tirapazamine and Glioblastoma

This phase II study tested the efficacy and safety of tirapazamine (Sanofi Synthelabo Research, Malvern, PA), a bioreductive agent, in glioblastoma multiforme (GBM) patients. The patients were staged according to a model constructed by a recursive partitioning analysis (RPA) of glioma patients in prior Radiation Therapy Oncology Group (RTOG) trials and compared with a matched standard population, as predicted by the model.. A total of 124 patients diagnosed with a GBM were treated with radiation therapy and intravenous tirapazamine between January 27,1995, and April 25,1997. All patients received 60 Gy in 2-Gy fractions. Tirapazamine was delivered three times a week for 12 treatments during radiotherapy. Fifty-five patients received tirapazamine at 159 mg/m(2). A second dose level, 260 mg/m(2), was opened, and 69 patients were entered.. There was no significant survival advantage to the drug in any RPA class at either dose level. The median survival time was 10.8 months for the patient population treated with the 159-mg/m(2) dose of tirapazamine and 9.5 months for the group treated with the 260-mg/m (2) dose of tirapazamine. Survival times by RPA class for patients receiving tirapazamine at 159 mg/m(2) were 27.4 months (class III), 10.8 months (class IV), 7.9 months (class V), and 3.8 months (class VI). Survival times by RPA class for patients receiving tirapazamine at 260 mg/m(2) were 16.2 months (class III), 10.3 months (class IV), 5. 1 months (class V), and 1.3 months (class VI). Patients in RPA class III treated in the 159 mg/m(2) dose arm had a notably longer survival than patients in the RTOG database RPA class III, but the difference did not reach statistical significance. There were no fatal toxicities. Grade 3/4 toxicities were more frequent at the higher dose level.. Survival in the population treated with radiation and tirapazamine was equivalent to the control population. Patients in RPA class III treated with radiation and tirapazamine at the 159-mg/m(2) dose had a longer survival when compared with the historical controls. The improvement in survival did not reach statistical significance. Toxicity was acceptable in both treatment arms, but grade 3/4 toxicities were more frequent in the higher dose regimen.

Topics: Adult; Aged; Antineoplastic Agents; Combined Modality Therapy; Female; Glioblastoma; Humans; Infusions, Intravenous; Male; Middle Aged; Radiation-Sensitizing Agents; Radiotherapy, High-Energy; Survival Analysis; Tirapazamine; Triazines

The purpose of this study was to investigate the feasibility and the efficacy of administering tirapazamine by a slow-releasing polymer disc that was implanted interstitially into a U251 (human glioblastoma multiforme) tumor grown in nude mice. Tumor-bearing animals, with a tumor nodule 0.8 cm3 in size, were distributed to groups receiving combinations of empty or drug-containing polymer implants in the tumor or contralateral leg, intraperitoneal (i.p.) drug, and/or irradiation. The drug (i.p.) alone (14 mg/kg x6) or in combination with tumor drug implant (2 mg) did not significantly increase the tumor volume doubling time compared to that of control animals. Given with 12 Gy of irradiation in twice a day 2-Gy fractions, combined i.p. drug and tumor drug implant significantly delayed tumor growth compared to irradiation alone, which was not achieved with either drug treatment alone added to irradiation. Toxicity, as manifested by transient weight loss, was primarily seen in animals receiving radiation and i.p. tirapazamine. These results indicated that a slow-releasing tirapazamine disc can be produced and the addition of an interstitially implanted tirapazamine disc further increased the effectiveness of i.p. tirapazamine.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Glioblastoma; Humans; Male; Mice; Mice, Nude; Radiation Tolerance; Radiation-Sensitizing Agents; Tirapazamine; Triazines

To measure the oxygen status of human malignant brain tumors in vivo and to determine the activities and expression of bioreductive enzymes in these same human brain tumor samples, as a means of assessing their suitability as targets for bioreductive drug therapy.. A polarographic oxygen electrode was used to measure the intratumoral oxygen tension in twenty patients with malignant brain tumors during open brain surgery, performed under standard anaesthetic conditions. Six different tracks, each with a path length of 22 mm, were recorded per patient representing 192 readings. Following pO2 measurements the tumors were resected and stored in liquid N2 for subsequent bioreductive enzyme analysis. Eight human malignant brain tumors were assessed, by enzyme activity and western blot expression, for the presence of various bioreductive enzymes. These enzymes included DT-diaphorase, NADH cytochrome b5 reductase, and NADPH cytochrome P-450 reductase. Of these eight gliomas analyzed six samples were incubated with the bioreductive drug tirapazamine, in the presence of cofactor(s), to establish whether human brain tumors could metabolize this compound.. Both the high grade intrinsic and metastatic brain tumors showed significant regions of hypoxia. All the tumors subjected to enzyme profiling contained the bioreductive enzymes, DT-diaphorase, NADH cytochrome b5 reductase and NADPH cytochrome P-450 reductase. Also all six of the brain tumors investigated could metabolize tirapazamine to the two-electron reduction product.. These findings would favor primary brain tumors as suitable targets for bioreductive therapy.

Topics: Brain Neoplasms; Cell Hypoxia; Cytochrome Reductases; Cytochrome-B(5) Reductase; Glioblastoma; Humans; NAD(P)H Dehydrogenase (Quinone); NADPH-Ferrihemoprotein Reductase; Oxidation-Reduction; Oxygen; Partial Pressure; Tirapazamine; Triazines