INTRATUMORAL CHEMOTHERAPY WITH A SUSTAINED-RELEASE DRUG-DELIVERY SYSTEM INHIBITS GROWTH OF HUMAN PANCREATIC-CANCER XENOGRAFTS

This study provides the first evidence that treatment of human pancrea tic adenocarcinoma is markedly improved by the intratumoral administra tion of chemotherapeutic agents in a novel drug delivery system. The e ffect of chemotherapeutic agents delivered in a sustained-release, pro tein-based, injectable gel was evaluated on the growth of human pancre atic adenocarcinoma cell line, BxPC-3, In vitro chemosensitivity of Bx PC-3 cells exposed for 24 or 72 h to fluorouracil (0.01-5 mM), cisplat in or doxorubicin (0.1-50 mu M) and floxuridine, vinblastine, mitomyci n or paclitaxel (1.0-100 mu M) was compared with that of untreated cel ls. In vitro chemosensitivity was also studied with fluorouracil and m itomycin in the poorly differentiated PANC-1, human pancreatic cancer cell line. Survival was determined after 7-10 days. All drugs decrease d cell growth in a dose-dependent fashion. The efficacy of fluorouraci l, cisplatin and doxorubicin increased with prolonged exposure, render ing these drugs most appropriate for a sustained-release preparation. For in vivo studies, athymic nude mice bearing BxPC-3 xenografts were treated either with fluorouracil, cisplatin or doxorubicin in the ther apeutic injectable gel containing epinephrine or with vehicle alone ad ministered intratumorally on days 1 and 4, After 28 days, the mice wer e sacrificed and tumors dissected and weighed. Tumors in mice treated with the injectable gel decreased in size by 72-79% compared with tumo rs in untreated controls and tumors treated with vehicle alone. Intrat umoral injection of drug solution and intraperitoneal injection of dru g in the injectable gel did not change tumor size compared with contro ls. In a drug-retention study, mice were injected intratumorally with [H-3]fluorouracil either in the injectable gel or in solution, Sustain ed radioactivity was observed in tumors injected with the gel, and, co nversely, greater radioactivity was detected In the liver and kidneys in mice receiving the radiolabeled solution. hese results suggest that the therapeutic injectable gel chemotherapy, when given intratumorall y, may improve tumor response with less systemic toxicity in compariso n with conventional systemic chemotherapy.