Selective therapy of metastasis. I. Quantitation of tumorigenic circulating and covert cancer cells disseminated from metastatic and nonmetastatic tumors.

To determine the potential efficacy of therapeutic agents and different drug delivery systems against metastases, it is necessary to develop methodologies that can assay the effects of treatment at each step of the metastatic process. This report presents quantitative studies on the total numbers and potential tumorigenicity of cancer cells in the circulation and also secondarily arrested in the lungs of mice following their spontaneous dissemination from methylcholanthrene-induced fibrosarcomas. MC1 fibrosarcomas rarely metastasize but MC2 fibrosarcomas frequently generate pulmonary metastases and it was found, using a combination of direct cancer cell isolation techniques and quantitative bioassays, that MC2 tumors released cancer cells into the bloodstream earlier and with greater frequency than MC1 fibrosarcomas. Also, although similar doses of radiolabeled MC1 and MC2 cells injected intravenously were cleared equally effectively following their arrest in the lung microvasculature, those MC2 cells that survived clearance processes had 10-fold greater lung colonization potential than MC1 cells. Therefore, these experimental systems can be used critically to evaluate the effects of therapeutic agents at individual stages of metastasis as an alternative to measuring their effects solely on solid tumors or the final incidence of metastases, which represents the net result of a number of sequential, complex interactions between cancer cells and the host.