Antiangiogenic scheduling of lower dose cancer chemotherapy.

Cancer chemotherapy utilized at maximum tolerated, toxic doses, rarely results in sustained total tumor eradication, with patients ultimately failing a variety of chemotherapeutic regimens. If tumors respond, the constituent cancer cells acquire resistance to chemotherapeutic agents, largely due to tremendous genetic instability. Changing the target of these agents to the tumor's proliferating microvasculature, a more genetically stable cell, may provide important therapeutic advantages. Modifying the cyclic schedule and high doses of chemotherapeutic agents to a continuous, lower dose, "metronomic" regimen increases the efficacy of targeting the tumor microvasculature, and produces therapeutic activity with decreased toxicity. Preclinically, the antiangiogenic properties of continuous, lower-dose chemotherapy can be further enhanced by the concurrent administration of a selective angiogenesis inhibitor. Because the target is not exclusively the tumor cell, this antiangiogenic combination strategy provides the opportunity to delay or possibly avoid acquired resistance. Preclinical and clinical observations provide a basis for treating cancer as a chronic disease, using protracted, continuous dosing. Because appropriate chemotherapeutic agents and commercially available compounds that inhibit angiogenesis are readily available, it would be beneficial to initiate clinical trials to evaluate the antiangiogenic scheduling of chemotherapy expeditiously.