Combination chemotherapy of the taxanes and antimetabolites: its use and limitations

doi:10.1016/S0959-8049(01)00309-4

European Journal of Cancer

Volume 37, Issue 18, December 2001, Pages 2310-2323

https://doi.org/10.1016/S0959-8049(01)00309-4 Get rights and content

Abstract

In an effort to improve response rates of chemotherapy, taxanes have been combined with other cytotoxic agents such as antimetabolites. However, the use of some of these combinations in patients has been restricted by severe toxicity. The significance of the sequence of drug administration in combining methotrexate (MTX) and taxanes was recognised in in vitro studies, showing synergistic effects for the sequence of MTX followed by paclitaxel, and antagonism for exposure in the reverse order. A possible explanation might be an MTX-induced synchronisation of cells in the S phase of the cell cycle, after which cells are more susceptible for the cytotoxic action of taxanes. Clinical studies using this sequence were hampered by severe neutropenia and mucositis at relatively low doses of both drugs. As no pharmacokinetic interactions were observed, the excess of toxicity may have been due to sequence-dependent synergistic actions on bone marrow and mucosa. In contrast, and confusingly, in vitro studies on 5-fluorouracil (5-FU) and taxanes indicate that 5-FU preceeding or simultaneously given to paclitaxel impairs cytotoxicity as compared with paclitaxel monotherapy, while the reverse sequence results in additive or synergistic cytotoxicity. While almost all clinical studies have used the sequence of a taxane followed by 5-FU, various schedules appeared feasible and effective. The combination of a 5-FU analogue, capecitabine and taxanes was supported by in vitro data. A large phase III trial confirmed the feasibility and superior efficacy of this combination in breast cancer patients relapsing after an anthracycline. Conflicting results exist on the benefit of combining gemcitabine and taxanes in tumour cell lines. Although the accumulation of gemcitabine triphosphate (dFdCTP) in mononuclear cells was significantly higher with an increasing dose of paclitaxel, no pharmacokinetic interactions for both agents were noticed. A pharmacokinetic analysis of the gemcitabine–docetaxel combination therapy has not been published in detail. Despite numerous trials, so far no optimum schedule has been established. Regarding data on actually delivered dose intensities, a 2- or 3-weekly cycle seems favourable and feasible. However, possible severe pulmonary toxicity warrants cautious monitoring of patients treated with this combination. Different outcomes of preclinical and clinical studies reveal that combining two chemotherapeutic agents is not simply a matter of putting antitumour activities together. Drug interaction may result in synergism, not only of efficacy but also of toxic side-effects. Adding two drugs may also implicate antagonism in drug efficacy due to unwanted interference in cytotoxicity or pharmacokinetics. For agents acting at a specific phase of the cell cycle, the sequence of administration may determine the efficacy and toxicity of a combination therapy. Because of an observed discrepancy between in vitro data and clinical studies, we would like to emphasise the need for adequate dose-finding clinical trials together with pharmacokinetic data analysis before examining any new combination chemotherapy in more detail in phase II studies.

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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ReviewCombination chemotherapy of the taxanes and antimetabolites: its use and limitations

Abstract

Introduction

Section snippets

Pharmacology of taxanes

Preclinical studies

Preclinical studies

Paclitaxel/5-FU

Preclinical studies

Preclinical studies

Paclitaxel/Gemcitabine

Conclusions

Ann. Oncol.

Ann. Oncology

Urology

J. Urol.

Ann. Oncol.

J Chromatogr. B

Biochem. Pharmacol.

Eur. J. Cancer

Ann. Oncol.

Eur. J. Cancer

Ann. Oncol.

Ann. Oncol.

Clin. Oncol.

Ann. Oncol.

Eur. J. Cancer

Ann. Oncol.

Ann. Oncol.

Principles of systemic therapy of cancer

Paclitaxel (taxol)

NEJM

Is there a place for “dose-dense” weekly schedules of the taxoids?

Semin. Oncol.

Cytotoxicity of the anticancer agents cisplatin and taxol during cell proliferation and the cell cycle

Int. J. Cancer

Cell kill kinetics and cell cycle effects of taxol on human and hamster ovarian cell lines

Cancer Chemother. Pharmacol.

Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol

Cancer Res.

Development of polyploidization in taxol-resistant human leukemia cells in vitro

Cancer Res.

Cytotoxic studies of paclitaxel in human tumour cell lines

Br. J. Cancer

Paclitaxel-induced cell death. Where the cell cycle and apoptosis come together

Cancer

S-phase specificity of cell killing by docetaxel in synchronised HeLa cells

Br. J. Cancer

Antitumour activity of novel taxanes that act at the same time as cytotoxic agents and P-glycoprotein inhibitors

Br. J. Cancer

Role of formulation vehicles in taxane pharmacology

Invest. New Drugs

Cremophor EL-mediated alteration of paclitaxel distribution in human bloodclinical pharmacokinetic implications

Cancer Res.

Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer

J. Clin. Oncol.

Rapid esterase-sensitive breakdown of polysorbate 80 and its impact on the plasma pharmacokinetics of docetaxel and metabolites in mice

Clin. Cancer Res.

New folate analogs of the 10-deaza-aminopterin series

Cancer Chemother. Pharmacol.

Synergistic action of taxol with tiazofurin and methotrexate in human breast cancer cellsschedule-dependence

Life Sci.

Schedule-dependent synergism and antagonism between paclitaxel and methotrexate in human carcinoma cell lines

Oncology Res.

Comparative study of sequential combinations of paclitaxel and methotrexate on a human bladder cancer cell line

Cancer Invest.

Schedule-dependent synergism of taxol or taxotere with edatrexate against human breast cancer cells in vitro

Cancer Chemother. Pharmacol.

Synergism of taxol and gallium nitrate in human breast carcinoma cellsschedule dependency

Oncol. Res.

Phase I study of escalating doses of edatrexate in combination with paclitaxel in patients with metastatic breast cancer

Clin. Cancer Res.

Regulation of RNA- and DNA-directed actions of 5-fluoropyrimidines in mouse T-lymphoma (S-49) cells

Cancer Res.

5-Fluorouracil interferes with paclitaxel cytotoxicity against human solid tumor cells

Clin. Cancer Res.

Schedule-dependent interaction between paclitaxel and 5-fluorouracil in human carcinoma cell lines in vitro

Br. J. Cancer

Antagonistic interplay between antimitotic and G1-S arresting agents observed in experimental combination therapy

Clin. Cancer Res.

Review
Combination chemotherapy of the taxanes and antimetabolites: its use and limitations

Antagonistic interplay between antimitotic and G₁-S arresting agents observed in experimental combination therapy