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 pancreatic adenocarcinoma is markedly improved by the intratumoral administration of chemotherapeutic agents in a novel drug delivery system. The effect of chemotherapeutic agents delivered in a sustained-release, protein-based, injectable gel was evaluated on the growth of human pancreatic adenocarcinoma cell line, BxPC-3. In vitro chemosensitivity of BxPC-3 cells exposed for 24 or 72 h to fluorouracil (0.01-5 mM), cisplatin or doxorubicin (0.1-50 microM) and floxuridine, vinblastine, mitomycin or paclitaxel (1.0-100 microM) was compared with that of untreated cells. In vitro chemosensitivity was also studied with fluorouracil and mitomycin in the poorly differentiated PANC-1, human pancreatic cancer cell line. Survival was determined after 7-10 days. All drugs decreased cell growth in a dose-dependent fashion. The efficacy of fluorouracil, cisplatin and doxorubicin increased with prolonged exposure, rendering 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 therapeutic injectable gel containing epinephrine or with vehicle alone administered intratumorally on days 1 and 4. After 28 days, the mice were sacrificed and tumors dissected and weighed. Tumors in mice treated with the injectable gel decreased in size by 72-79% compared with tumors in untreated controls and tumors treated with vehicle alone. Intratumoral injection of drug solution and intraperitoneal injection of drug in the injectable gel did not change tumor size compared with controls. In a drug-retention study, mice were injected intratumorally with [3H]fluorouracil either in the injectable gel or in solution. Sustained radioactivity was observed in tumors injected with the gel, and, conversely, greater radioactivity was detected in the liver and kidneys in mice receiving the radiolabeled solution. These results suggest that the therapeutic injectable gel chemotherapy, when given intratumorally, may improve tumor response with less systemic toxicity in comparison with conventional systemic chemotherapy.
Smith
J P
JP
Department of Medicine, Pennsylvania State University, Hershey 17033, USA.
Stock
E
E
Orenberg
E K
EK
Yu
N Y
NY
Kanekal
S
S
Brown
D M
DM
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D003692:Delayed-Action Preparations; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000493:pharmacokinetics; D005782:Gels; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D003692:Delayed-Action Preparations; D005782:Gels; D005472:Fluorouracil