tirapazamine and Ovarian-Neoplasms

To estimate the anti-tumor activity, nature and degree of toxicity of tirapazamine in combination with cisplatin in patients with recurrent platinum-sensitive ovarian or primary peritoneal cancers.. Eligible consenting patients had to have recurrent epithelial ovarian or primary peritoneal carcinoma with measurable disease. Patients were not allowed to have received any additional cytotoxic chemotherapy for management of recurrent or persistent disease, including re-treatment with initial chemotherapy regimens. Patients must have been platinum-sensitive, meaning a treatment-free interval of >6 months after response to a platinum-based regimen. The RECIST criteria were used for parameters of response. Tirapazamine was administered at a dose of 390 mg/m2 IV over 2 h followed 1 h later by cisplatin 60 mg/m2 IV every 3 weeks until disease progression or adverse effects prohibited further therapy. RESULTS.: Between June 2001 and February 2004, 65 patients were entered onto this study by 27 institutions; one patient was excluded due to ineligible tumor type. Twenty-six patients (41%) received six or more cycles of therapy; however, 16 (25%) received one course of therapy (mainly due to side effects or patient request). There were six (9%) complete responders and 28 (44%) partial responders for a total response rate of 53%. Only two patients (3%) developed increasing disease on this protocol, and response could not be assessed in 18 patients (28%). The median progression-free and overall survival for all patients is 10.9 and 26.4 months, respectively. The regimen did not cause major hematologic toxicity, however, it did cause frequent constitutional (23%) and gastrointestinal (mostly nausea/vomiting) (44%) grade 3 or 4 toxicity.. The combination of tirapazamine and cisplatin has definite activity in the treatment of recurrent platinum-sensitive ovarian or primary peritoneal cancer. However, toxicity, primarily non-hematologic, was substantial. Reducing the toxicity of a tirapazamine-platinum combination should be pursued in future trials.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Synergism; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Peritoneal Neoplasms; Tirapazamine; Triazines

To study the inhibitory effect of tirapazamine (TPZ) combined with LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), on the growth of human ovarian carcinoma cells.. Human ovarian carcinoma cells of the line HO8910PM were cultured and treated with tirapazamine alone and treated with TPZ of different concentrations combined with LY294002 of the concentration of 50 micromol/L respectively under aerobic and hypoxic conditions. And human ovarian carcinoma cells of the line OVCAR-3 were cultured and treated with YPZ alone and treated with TPZ of different concentrations combined with LY294002 of the concentration of 25 micromol/L respectively under aerobic and hypoxic conditions. MTT method was used to detect the surviving fractions of these carcinoma cells.. The IC(50) values of TPZ on the HO8910PM cells under hypoxic condition was 40.6 micromol/L, significantly lower than that under aerobic condition (53.0 micromol/L, P < 0.01). The IC(50) values of TPZ on the OVCAR-3 cells under hypoxic condition was 65.9 micromol/L, significantly lower than that under aerobic condition (97.4 micromol/L, P < 0.01). The IC(50) value of TPZ combined with LY294002 on the HP8910PM cells under hypoxic condition was 22.7 micromol/L, significantly lower than that under aerobic condition (31.5 micromol/L, P < 0.01). The IC(50) value of TPZ combined with LY294002 on the OVCAR-3 cells under hypoxic condition was 49.1 micromol/L, not significantly different from that under aerobic condition (51.0 micromol/L, P > 0.05).. TPZ inhibits the growth of human ovarian carcinoma cells. The inhibitory effects of TPZ on the growth of human ovarian carcinoma cell of the lines HO8910PM and OVCAR-3 under hypoxic conditions are significantly higher than those under aerobic condition1. LY294002 increases the inhibitory effect of TPZ on the ovarian cancer cells, compared with TPZ treatment alone, TPZ combined with LY294002 decreases the IC(50) of HO8910PM and OVCAR-3 cells significantly.

Topics: Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Chromones; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Female; Humans; Inhibitory Concentration 50; Morpholines; Ovarian Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Tirapazamine; Triazines