ReviewCombination chemotherapy of the taxanes and antimetabolites: its use and limitations
Introduction
Curative cancer chemotherapy nearly always consists of a combination of cytotoxic agents. Increased efficacy of combination chemotherapy may result from the increase of total exposure to a cytotoxic effect due to the addition of other agents, especially if non-overlapping toxicities allow dose intensities for the combination to be similar to those of the single agents. Other rationales for combination chemotherapy are the possibility to overcome (multi)drug resistance and synergistic effects of certain antitumour drugs [1]. Concomitant administration of anticancer agents may affect the pharmacokinetic parameters such as absorption, distribution, metabolism or excretion of a drug, or may result in pharmacodynamic interactions at the level of cellular targets or the cell cycle, which can have both a positive or a negative impact on the cytotoxic effects of the drugs involved.
Since the late 1980s, taxanes have proved to be effective agents in the treatment of a variety of solid tumours [2]. Paclitaxel is currently registered for the treatment of advanced breast cancer, ovarian cancer and non-small cell lung cancer and as a single agent it is usually dosed at 135–225 mg/m2 as a 3-h intravenous (i.v.) infusion every 3 weeks [3]. Docetaxel is registered for the treatment of metastatic breast cancer and non-small cell lung cancer and is most often given at a dose of 100 mg/m2 as a 1-h i.v. infusion in a 3-weekly schedule. Currently, weekly administration of taxanes, enabling a higher dose per time period and inducing less toxicity, is being explored in several phase I-II studies [4].
In view of the established efficacy of taxanes, numerous combinations of taxanes with other agents in various treatment schedules have been investigated in an effort to improve the response rates to palliative chemotherapy in solid tumours. Such combinations included those of taxanes with antimetabolites, but some of these yielded major problems in patients due to severe toxicity, which prevented maximum tolerable doses (MTDs) that were considered to be relevant for the single agents 5, 6. This contrasts with the feasibility of combining taxanes with other classes of cytotoxic agents almost at their respective recommended single doses. This review will summarise both preclinical and clinical studies on combinations of taxanes and the antimetabolites methotrexate (MTX), 5-fluorouracil (5-FU), capecitabine and gemcitabine, respectively, and consider possible mechanisms of interaction accounting for their efficacy and clinical feasibility. Combinations of other antimetabolites with taxanes have rarely been investigated and will therefore not be discussed.
Section snippets
Pharmacology of taxanes
Taxanes exert their cytotoxic effect by stabilising the assembly of intracellular microtubules from tubulin dimers, thereby disrupting mitosis and other vital cellular functions. In studies with hamster ovarian cell lines and human ovarian and leukaemic cell lines, paclitaxel appeared to be a phase-specific agent, being more cytotoxic to mitotic (M) cells than interphase (G1, S, G2) cells 7, 8. In studies with human leukaemic cell lines, paclitaxel induced a temporary accumulation of cells in G2
Preclinical studies
MTX is one of the oldest anticancer drugs in clinical use. Antimetabolites such as MTX interfere with DNA synthesis, that is necessary for cell proliferation. Due to their mode of action, most antimetabolites act at specific phases of the cell cycle. MTX inhibits dihydrofolate reductase, which results in the depletion of intracellular tetrahydrofolate, and thereby impedes synthesis of thymidylate and purines required for DNA synthesis. It acts as a phase-specific agent by arresting cells in the
Preclinical studies
5-FU is a pyrimidine antimetabolite, which is phosphorylated to 5-fluorouridine triphosphate (5-FUTP). Subsequent incorporation into RNA interferes with cellular RNA processes. Another activated 5-FU metabolite, 5-fluorodeoxyuridine monophosphate (5-FdUMP), inhibits thymidylate synthase, which is required for DNA synthesis. In vitro treatment of mouse T-lymphocytes and human breast cancer cell lines with 5-FU resulted in an interruption at the G1–S phase of the cell cycle 32, 33.
Paclitaxel/5-FU
Kano and
Preclinical studies
Capecitabine is an oral prodrug of 5-FU that is converted along a pathway with three enzymes to the active compound 5-FU. The final step of conversion into 5-FU is catalysed by thymidine phosphorylase (TP), an enzyme that is more abundantly expressed in tumour tissue than in healthy cells. In studies with human colon and breast cancer xenografts in nude mice, both paclitaxel and docetaxel enhanced the level of TP in tumour cells [54]. These in vitro data support the use of the combination of
Preclinical studies
Gemcitabine is a nucleoside analogue that impairs DNA synthesis. It is phosphorylated intracellularly to active triphosphate metabolites, the intracellular concentrations are increased and prolonged by several self-potentiating mechanisms [62]. After in vitro exposure to gemcitabine, human lung cancer cells accumulated in the G0–G1 and S phases 63, 64.
Paclitaxel/Gemcitabine
Clonogenic survival assays of human tumour cell lines have shown less than additive cytotoxicity for any sequential exposure to gemcitabine and
Conclusions
Table 8 summarises preclinical, clinical and pharmacokinetic data on the combination treatment of taxanes and antimetabolites.
Preclinically observed synergism for the sequence of MTX prior to a taxane might explain excessive bone marrow toxicity found in some clinical studies. However, despite in vitro observed antagonism, simultaneous exposure resulted in high response rates and good tolerance in patients with breast cancer and urothelial cancer, although the results do not look strikingly
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