LOCAL INFLAMMATORY RESPONSE AND VECTOR SPREAD AFTER DIRECT INTRAPROSTATIC INJECTION OF A RECOMBINANT ADENOVIRUS CONTAINING THE HERPES-SIMPLEX VIRUS THYMIDINE KINASE GENE AND GANCICLOVIR THERAPY IN MICE

We have evaluated the safety and potential toxicity of an adenoviral v ector containing the herpes simplex virus thymidine kinase gene (adeno virus/Rous sarcoma virus thymidine kinase in a preclinical model for p rostate cancer. Clinical grade vector prepared for human trials was in jected directly into the dorsolateral prostate of C57Bl/6 mice in a vo lume of 5 mu L at doses of 2.5 x 10(6), 2.5 x 10(7), or 2.5 x 10(8). T he mice received intraperitoneal injections of either ganciclovir or s aline twice daily for 6 days, beginning 12 hours after vector injectio n. Representative tissues and fluids were collected for evaluation the day after the final dose. Microscopic pathologic evaluation revealed inflammatory infiltration without necrosis within the dorsolateral and ventral prostate, but no necrosis or leukocyte infiltration was obser ved in sample tissues from lung, liver, large intestine, bladder, semi nal vesicle, testis, or epididymis. DNA was extracted from the above t issues as well as pelvic lymph nodes, blood, seminal fluid, urine, and sperm and analyzed by polymerase chain reaction for the presence of v ector sequences. The vector was readily detected in the dorsolateral p rostate, the site of injection. The amount of vector detected was redu ced in some samples from ganciclovir-treated animals. At the highest d ose, vector spread was observed in the ventral prostate, seminal vesic le, testis, pelvic lymph nodes, gut, and liver. Spread to the testis w as observed in only one animal. Vector DNA was not detected in urine, seminal fluid, or sperm but was detected in the blood of one animal. T his adenoviral vector, therefore, appears to have minimal spread to si tes distant from the site of injection and no delectable pathological sequelae within this dose range in this preclinical model for prostate cancer, which may be generalizable to other solid tumors.