homocamptothecin and Disease-Models--Animal

Studies have demonstrated that hydroxycamptothecin (HCPT) had therapeutic effect on many malignant tumors, but few studies on oral squamous cell carcinoma were reported. This study was designed to investigate the anticancer effect and mechanism of hydroxycampothecin (HCPT) on oral squamous carcinoma cell line (Tca8113).. The cytotoxicity of HCPT on Tca8113 cell line was measured by MTT assay and cell cycle detected by flow cytometry(FCM). The growth status of Tca8113 cell xenografts following treatment with HCPT was observed. The doubling times and tumor inhibition rate were calculated.. HCPT had strong cytotoxicity on Tca8113 cells, the IC50 was 2 mumol/L. After treatment with low concentration of HCPT, the cell cycle was arrested in S phase or G2 + M phase; while at high concentration, apoptosis was obviously found and the rate of apoptosis was increased as the time and concentration of HCPT. Compared with control group, the xenografts of HCPT treated group grew slower and tumor doubling time was prolonged, The tumor volumes of HCPT treated group at 28th day were significantly smaller(P < 0.001) with tumor inhibition rate of 69.6%.. The result showed that HCPT had strong cytotoxicity effect to oral squamous carcinoma cells and significant growth inhibition on Tca8113 xenografts. HCPT can arrest cell cycle in S phase and G2 + M phase and induce cell apoptosis.

Topics: Animals; Antineoplastic Agents; Apoptosis; Camptothecin; Carcinoma, Squamous Cell; Cell Cycle; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Inbred BALB C; Mouth Neoplasms; Neoplasm Transplantation; Neoplasms, Experimental; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Homocamptothecin (hCPT) is a semisynthetic analogue of camptothecin (CPT) with a seven-membered beta-hydroxylactone resulting from the insertion of a methylene spacer between the alcohol moiety and the carboxyl function of the naturally occurring six-membered alpha-hydroxylactone of CPT. This E-ring modification provides a less reactive lactone with enhanced stability and decreased protein binding in human plasma. Biological testing against CPT revealed that, instead of being detrimental, the modified lactone of hCPT has a positive impact on topoisomerase I (Topo I) poisoning properties. In vitro tests showed hCPT to fully conserve the ability to stabilize Topo I-DNA cleavage complexes and to stimulate a higher level of DNA cleavage than CPT. A similar trend toward improvement was also observed in antiproliferative assays with human tumor cell lines (including cells overexpressing P-glycoprotein). In two distinct in vivo models, using L1210 murine leukemia or human colon carcinoma HT29, hCPT was found to be more efficacious than CPT. The slow, but irreversible, hydrolysis of hCPT, instead of the fast equilibrium of CPT, may account for its good in vivo activity. Overall, these results provide evidence that a highly reactive lactone is not a requisite for the Topo I-mediated antitumor activity of CPT analogues, and that hCPT is an interesting pharmacological tool with improved solution behavior as well as a promising new template for the preparation of more efficacious Topo I poisons.

Topics: Animals; Antineoplastic Agents; Camptothecin; Cell Division; Disease Models, Animal; DNA; Drug Screening Assays, Antitumor; Drug Stability; Enzyme Inhibitors; HT29 Cells; Humans; K562 Cells; Lactones; Leukemia L1210; Leukemia, Experimental; Neoplasm Transplantation; Topoisomerase I Inhibitors; Transplantation, Heterologous; Tumor Cells, Cultured