Elsevier

Pharmacology & Therapeutics

Volume 87, Issues 2–3, August–September 2000, Pages 227-253
Pharmacology & Therapeutics

Review article
Basis for effective combination cancer chemotherapy with antimetabolites

https://doi.org/10.1016/S0163-7258(00)00086-3Get rights and content

Abstract

Most current chemotherapy regimens for cancer consist of empirically designed combinations, based on efficacy and lack of overlapping toxicity. In the development of combinations, several aspects are often overlooked: (1) possible metabolic and biological interactions between drugs, (2) scheduling, and (3) different pharmacokinetic profiles. Antimetabolites are used widely in chemotherapy combinations for treatment of various leukemias and solid tumors. Ideally, the combination of two or more agents should be more effective than each agent separately (synergism), although additive and even antagonistic combinations may result in a higher therapeutic efficacy in the clinic. The median-drug effect analysis method is one of the most widely used methods for in vitro evaluation of combinations. Several examples of classical effective antimetabolite-(anti)metabolite combinations are discussed, such as that of methotrexate with 6-mercaptopurine or leucovorin in (childhood) leukemia and 5-fluorouracil (5FU) with leucovorin in colon cancer. More recent combinations include treatment of acute-myeloid leukemia with fludarabine and arabinosylcytosine. Other combinations, currently frequently used in the treatment of solid malignancies, include an antimetabolite with a DNA-damaging agent, such as gemcitabine with cisplatin and 5FU with the cisplatin analog oxaliplatin. The combination of 5FU and the topoisomerase inhibitor irinotecan is based on decreased repair of irinotecan-induced DNA damage. These combinations may increase induction of apoptosis. The latter combinations have dramatically changed the treatment of incurable cancers, such as lung and colon cancer, and have demonstrated that rationally designed drug combinations offer new possibilities to treat solid malignancies.

Introduction

Anticancer agents are rarely used singly to treat cancer. Only a few tumors are sensitive enough to be cured by single agents. Effective chemotherapy usually depends on the identification of suitable combinations to treat a specific type of tumor (Frei et al., 1998). In some tumors, such as childhood acute lymphoblastic leukemia (ALL), combinations are curative, with over 80% survivors, whereas each single agent involved has very low activity (Pui & Evans, 1999). For other tumor types, combinations can lead to complete responses, but the tumors recur. In the last decade, the availability of several new active drugs has led to the development of new combinations that have substantially increased the response rate of tumor types until recently considered as untreatable. These include common malignancies, such as non-small cell lung cancer and advanced colon cancer Giaccone 1995, Van Moorsel et al. 1997a, Peters & Köhne 1999.

Many combinations in clinical use consist of an antimetabolite together with one or more other anticancer agents. Normal intermediates of purine and pyrimidine metabolism are also used in combination chemotherapy as modulators Martin 1987, Peters & Van Groeningen 1991. The efficacy of the antimetabolites in certain tumor types and the ease with which antimetabolites can be combined are factors that contribute to their selection. Since the introduction in the 1950s of the widely used antimetabolites methotrexate (MTX), 5-fluorouracil (5FU), and the thiopurines, knowledge about purine and pyrimidine metabolism in normal and tumor cells has increased dramatically, enabling the rational design of new combinations. Nonetheless, new combinations are often still designed empirically, based on (a) the efficacy of each agent and (b) the lack of overlapping toxicities. Serendipity sometimes plays a substantial role in the development of a new combination, while occasionally logical design occurs, e.g., combinations based on known preclinical mechanistic interactions.

This review discusses the design of combinations of antimetabolites with other anticancer agents, and with treatment modalities, such as radiotherapy and immunotherapy. It is preferable that a combination be designed rationally rather than empirically. In addition, it is of utmost importance that a proper translation is performed from preclinical studies (test tube or culture dish) to a suitable animal model system and subsequently to the patient. As frequently pointed out, selectivity is the ultimate aim of cancer treatment, including combination chemotherapy, with little or no side effects in normal tissues and a selective reduction in the size (or disappearance) of the tumor Elion 1985, Martin 1987, Frei et al. 1998.

Section snippets

How to design and test combinations?

Ideally, when a new combination is first contemplated, a possible biochemical mechanism, which may serve as the basis for the action and interaction of the agents, should be considered. This hypothetical mechanism may subsequently determine the way in which the combination is tested. The interaction between two or more drugs can be synergistic, i.e., the effect of the combination is larger than the algebraic sum of the effect of each agent separately (Berenbaum, 1989). If the combined effect of

Rationale for combinations with antimetabolites

Because of their efficacy and generally moderate toxicity, antimetabolites are widely used in cancer combination chemotherapy, either together with another antimetabolite or with another anticancer agent. A list of several widely used combinations is given in Table 1. Because of their generally well-defined mechanisms of action, antimetabolites are also widely used in the treatment of other diseases, such as viral infections (herpes, human immunodeficiency virus, cytomegalovirus), psoriasis,

Translation of preclinical studies to the clinic

The extensive knowledge of the metabolism of normal purine and pyrimidine precursors and of the mechanism of action of antimetabolites, together with their relatively mild toxicity profile, has led to an extensive use of these agents in clinical combination chemotherapy. Numerous combinations have been tested, but not all were clinically successful (Table 2). A number of clinical trials have suffered from inappropriate scheduling. It already has been pointed out by Martin (1987) and

Biochemical modulation of 5-fluorouracil with leucovorin and interferons

The combination of 5FU (Fig. 7) with LV is one of the first beneficial clinical combinations in cancer treatment with a basis in biochemical pharmacology. Initial studies demonstrated that the binding of FdUMP to thymidylate synthase (TS) was strengthened by the presence of 5,10-methylene tetrahydrofolate (CH2-THF), resulting in more sustained TS inhibition and greater cytotoxicity of tumor cells in vitro (reviewed in Van der Wilt & Peters, 1994). Thus, the combination of 5FU with LV is based

Cytarabine combinations

An interesting combination is that of fludarabine and arabino-furanosyl-cytosine (ara-C) Fig. 14, Fig. 15; both require activation catalyzed by deoxycytidine kinase. Ara-C is widely used in the treatment of acute myeloid leukemia (Table 1). Ara-C acts by its metabolite ara-CTP Grant 1998, Plunkett & Gandhi 1993. Fludarabine is a prodrug for F-ara-A, and has to be dephosphorylated before it can enter the cell. The active metabolite F-ara-ATP can be incorporated into DNA, leading to apoptosis

Mechanisms of action and self-potentiation

The metabolism of gemcitabine (Fig. 14) is well understood, and in several aspects, is similar to that of other deoxynucleoside analogues Plunkett et al. 1995, Heinemann et al. 1995, Peters & Jansen 1996 (Fig. 16). Membrane transport is mediated by facilitated diffusion (Heinemann et al., 1988) catalyzed by the so-called hENT1 (Mackey et al., 1998). Subsequent activation of gemcitabine to its mononucleotide is catalyzed by deoxycytidine kinase. However, gemcitabine is also a substrate for the

Other combinations

MTX and 6-mercaptopurine (6-MP) are commonly given together in the treatment of childhood leukemia, but it has been postulated that the schedule usually used is not optimal Bökkerink et al. 1986, Pinkel 1993. MTX stimulates 6-MP metabolism Bökkerink et al. 1986, Giverhaug et al. 1998. In a sequential MTX-6-MP schedule, all 59 patients with ALL entered remission; three relapsed after 2–3 years (Camitta et al., 1989). Schmiegelow et al. (1995) demonstrated that the pharmacokinetics of MTX and

Conclusions

Combinations with antimetabolites are commonly used not only in cancer chemotherapy, but also in many other diseases. The selection of combinations is often based on the efficacy of each agent separately, but the prior identification of a mechanistic basis for a combination may optimize scheduling and dosing of the combination. First, a potential hypothesis about the interaction between two agents should be developed, which is often facilitated by an extensive knowledge of the individual

Acknowledgements

We thank Mrs. A.M.B. Paalman for excellent secretarial assistance and K. Smid for the figures.

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