Cancer metastasis: A search for therapeutic inhibition

Failure of cancer treatment is often due to the growth of secondary metastatic lesions in distant organs. Because initiation of metastasis is an entry event in malignancy patients often present not only with a primary tumor but also with occult metastases. Treatment of these metastases requires aggressive, systemic chemotherapy, since surgical removal of all metastatic foci is normally not feasible. However, drug toxicity caused by many of the currently used anticancer agents often limits chemotherapeutic approaches to malignant disease. In contrast, the development and use of novel cytostatic, antimetastatic agents could be less toxic and more applicable for long-term treatment in combating latent and/or residual disease. Practical intervention with such nontoxic agents has been envisioned as maintenance therapy after cytoreduction of a tumor or as a prophylactic treatment after the removal of a precancerous tumor exhibiting a genetic predisposition to a carcinomatous state. In this review, we discuss targets of the metastatic cell that may be potentially exploitable with chemotherapy, and present the current status of several novel, antimetastatic agents. Clinical evaluation of such agents will require new and appropriate clinical models for evaluating their antimetastatic efficacy. The recent successes achieved with certain proteinase inhibitors for the treatment of cancer are paving the way for the development of other therapeutic agents of this type, aimed at unique biochemical pathways associated with oncogenic behavior.