Antitumor activity of XSJ81, a 20-sulfonated camptothecin derivative, targeting topoisomerase I against ampullary carcinoma.

Ampullary carcinoma (AC) lacks effective chemotherapy drugs in clinic. Camptothecin (CPT) and its derivatives are widely used as chemotherapy drugs in clinic. As their application is limited by systemic toxicity, structural modification of CPT to improve its efficacy has become an effective and robust method. In order to obtain highly active CPT derivatives, a new CPT sulfonated derivative XSJ81 was designed, synthesized and evaluated in this study. The efficacy and safety of inhibiting the proliferation of AC cells were evaluated by in vitro and in vivo experiments. In vitro, XSJ81 significantly inhibited the proliferation of AC cells (IC = 0.655 ± 0.036 μM) compared with the positive drug 5-Fluorideuracil (5-FU). In vivo, XSJ81 showed stronger antitumor activity than 5-FU in the nude mouse model of AC. Acute toxicity studies demonstrated that administration of XSJ81 at an elevated dosage (100 mg/kg) failed to induce notable body weight reduction. In addition, at therapeutic doses, XSJ81 had no obvious toxic effect on major organs of mice. On the mechanism, XSJ81 inhibited AC cell proliferation by inhibiting topoisomerase I (Topo I) activity, causing DNA damage, hindering cell cycle to G2/M phase and inducing early apoptosis. In summary, the study results showed that XSJ81 has significant anti-tumor activity and good safety, and has clinical application potential.