NUDE RAT MODELS FOR HUMAN TUMOR-METASTASIS TO CNS - PROCEDURES FOR INTRACAROTID DELIVERY OF CANCER-CELLS AND DRUGS

Models for hematogenous spread of human cancer to the central nervous system (CNS) were established by injecting human tumor cells into the internal carotid artery of nude rats. With 4 out of 10 cell lines, bel onging to four different tumor types, metastases developed in all inje cted animals. Tumor growth manifested clinically as neurological sympt oms which appeared after a median latency ranging from 19-87 days for the different tumors. The H-146 and DMS-273 small cell lung cancers an d the LOX melanoma almost exclusively gave meningeal tumors, whereas w ith FEMX-I melanoma cells bone metastases in the skull dominated. For these tumor types a correlation was found between the capacity for exp erimental metastasis formation and the s.c. tumorigenicity. In agreeme nt with clinical experience, none of the 2 sarcoma and 2 glioblastoma lines gave CNS metastases. With a modified microsurgical technique, al lowing for repeated ipsilateral intracarotid injections, we analyzed t he drug concentrations obtained in tumor and surrounding brain tissue after i.v. treatment with doxorubicin. The concentration in the LOX tu mor reached therapeutic levels and was approximately 100 x higher than in normal brain tissue, both with and without intraarterial pretreatm ent with arabinose. In the same model, the tissue concentrations of 9. 2.27-abrin immunotoxin 10 min after intracarotid injection were examin ed. Although the levels were low, a tumor to brain concentration ratio of up to 9 was achieved. The data demonstrate that clinically relevan t tumor models can be established with the techniques described, and t hese models may successfully be used to evaluate the pharmacokinetics and effect of intravenous or intraarterial therapy.