C26 Tumor-bearing Mice Research Articles

Polymeric prodrugs of 5-fluorouracil

Polymeric conjugates of 5-fluorouracil (5-FU) were designed to selectively generate the free drug under the action of enzymes occurring near or at the tumor site. Oligopeptide chains, having a 2-(5-fluorouracil-1-yl)glycine ethyl ester residue at the C-terminus, were covalently attached to poly(ethylene glycol) (PEG), dextran and poly[ N 5-(2-hydroxyethyl)- l-glutamine]. Their hydrolytic stability was examined in buffer solutions, calf serum, in the presence of tumor-associated enzymes or a mixture of liver lysosomal enzymes. The conjugates were stable in buffer solutions and serum, but collagenase type IV, cathepsin B and tritosomes cleaved the oligopeptide chains releasing free 5-FU and/or its peptide derivatives. The in vitro cytotoxicity of conjugates was evaluated against C26 colorectal carcinoma cells. All conjugates were less cytotoxic than free 5-FU, due to the slow release of the active drug in the culture medium. The highest cytotoxicity was displayed by the conjugates P-Gly-Phe-Gly-Gly(OEt) ( l, d) and was higher for P=dextran than for P=PEG. The cytotoxic efficacy of i.p. administered PEG-Gly-Phe-Gly-Gly(FU)OEt ( l, d) to C26 tumor-bearing mice was studied by monitoring the survival time, the body weight and the number of long-term survivors. The conjugate caused no acute toxicity, increased the survival time compared to the control (T/C=158%) and produced a long-term survivor.

頭頚部癌に対する局所免疫化学療法の基礎的研究

The mechanism of induction of antitumor activity by local administration of recombinant interleukin-2 (rIL-2) combined with cisplatin (CDDP) was investigated in order to establish a method of immunochemotherapy against head and neck cancer. Local administration of rIL-2 had significantly greater inhibitory effects on tumor growth in both Meth A and C26 tumor bearing mice than did systemic administration. The cytotoxic activity of tumor infiltrating lymphocytes (TILs) obtained from C26 tumor bearing mice was studied. Local injection of rIL-2 around the tumor site for 4 days induced augmentation of the cytotoxicity of TILs not only in NK sensitive tumors but also in NK resistant C26 tumors. This phenomenon was not observed in spleen cells. Both negative selection assay and cold target inhibition assay revealed that the effector cells were tumor nonspecific asialoGM1 positive activated NK cells. Additional experiments were performed to determine the effectiveness of combined immunochemotherapy using CDDP and rIL-2 in C26 tumor bearing mice. The intraperitoneal administration of CDDP following the local administration of rIL-2 was more effective in suppressing tumor growth and in promoting well-survival than the use of CDDP or rIL-2 alone. To investigate the mechanism of antitumor activity, the effects of CDDP on the tumor cells and immunological changes were observed in tumor bearing mice. The susceptibility of tumor cells to effector cells was enhanced after in vitro culture with CDDP. In vivo administration of CDDP augmented the cytotoxic activity of effector cells and responsiveness to IL-2 of TIL. These results suggest that local immunochemotherapy using locally administered rIL-2 combined with CDDP may be available as a therapy for head and neck cancers.