Resistance to cytotoxic and anti-angiogenic anticancer agents: similarities and differences

This review is dedicated to Prof. Herbert (Bob) M. Pinedo on the occasion of his leave as head of the department of Medical Oncology of the Vrije Universiteit Medical Center in appreciation of his 20 years of inspiring leadership.
https://doi.org/10.1016/S1368-7646(03)00026-8Get rights and content

Abstract

Intrinsic resistance to anticancer drugs, or resistance developed during chemotherapy, remains a major obstacle to successful treatment. This is the case both for resistance to cytotoxic agents, directed at malignant cells, and for resistance to anti-angiogenic agents, directed at non-malignant endothelial cells. In this review, we will discuss mechanisms of resistance which have a bearing on both these conceptually different classes of drugs. The complexity of drug resistance, involving drug transporters, such as P-glycoprotein, as well as resistance related to the tissue structure of solid tumors and its consequences for drug delivery is discussed. Possible mechanisms of resistance to endothelial cell-targeted drugs, including inhibitors of the VEGF receptor and EGF receptor family, are reviewed. The resistance of cancer cells as well as endothelial cells related to anti-apoptotic signaling events initiated by cell integrin–matrix interactions is discussed. Current strategies to overcome resistance mechanisms are summarized; they include high-dose chemotherapy, tumor targeting of cytotoxics to improve tumor uptake, low-dose protracted (metronomic) chemotherapy and combinations of classical agents with anti-angiogenic agents. This review discusses primarily literature published in 2001 and 2002.

Introduction

Most tumor types are resistant to current chemotherapy or become resistant during treatment. Resistance in the clinic manifests itself as initial lack of a meaningful response (refractoriness) to treatment or regrowth of tumor after an initial response. In the latter case, the recurrent tumor is almost invariably more resistant to treatment than it was at first presentation and treatment. Another manifestation of clinical drug resistance is the frequent occurrence of partial responses. Different subpopulations of tumor cells will be invariably present in tumors, where the predominant cell type will determine anti-tumor response, but the most resistant cells may determine the probability of cure (Pusztai and Hortobagyi, 1998). Knowledge of the determinants of resistance to anticancer agents is essential for the design of new treatments that have a chance of a meaningful tumor response and patient’s survival (Broxterman and Georgopapadakou, 2001).

The typical strategy to identify cellular drug resistance mechanisms has been by exposing tumor cell lines in tissue culture to increasing concentrations of drugs and analyzing the surviving clones for chromosomal, gene, protein expression or morphological alterations (Biedler and Riehm, 1970, Juliano and Ling, 1976). The implicit anticipation was that these alterations would explain the unresponsiveness of human cancers in the clinic. However, while a wide variety of resistance mechanisms have been identified to date, this insight has not yet resulted in significant improvements in survival with any of the major treatment-refractory cancer types (Sandor et al., 1998, Bates, 1999, Verweij and de Vries, 2001).

In recent years, an increasing number of anti-tumor drug targets has been identified. New drug development has focused on these targets rather than trying to improve the tumor response to old drugs by adding resistance modifiers. Whereas the new types of biological agents, such as the BCR/Abl kinase-targeted drug imatinib (Gleevec), have been successful in the clinic, drug resistance also occurs (Weisberg and Griffin, 2001).

An important new drug target is the endothelial cell compartment that lines the tumor (micro-) vessels. One argument used to target the endothelial cells in a tumor is their non-transformed phenotype. Whereas in a human tumor at diagnosis every single cancer cell has thousands of mutations, which may facilitate the development of drug resistance (Loeb et al., 2003), it is thought that tumor endothelial cells are unlikely to develop resistance to multiple drugs because of their genomic stability and low mutation frequency (Kerbel, 1991, Kerbel and Folkman, 2002).

In this review, we will discuss mechanisms of anticancer drug resistance relevant to both “old” cytotoxic drugs as well as “new” anti-angiogenic drugs. Current cytotoxic drugs, by virtue of their DNA, topoisomerase or tubulin binding and damaging properties, are almost invariably directed at the proliferating tumor cells, a property that poses a major problem. Because of the limited specificity and (increased) repair capacity of tumor cells, it is often not possible to apply doses which kill all or even a significant fraction of the tumor cells in vivo. On the other hand, anti-angiogenic agents are designed to act more specifically on a particular receptor or pathway of endothelial cell biology. Because endothelial cells in tumors can exploit different pathways for proliferation, they may escape specifically targeted drugs, leading to resistance.

We will survey recent literature, particularly of 2001 and 2002, on the causes of drug resistance, concentrating on impaired drug delivery and the involvement of common effector pathways to cause cell death. Our discussion will revolve around two classical cytotoxic drugs, the anthracycline doxorubicin (Table 1) and the taxane paclitaxel (Table 2) and anti-angiogenic drugs in clinical trials.

Section snippets

Resistance to chemotherapy

Possible resistance mechanisms to cancer chemotherapy have been frequently reviewed. In this paper, we restrict ourselves to resistance related to the availability of drugs at their target and to the involvement of matrix–tumor cell interactions and signaling in cell death pathways. Other mechanisms such as cell cycle-related resistance or DNA repair mechanisms will not be reviewed here.

Resistance to anti-angiogenic or anti-vascular therapy

It is important to realize that resistance to anti-angiogenic agents is related to the fact that angiogenesis supports, but does not dictate tumor biology. Therefore, anti-tumor effects may arise slowly. However, the initial findings in the clinic do not match the impressive results of anti-angiogenic drugs in mouse tumor models.

The first clinical trials with the VEGF-R2 blocker SU-5416 show a result reminiscent of that for many new cytotoxic agents: a potent anti-tumor effect in animal tumor

Modulation of drug transporter activity

The promise of using (competitive) inhibitors of Pgp-mediated cytotoxic drug export from cancer cells to improve the outcome of current cancer therapy has not been realized. In fact only one randomized study, the Southwest Oncology Group study in acute myeloid leukemia, showed some clinical benefit of Pgp inhibition (List et al., 2001). In this study, the Pgp inhibitor cyclosporin A was administered together with cytarabine and daunorubicin without adjustment of chemotherapy dose, which was

Conclusions and future developments

The progress in understanding cell survival pathways in non-transformed (endothelial) and transformed (cancer) cells in the past 2 years has been impressive. Many past observations on tumor drug resistance, referred to as “multicellular”, “multidrug”, “cell-adhesion-mediated”, “kinetic” or “in vivo” resistance are now becoming understood in terms of signaling pathways involved in the regulation of cell survival.

A major group of proteins involved in cell survival are the integrins, which

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