Collaboration between hepatic and intratumoral prodrug activation in a P450 prodrug-activation gene therapy model for cancer treatment.

ABSTRACT: Presently, we investigate the mechanisms whereby intratumoral expression of a cyclophosphamide-activating hepatic cytochrome P450 gene enhances therapeutic activity when cyclophosphamide is given on an every 6-day (metronomic) schedule. In P450-deficient 9L gliosarcomas grown in severe combined immunodeficient mice, metronomic cyclophosphamide substantially decreased tumor microvessel density and induced a approximately 70% loss of endothelial cells that began after the second cyclophosphamide treatment. These responses were accompanied by increased expression of the endogenous angiogenesis inhibitor thrombospondin-1 in tumor-associated host cells but by decreased expression in 9L tumor cells. These antiangiogenic responses preceded tumor regression and are likely key to the therapeutic ac

SUBMITTER: Ma J 

PROVIDER: S-EPMC2613795 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature