ABSTRACT
Background: The benefits of achieving better response by adding tirapazamine, a specific hypoxic cancer cell killer to chemo and or radiotherapy is contradictory. This study aims at analyzing the efficacy and safety of tirapazamine, apart from understanding the reasons for its doubtful and inconsistent benefits.Methods: Electronic database search in PUBMED, EMBASE, Cochrane library was conducted using search term 搕irapazamine�. Randomized or cross-over studies comparing effects of tirapazamine vs other active treatment or placebo in patients >18yrs with any type of cancers were included under analysis. Overall Survival rate was the primary outcome measure while the incidences of grade-3 and 4 adverse drug reactions were the secondary outcome measure. Inverse variance method and both random and fixed effect models were used in the analysis by RevMan 5.3 software.Results: Total six studies were eligible with 1034 patients included in the analysis. Tirapazamine failed to show significant effect on overall survival rate at the end of one year (HR: 0.96, 95% CI: 0.88, 1.05), two year (HR: 1.04, 95% CI: 0.98, 1.12), three year (HR: 1.01, 95% CI: 0.89, 1.15) and five year (HR: 0.97, 95% CI: 0.77, 1.23) compared to placebo group. There was a significantly higher incidence of muscle cramps (Risk Difference, RD: 0.06, 95% CI: 0.02, 0.11) and dermal adverse events (RD: 0.03, 95% CI: 0.01, 0.06) in tirapazamine group.Conclusions: With the available evidences from clinical trials and preclinical studies, use of tirapazamine may not be justifiable and so is to side line this drug as another failed drug.
ABSTRACT
To synthesize 3-nicotinamide-1, 2, 4-benzotriazine-1, 4-dioxide and to determine its anti-tumor activity in vitro. METHODS: Cyanogenamide and benzofuroxan were used as starting materials to prepare the intermediate (3-amino-1, 2, 4-benzotriazine-1, 4-dioxide, Tirapazamine). The objective substance was obtained from the reaction of the intermediate and nicotinic acyl chloride. The in vitro antitumor activities of the synthesized compounds were determined by MTT method using MCF-7 and HepG2 cells. RESULTS: The obtained compounds were identified by 1H-NMR, MS and IR. The purity of the objective substance determined by HPLC was 99.24%. CONCLUSION: The anti-tumor activity of 3-nicotinamide-1, 2, 4-benzotriazine-1, 4-dioxide is much better than tirapazamine. Copyright 2012 by the Chinese Pharmaceutical Association.
ABSTRACT
PURPOSE: Tumor hypoxia can be overcome with hypoxic cytotoxin. In mouse tumor, tirapazamine's efficacy of the potentiating radiation effect was tested by the tumor oxygenation status combined with hyperfactionated radiotherapy. MATERIALS AND METHODS: The control and hypoxic mouse tumors were established by inoculation of RIF-1 tumor cells into the normal or previously irradiated back and thigh of C3H mice. When the tumors reached a proper size, both the control and hypoxic tumors were given hyperfractionated treatments (8 fractions/4 days) with saline (0.02 ml/g), tirapazamin (0.08 mM/0.02 ml/kg), irradiation (2.5 Gy), irradiation combined with tirapazamine given 30 minutes prior to each irradiation. The response was evaluated by the growth delay assay by measuring tumor size from day 0 (12 hrs prior to the first fractionation) to the day when the volume had 4-fold increase or cross sectional area had 2-fold increase. RESULTS: Overall growth pattern showed that tirapazamine potentiated radiation effect in back and thigh tumors grew in the normal and preirradiated tumor bed. With growth delay assay using reference point of initial tumor volume or cross sectional area, tirapazamine potentiated radiation effect 1.9 times for the control and 2.4 times for the hypoxic tumors in back, and 1.85 times for the control and 1.6 times for the hypoxic tumors. With reference of 4-fold increase of the initial volume or 2-fold increase of the cross sectional area, tirapazamine potentiated radiation effect 1.48 times for the control and 2.02 times for the hypxic tumors in back, and 1.85 times for the control and 1.6 times for the hypoxic tumors. CONCLUSION: Present result indicated that radiation response of hypoxic tumors was potentiated by tirapazamine in the back or thigh tumors grew in the control or preirradiated tumor bed, and potentiation of the hypoxic tumors was equal to or greater than that of the control tumors in the back or thigh.
Subject(s)
Animals , Mice , Hypoxia , Mice, Inbred C3H , Oxygen , Radiation Effects , Radiotherapy , Thigh , Tumor BurdenABSTRACT
Hypothesis that hypoxic tumors should be more responsive to the addition of preferential hypoxic cell cytotoxin SR 4233 (tirapazamine) to fractionated irradiation was tested in the mouse SCCVII carcinoma and RIF-1 sarcoma, Model of hypoxic tumor was established using the tumor bed effect; tumors growing in the preirradiated tissue (preirradiated tumors) were more hypoxic than tumors growing in the unirradiated tissue (unirradiated tumors). When the tumors reached a mean volume of 100 mmdegree, both unirradiated and preirradiated tumors were treated with a fractionated course of 62 Gy in 3 days or 8 2.5 Gy in 4days with SR 4233 (0.08 mmlo/kg/injuection) given 30 minutes before each irradiation or without SR 4233. Compared to the unirradiated tumors, hypoxic preirradiated tumors were approximately 5 times more resistant to fractionated irradiation alone but were approximately 5 times more responsive to SR 4233. Addition of SR 4233 potentiated the effect of fractionated irradiation in both unirradiated and preirradiated tumors. Potentiation in the preirradiated tumors was morequal to or greater than that in the unirradiated tumors and seemed to be higher for more fractionated treatment. We confirm the hypothesis in a transplantable mouse tumor. Present results suggest that radioresistance of some hypoxic tumors can be overcome with hypoxic cytotoxin.