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Resistance to chemotherapeutic antimetabolites: a function of salvage pathway involvement and cellular response to
A R Kinsella1, D Smith, M Pickard
1Department of Surgery, University of Liverpool, UK.
Abstract:
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-beta-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.
Insights
Drug resistance in tumors is a major clinical challenge. This review details how normal and tumor cells respond to antimetabolite drugs like methotrexate, PALA, and 5-FU, focusing on DNA synthesis and damage.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Tumor resistance to cytotoxic drugs presents a significant clinical challenge.
- Mechanisms of drug resistance include gene mutation, amplification, altered repair, transport, and salvage pathways.
- Antimetabolites like methotrexate (MTX), PALA, and 5-fluorouracil (5-FU) are widely used in treating common solid tumors.
Purpose of the Study:
- To review the response mechanisms of normal and tumor cells to MTX, PALA, and 5-FU.
- To evaluate the role of DNA synthesis salvage pathways in cellular response to these antimetabolites.
- To discuss current theories on DNA damage response in the context of antimetabolite chemotherapy.
Main Methods:
- Review of existing literature on cytotoxic drug resistance and antimetabolite mechanisms.
- Analysis of in vitro studies elucidating drug resistance pathways.
- Synthesis of information on cellular response to MTX, PALA, and 5-FU.
Main Results:
- Drug resistance involves diverse mechanisms including genetic alterations and altered metabolic pathways.
- Cellular response to antimetabolites is influenced by the interplay of drug targets and salvage pathways.
- Understanding these mechanisms is crucial for optimizing chemotherapy efficacy.
Conclusions:
- Elucidating cellular response mechanisms to antimetabolites is key to overcoming drug resistance.
- Targeting salvage pathways and DNA damage response may offer novel therapeutic strategies.
- Further research is needed to translate in vitro findings into clinical practice for solid tumor treatment.