ANTIANGIOGENESIS AND APOPTOSIS AS MEDIATORS OF CONCOMITANT TUMOR RESISTANCE INDUCED BY CALU-6, A HUMAN LUNG-CARCINOMA CELL-LINE, IN NUDE-MICE

Concomitant resistance (CR), the phenomenon by which tumor-bearing hos ts are able to inhibit secondary implants of the same tumor at distant sites of the body, has been previously observed by us and others in d ifferent murine tumor models. Here, we verified the generation of CR i n nude mice by tumors induced by SC inoculation of Calu-6, a human lun g carcinoma cell line. Histological analysis of secondary tumors subje ct to CR did not reveal macrophage infiltration nor cytotoxic signs. A lthough serum from tumor bearing mice inhibited in vitro [H-3]thymidin e uptake by Calu-6 cells, no significant differences in [H-3]thymidine labeling index of tumors implanted in the right flank of mice with an d without a primary tumor in the left flank were detected. In our mode l, the presence of a primary tumor hindered remote tumor angiogenesis, as well as serum from tumor-bearing mice inhibited in vitro prolifera tion of an endothelial cell line derived from a murine hemangioendothe lioma. Conversely, an enhancement of the apoptotic index was observed in secondary tumor implants carried out in tumor-bearing mice. The res ults reported herein show that human tumor cells are capable of induci ng CR, and that this phenomenon would be a consequence of an impaired neovascularization as well as an increased programmed cell death at si tes distant from the primary tumor.