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Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice
Douglas Hanahan,1,2 Gabriele Bergers,1,2 and Emily Bergsland2,3
1Department of Biochemistry and Biophysics,2 Hormone Research Institute, and3 Department of Medicine, University of California San Francisco, San Francisco, California, USA
Address correspondence to: Douglas Hanahan, Departments of Biochemistry and Biophysics, and Hormone Research Institute, University of California San Francisco, San Francisco, California 94143-0534, USA. Phone: (415) 476-9209; Fax: (415) 731-3612; E-mail: dh@biochem.ucsf.edu.
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1Department of Biochemistry and Biophysics,2 Hormone Research Institute, and3 Department of Medicine, University of California San Francisco, San Francisco, California, USA
Address correspondence to: Douglas Hanahan, Departments of Biochemistry and Biophysics, and Hormone Research Institute, University of California San Francisco, San Francisco, California 94143-0534, USA. Phone: (415) 476-9209; Fax: (415) 731-3612; E-mail: dh@biochem.ucsf.edu.
Find articles by Bergers, G. in: PubMed | Google Scholar
1Department of Biochemistry and Biophysics,2 Hormone Research Institute, and3 Department of Medicine, University of California San Francisco, San Francisco, California, USA
Address correspondence to: Douglas Hanahan, Departments of Biochemistry and Biophysics, and Hormone Research Institute, University of California San Francisco, San Francisco, California 94143-0534, USA. Phone: (415) 476-9209; Fax: (415) 731-3612; E-mail: dh@biochem.ucsf.edu.
Find articles by Bergsland, E. in: PubMed | Google Scholar
Published April 15, 2000 - More info
J Clin Invest. 2000;105(8):1045–1047. https://doi.org/10.1172/JCI9872.
© 2000 The American Society for Clinical Investigation
Chemotherapeutic drugs, long the mainstay of cancer treatment, cause DNA damage and disrupt DNA replication in proliferating cells. Drug regimens have been designed to kill as many tumor cells as possible by treating with “maximum tolerated doses” (MTDs) of these cytotoxic agents. Side effects such as neurotoxicity and damage to proliferating cells in healthy tissues pose serious constraints on the use of chemotherapy. In an effort to balance toxicity with efficacy, a conventional dosing schedule calls for episodic application of a cytotoxic drug at or near the MTD, followed by periods of rest to allow normal tissues to recover. Many such chemotherapy regimens are initially efficacious, resulting in tumor regression or stabilization and prolonged survival. In rare cases, cures are achieved. In general, however, responses are short-lived, with relapses often marked by aggressive cancers that are resistant to the cytotoxic drug. Furthermore, the standard MTD regimen as a rule seriously impairs quality of life.
The harsh side effects and the ultimate failures of most chemotherapies have fueled broad investigation of alternatives, including drugs that target not the transformed tumor cells themselves, but rather a genetically stable constituent cell type of tumors, the endothelial cells that form blood vessels. Angiogenesis, the process by which new blood vessels are formed, is a hallmark capability of cancer (1); a compelling body of evidence argues that tumor growth depends on the vasculature, and, in particular, on continuing angiogenesis (2, 3). More than two dozen new drugs that are in or soon to enter clinical trials appear to interfere with tumor angiogenesis (3, 4); there is considerable anticipation about their benefits in treating cancer. Now, two studies suggest a potentially complementary strategy of rescheduling the administration of classical cytotoxic drugs in order to target tumor endothelial cells.
It is well established that tumor-associated endothelial cells proliferate during chronic angiogenesis in tumors, albeit at lower frequencies than the tumor cells themselves. Apparently because of their lower rate of cell division, replication of these endothelial cells is only weakly disrupted by the episodic regimens of standard chemotherapeutic protocols. In these two new studies, however, cytotoxic drugs were administered routinely, to target the slowly proliferating tumor endothelial cells and abrogate their apparent capability to repair and recover during the usual rest periods. Both groups worked with mice bearing subcutaneous tumors, and each presents data suggesting that “metronomic” dosing regimens—either continuous infusion or frequent administration without extended rest periods—could have real value in the clinic. Both also demonstrated combinatorial effects of such altered cytotoxic drug regimens with newer, more specific angiogenesis inhibitors.
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Renewed promise for discarded drugs
In a parallel study, Browder et al. (9) grew cyclophosphamide-resistant tumors (Lewis lung carcinoma and EMT-6 breast carcinoma) in immunocompetent mice to focus more specifically on the effects of a cytotoxic drug on tumor endothelium under different dosing schedule. Cyclophosphamide treatment in a conventional MTD regimen only modestly delayed growth of both tumor types in mice. In contrast, when cyclophosphamide was instead supplied regularly (once every 6 days), tumor growth was significantly impaired, although the tumors eventually prevailed. Provocatively, the relapse of drug-resistant Lewis Lung tumors could be prevented by a combination therapy, this time involving similar metronomic dosing with the experimental angiogenesis inhibitor TNP-470. TNP-470 had previously been shown to impair but not regress subcutaneous tumor growth in mice (10) and to enhance high-dose episodic chemotherapy (11). In combination, cyclophosphamide and TNP-470 eradicated aggressive drug-resistant tumors in 32/38 tumor-bearing mice. Other trials assessed drug-sensitive Lewis Lung carcinomas and L1210 leukemias, both of which could be regressed without relapse using metronomic dosing of cyclophosphamide alone. The dose of cyclophosphamide used in this study was relatively high and resulted in significant toxicity; one wonders whether lower, nontoxic levels of cyclophosphamide would have sufficed, in combination with TNP-470, to induce the regression of these tumors. As predicted, metronomic cytotoxic dosing elicited repeated waves of apoptosis of tumor endothelial cells. Using an angiogenesis bioassay in normal mice, Browder et al. (9) confirmed that metronomic dosing of cyclophosphamide, as well as of a number of other cytotoxic drugs (including 5-fluorouracil [5-FU]), was antiangiogenic.
Collectively, these two studies (5, 9) clearly establish that metronomic regimens of cytotoxic drugs can be antiangiogenic, repositioning cytotoxic therapies as bi- or multifunctional against distinct heterotypic cell types in tumors (Figure 1). [The concept of antiangiogenic dosing was originated by Browder et al. (9), as noted by Klement et al. (5).] Both studies further demonstrated the value of combining modified chemotherapeutic regimens with experimental angiogenesis inhibitors. While the data presented are compelling, direct extrapolation to the clinical setting presents several immediate challenges related to the choice of drug, dose, and schedule for maximum antiangiogenic activity. In de-emphasizing the tumor cell as a target, this strategy requires a fundamental change in our approach to therapy, one that potentially includes retreatment of refractory cancers with agents that have previously failed, or the use of agents traditionally deemed inactive or ineffective in a particular cancer type. Second, identification of a MTD by standard toxicity criteria is relatively straightforward, whereas selecting the optimum antiangiogenic dose that is nontoxic yet efficacious may be difficult; surrogate markers of response and/or accurate preclinical models will be important. Novel imaging modalities designed to monitor angiogenesis may prove instrumental in this regard.
Figure 1The changing logic of chemotherapy: metronomic dosing at lower levels, in combination with other agents. The conventional logic of chemotherapy has been to treat cancers with closely spaced bolus infusions of drugs at or near the MTD, followed by substantial rest periods. The typical results were transitory improvements in tumor burden and life-span extension accompanied by disturbing side effects and eventual relapse. The new logic of chemotherapy involves dosing at constant intervals without rest periods (metronomic scheduling), the use of lower doses to minimize toxic side effects and eliminate the obligatory rest periods, and combination with other drugs targeting distinct aspects of a cancer’s functionality. The metronomic and combinatorial dosing strategies can kill tumor endothelial cells as well as overt cancer cells and, perhaps, other cellular constituents of a tumor, offering the prospect for genuine efficacy. The bullets refer to doses of chemotherapy, which can be large and episodic (upper scheme) or smaller and metronomic (lower); the bombs indicate other anti-cancer agents providing additive or synergistic benefits.
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