[Antitumor effects of ring-closed and ring-opened hydroxycamptothecin on oral squamous carcinoma cell line Tca8113]

Abstract

Background & objective: The antitumor effect of hydroxycamptothecin (HCPT) closely relates with its lactone form (including ring-closed form and ring-opened form), but the antitumor effects of ring-closed HCPT (C-HCPT) and ring-opened HCPT (O-HCPT) remain controversial. Researches have showed that O-HCPT has obvious in vitro and in vivo antitumor effects on oral squamous cell carcinoma. This study was to compare the antitumor effects of C-HCPT and O-HCPT on oral squamous carcinoma cell line Tca8113, and explore the mechanisms.

Methods: Tca8113 cells and its xenografts in BALB/C nude mice were treated with C-HCPT and O-HCPT. The cytotoxicity of HCPT was measured by MTT assay. Cell cycle was detected by flow cytometry. The growth state of Tca8113 cells xenografts was observedû the tumor doubling time and inhibition rate were calculated. The concentration of total HCPT in plasma and tumor tissue was quantitated by high-performance liquid chromatography (HPLC); the pharmacokinetic parameters were estimated.

Results: C-HCPT and O-HCPT showed similar cytotoxicity effects on Tca8113 cells in vitro. Low concentration of HCPT (< 1 micromol/L) arrested cell cycle of Tca8113 cells at S phase and G(2)/M phase; high concentration of HCPT (100 micromol/L) obviously induced apoptosis of Tca8113 cells. Compared with control group, the xenografts of HCPT-treated group grew slowly, and the tumor doubling time was prolonged. The tumor inhibition rates were 69.6% (3 mg/kg of O-HCPT), 65.0% (3 mg/kg of C-HCPT), and 74.1% (10 mg/kg of O-HCPT), respectively. The plasma AUC was 2.66 microg . h . ml(-1) for C-HCPT (10 mg/kg) and 0.42 microg . h . ml(-1) for O-HCPT (10 mg/kg). HCPT could be detected in tumor tissue. No obvious toxicity was observed in 3 mg/kg of HCPT group; obvious gastrointestinal reaction was observed in 10 mg/kg of O-HCPT group; all nude mice in 10 mg/kg of C-HCPT group died 2 days after treatment.

Conclusions: Both C-HCPT and O-HCPT have strong in vitro and in vivo cytotoxic effects on Tca8113 cells, which relate to cell cycle arrest and cell apoptosis inducement. Cytotoxicity of C-HCPT is more severe than that of O-HCPT.