5-fluorouracil resistance marker in patients with primary breast cancer

“…6). TS expression in tumor cells is considered as a key prognostic factor for patients receiving chemotherapy containing 5-FU (7).However, clinical evidence did not fully support this expectation (6,(8)(9)(10)(11)(12)(13). On the other hand, expression of the rTS (ENOSF1) gene (14-16) was found to be closely associated with 5-FU sensitivity besides nucleotide metabolism-related enzymes, e.g., thymidine phosphorylase, ribonucleotide reductase, uridine phosphorylase and thymidine kinase (17-19) that directly affects pyrimidine synthesis in de novo or salvage pathways (11).…”

“…On the other hand, expression of the rTS (ENOSF1) gene (14-16) was found to be closely associated with 5-FU sensitivity besides nucleotide metabolism-related enzymes, e.g., thymidine phosphorylase, ribonucleotide reductase, uridine phosphorylase and thymidine kinase (17)(18)(19) that directly affects pyrimidine synthesis in de novo or salvage pathways (11).…”

Avemar, a nontoxic fermented wheat germ extract, attenuates the growth of sensitive and 5-FdUrd/Ara-C cross-resistant H9 human lymphoma cells through induction of apoptosis

“…Several mechanisms have been hypothesized for observed resistance to 5-FU in tumor cells. These include loss or decreased activity of the key enzyme required for its activation, increased clearance and overproduction of thymidylate synthase (acquired resistance) through gene amplification, overexpression, or mutation (23). In attempts to circumvent resistance to 5-FU by tumor cells, a number of modulators have been used to increase the antitumor effects of the drug, including leucovorin and eniluracil (24).…”

Chemotherapy for pancreatic cancer

“…5-Fluorouracil: Until the development of gemcitabine only 5-fluorouracil (5-FU) and mitomycin C had consistently shown a beneficial effect. 8,25,26 5-FU is an S-phase-specific, fluorinated pyrimidine that is metabolised intracellularly to its active form fluorodeoxyuridine monophosphate (FdUMP) via the de novo pyrimidine pathway; [27][28][29][30][31] see Figure 1.…”