Attempts to improve locoregional chemotherapy for the prevention of colonic cancer liver metastasis in the rat.

AIM OF THE STUDY: To improve prophylactic local treatment of hepatic metastasis from colonic cancer cells in the rat. METHODS: The in vitro anticancer activity of 30 mn exposure to different drugs was first evaluated by dimethyl-thiazol-diphenyl-tetrazolium-bromide assay on confluent DHD/K12/PROb rat and HT29 human colonic cancer cells. Hepatic metastasis was induced by portal vein infusion of 12 x 106 PROb colonic cancer cells in syngenic BDIX rats. Hepatic and general tolerance to epirubicin was studied. Rats were treated with epirubicin delivered by either intravenous (IV), intraperitoneal (IP) or intraportal (Ipo) administration to compare their antitumoral effects. Hepatic distribution of epirubicin was assessed by fluorescence microscopy after IV, IP, Ipo, and combined administration. High pressure liquid chromatography was used to measure hepatic concentrations of epirubicin. RESULTS: Only pirarubicin was fully cytotoxic in vitro against the two types of tumor cells. No general or hepatic toxicity was observed. The preventive effect on hepatic metastasis was similar for IV, IP, and Ipo pirarubicin treatments. Hepatic pirarubicin concentrations obtained by Ipo administration were 4.1-fold higher than those obtained after IV administration (P=0.013). Three hours after IP and Ipo administration, hepatic remnants of pirarubicin were similar and significantly higher that those obtained after IV administration (P=0.074). Clamping the hepatic vein doubled hepatic pirarubicin concentrations after Ipo administration (P=0.048). Combined hepatic and intraportal administration was necessary to achieve diffuse, intense and homogeneous fluorescence throughout the entire liver. CONCLUSION: Homogeneous hepatic diffusion of pirarubicin was successfully achieved with combined hepatic vein and intraportal administration but systemic, intraperitoneal or intraportal administration had no preventive effect on hepatic metastasis. Other drugs could be tested using this approach to evaluate their efficacy and toxicity.

Rationale supporting the use of vasoconstrictors for intraperitoneal chemotherapy with platinum derivatives.

By decreasing drug drainage through the peritoneal and tumoral vascular networks, epinephrine increases the penetration of cisplatin and oxaliplatin into the metastatic peritoneal tumor nodules. This improved drug penetration increases their antitumor efficacy, allowing the cure of millimetric-sized peritoneal tumor nodules that could not be obtained with cisplatin or oxaliplatin used alone. However, limited drug diffusion into supramillimetric nodules did not result in curing advanced peritoneal carcinomatosis, unless complete resection of macroscopic localized tumor nodules is performed before intraperitoneal chemotherapy. In our opinion, the intraperitoneal epinephrine-cisplatin combination should be clinically assessed in completely or almost completely surgically resected peritoneal carcinomatosis with the objective of preventing recurrent tumors. Due to its reduced toxicity, repeated courses of intraperitoneal oxaliplatin associated with epinephrine could be an interesting alternative to cisplatin for the unresectable disease.

Prevention of peritoneal carcinomatosis from colon cancer cell seeding using a pirarubicin solution in rats and nude mice.

Free malignant cells, which are frequently detected in the washing liquid from the peritoneal cavity before and after resection of human colorectal cancer, are suspected to cause recurrent peritoneal cancer. We carried out an experimental study to compare the prophylactic efficacy of washing the peritoneum with several anticancer drugs and the antiseptic povidone-iodine against the development of peritoneal carcinomatosis from colonic origin in rats and nude mice. The in vitro anticancer activity of a short, 15-minute exposure of pirarubicin, doxorubicin, 5-fluorouracil, cisplatin, mitomycin C, and 1% povidone-iodine was first evaluated by an MTT assay on DHD/K12/PROb rat and LS174T human colon cancer cells. For the in vivo experiments, BDIX rats were inoculated intraperitoneally (i.p.) with 1 x 10(6) DHD/K12/PROb cells followed by peritoneal scarring and a colocolic anastomosis. A 15-minute peritoneal washing with the anticancer drugs or povidone-iodine was then performed. Nude mice were i.p.-inoculated with 1 x 10(7) LS174T human cells and treated 2 hours later with i.p. pirarubicin. Only pirarubicin, mitomycin C, and povidone-iodine were fully cytotoxic in vitro against DHD/K12/PROb rat colon cancer cells. In contrast to pirarubicin and povidone-iodine, mitomycin C was not completely active against LS174Tcells. In vivo, pirarubicin cured DHD/K12/PROb-inoculated rats, even at the site of the peritoneal scarring and intestinal anastomosis. i.p. pirarubicin prevented the development of peritoneal carcinomatosis and liver metastasis in LS174T-inoculated mice. i.p. washing with pirarubicin cured 2-day-old, but not 7-day-old, peritoneal carcinomatosis in rats. Short exposure to i.p. pirarubicin is nontoxic and more active than povidone-iodine and other anticancer drugs in preventing the development of peritoneal carcinomatosis from colonic origin in rats and mice. The prophylactic effect of preoperative peritoneal washing with pirarubicin on the development of recurrent peritoneal cancer should be evaluated in a randomized clinical trial.