Combination of antiangiogenesis with chemotherapy for more effective cancer treatment

Abstract

Angiogenesis is a hallmark of tumor development and metastasis and is now a validated target for cancer treatment. However, the survival benefits of antiangiogenic drugs have thus far been rather modest, stimulating interest in developing more effective ways to combine antiangiogenic drugs with established chemotherapies. This review discusses recent progress and emerging challenges in this field; interactions between antiangiogenic drugs and conventional chemotherapeutic agents are examined, and strategies for the optimization of combination therapies are discussed. Antiangiogenic drugs such as the anti-vascular endothelial growth factor antibody bevacizumab can induce a functional normalization of the tumor vasculature that is transient and can potentiate the activity of coadministered chemoradiotherapies. However, chronic angiogenesis inhibition typically reduces tumor uptake of coadministered chemotherapeutics, indicating a need to explore new approaches, including intermittent treatment schedules and provascular strategies to increase chemotherapeutic drug exposure. In cases where antiangiogenesis-induced tumor cell starvation augments the intrinsic cytotoxic effects of a conventional chemotherapeutic drug, combination therapy may increase antitumor activity despite a decrease in cytotoxic drug exposure. As new angiogenesis inhibitors enter the clinic, reliable surrogate markers are needed to monitor the progress of antiangiogenic therapies and to identify responsive patients. New targets for antiangiogenesis continue to be discovered, increasing the opportunities to interdict tumor angiogenesis and circumvent resistance mechanisms that may emerge with chronic use of these drugs.

Figure 1. Inhibition of tumor metastasis by anti-angiogenic drugs

Tumor metastases can be targeted by angiogenesis inhibitors at multiple steps. Prunning of tumor blood vessels and decreased vascular permeability following anti-angiogenic drug treatment limit the shedding of metastastic cells from the primary tumor (1). Inhibition of VEGFR-1 or VEGFR-2 suppresses the attachment of disseminated tumor cells to metastatic niches (2). Growth of avascular micrometastases to macrometastases also requires angiogenesis and can be inhibited by anti-angiogenic agents (3).

Figure 2. Effect of anti-angiogenesis treatment schedule on chemotherapeutic drug uptake by tumors

A, some anti-angiogenic drugs induce functional normalization of tumor vasculature resulting in a transient increase in tumor drug uptake. However, continuous treatment with angiogenesis inhibitors ultimately leads to a decrease in tumor blood flow and decreased tumor uptake of co-administered cytotoxic drugs. B, intermittent anti-angiogenesis treatment schedules may allow for the recovery of tumor vascular patency between each cycle of drug administration and thereby minimize the adverse effects of angiogenesis inhibitors on the delivery of cytotoxic agents to tumors. However, the potential that such cycles of re-normalization of the tumor vasculature might facilitate tumor cell recovery from cytotoxic drug treatment needs to be carefully considered. Vertical arrows under each panel indicate repeated dosing with anti-angiogenic drugs.

Figure 3. Balance between the antitumor activity of an anti-angiogenesis inhibitor and a co-administered cytotoxic drug determines the outcome of the combination therapy

Tumor cell exposure to cytotoxic drugs can be reduced by anti-angiogenesis treatment, but the therapeutic outcome of the combination therapy depends on the relative contribution of each treatment regimen to overall antitumor activity. A, for tumors that are highly sensitive to angiogenesis inhibition, anti-angiogenesis may dominate the therapeutic activity of the combination treatment such that anti-angiogenesis-induced tumor cell starvation enhances chemotherapeutic drug action, despite a decrease in drug uptake. B, in contrast, for tumors that have limited intrinsic responsiveness to angiogenesis inhibition, the cytotoxic drug becomes the major determinant of the overall antitumor effect, and anti-angiogenesis may compromise antitumor activity by decreasing chemotherapeutic drug uptake. Model is based on data presented elsewhere (92, 97).