GROWTH-INHIBITION OF HUMAN CANCER METASTASES BY CAMPTOTHECINS IN NEWLY DEVELOPED XENOGRAFT MODELS

Several metastatic models have been developed using clonal selection o f human malignant cells metastasizing into a specific organ in NIH-I S wiss immunodeficient mice. The organs of choice were the central nervo us system (CNS), targeted by metastases of malignant melanoma, and the Liver, with metastases of colon adenocarcinoma. Additional models of adrenal metastases by malignant melanoma, and CNS involvement by impla nted human lung squamous carcinoma or lymphoblastoid cells, are also a vailable. Organ metastases, as well as the effects of treatment, were confirmed by autopsies and histological examination of the tissues or by a surgical inspection of the liver. The treatment end points were e stablished as the increases in survival times of treated mice relative to placebo-treated controls. Camptothecins injected i.m. or delivered via gastrointestinal tract inhibit the growth of CNS metastases and i ncrease the survival of treated animals. 9-Amino-20(S)-camptothecin wa s effective in the CNS model and in the model of liver metastases. The drug increased 3.3- and 5.7-fold the survival rates relative to untre ated controls with metastases of colon adenocarcinoma to the liver, an d all camptothecins were significantly more effective than 5-fluoroura cil, currently a drug of choice in treatment of this disease. The xeno graft models of metastases are available for studies of drug passage t hrough the blood-brain barrier optimization of drug delivery to the li ver, and for the development of new camptothecin-based treatment strat egies.