Disease relevance of SR 4233

• Moreover, the in vivo administration of the hypoxic cytotoxic agent tirapazamine exhibited selective toxicity to the primitive stem cell subset [1].
• Tirapazamine (TPZ) is a bioreductive agent that forms a toxic-free radical in hypoxia [2].
• The addition of hyperthermia to treatment with SR-4233 increased the killing of dim cells by about 5-fold but of bright cells by only 2-fold [3].
• Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003 [4].
• Stably transfected clones of MDA231 human breast cancer cells overexpressing human CYPRED immunoreactive protein and catalytic activity showed enhanced sensitivity to the aerobic cytotoxicity of tirapazamine, a bioreductive drug known to be activated by CYPRED; however, no sensitization to the cytotoxic effects of doxorubicin was observed [5].
• Whereas RT delayed tumor growth regardless of the level of hypoxia, an additive beneficial therapeutic effect of tirapazamine to RT was observed only in hypoxic tumors (aGD, 12.9 d) but not in normoxic tumors (aGD, 6.0 d) [6].

High impact information on SR 4233

• Combination of LDM cyclophosphamide with tirapazamine results in significantly improved tumor control in the PC-3, HT-29 colon adenocarcinoma, and MDA-MB-231 breast cancer human xenograft models without having a negative effect on the favorable toxicity profile of LDM cyclophosphamide [7].
• However, hypoxia can also be exploited therapeutically through the use of hypoxic cell cytotoxins, such as tirapazamine [7].
• Frozen sections of tumors confirmed the greater intensity of gammaH2AX staining in cells close to blood vessels of tumors soon after treatment with etoposide and the opposite pattern for tumors exposed to tirapazamine [8].
• Antagonism of buthionine sulfoximine cytotoxicity for human neuroblastoma cell lines by hypoxia is reversed by the bioreductive agent tirapazamine [2].
• PATIENTS AND METHODS: The starting schedule was conventionally fractionated radiotherapy (70 Gy in 7 weeks) with concomitant cisplatin 75 mg/m2 and tirapazamine 290 mg/m2 (before cisplatin) in weeks 1, 4, and 7 and tirapazamine alone 160 mg/m2 three times a week in weeks 2, 3, 5, and 6 [9].

Chemical compound and disease context of SR 4233

• PURPOSE: A phase II study was conducted to evaluate the safety and efficacy of tirapazamine combined with cisplatin for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) [10].
• Synergistic interaction between tirapazamine and cyclophosphamide in human breast cancer xenografts [11].
• Under identical circumstances, there was no effect of the hypoxic cell radiosensitizer SR 2508, showing that SR 4233 with intermittent hypoxia was superior to a protocol which sensitized the hypoxic cells to doses of 2.5 Gy per fraction [12].
• The dose enhancement ratios for SR 4233 and RSU 1069 were 8.8 and 8.5, respectively, showing that these agents had an equivalent and substantial enhancement of their cytotoxicity when combined with hypobaric hypoxia [13].
• The contribution of H2O2 to the observed aerobic cytotoxicity of SR-4233 is minimal however, since toxicity is only slightly reduced in the presence of exogenous catalase and antioxidants such as vitamin E. The level of PC stimulation by SR-4233 suggests that the rate of electron addition to the drug is independent of O2 concentration [14].

Biological context of SR 4233

• Tirapazamine-induced cytotoxicity and DNA damage in transplanted tumors: relationship to tumor hypoxia [15].
• Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2 [16].
• The proportion of comets with tail moments </= 20 (i.e., with damage comparable to that produced by about 10 Gy) correlated with cell survival irrespective of cell type, dose of tirapazamine, time of treatment, or position of cell in the spheroid [17].
• SR 4233 produced lower initial but similar final (after 6 h of repair) numbers of chromosome breaks compared to gamma-rays at equitoxic doses [18].
• Using the technique of pulsed field gel electrophoresis, we found that the kinetics of rejoining of DNA double-strand breaks in CHO cells after treatment with SR 4233 was concentration dependent, varying from 95% (less than 50 microM) to 10% (200 microM) by 24 h [18].

Anatomical context of SR 4233

• We investigated the toxicity of SR 4233 in primary cultures of hepatocytes under various oxygen tensions, ranging from 1% to 20% oxygen [19].
• XR-1 cells were 2-fold more sensitive than wild-type CHO cells to SR 4233 but were 10-fold more sensitive than CHO to gamma-rays [18].
• These forms contributed at least 53% and 26%, respectively, of the cytochrome P450-associated SR 4233 reductase activity in the induced microsomes [20].
• Electron paramagnetic resonance (EPR) spectrometry was used to investigate directly the formation of free radicals as the result of tirapazamine reduction by NADPH-supplemented liver microsomes [21].
• SR 4233 reduction was also catalysed by mouse liver cytosol under N2 [22].

Associations of SR 4233 with other chemical compounds

• The combination of tirapazamine, cisplatin, and radiotherapy resulted in remarkably good and durable clinical responses in patients with very advanced head and neck cancers [9].
• Using this concept of a "threshold" for DNA damage, cell survival could be predicted for exposure to 4NQO, tirapazamine, nitrogen mustard, RSU 1069, and actinomycin D and was largely independent of cell type [23].
• CONCLUSION: Dose levels 3 (carboplatin AUC of 6, 225 mg/m(2) paclitaxel, and 330 mg/m(2) tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m(2) paclitaxel, and 260 mg/m(2) tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively [24].
• A lower degree of potentiation was seen with the clinically used agent mitomycin C (6- to 7-fold) and the EO9 analogs, EO7 and EO2, that are poorer substrates for DT-diaphorase (5- to 8-fold and 2- to 3-fold potentiation, respectively), and there was no potentiation or protection with menadione and tirapazamine [25].
• Using a high-speed micellar electrokinetic chromatography (MEKC) separation, resolution of the investigational antineoplastic SR 4233 from its main metabolite SR 4317 was achieved in less than 60 s [26].

Gene context of SR 4233

• No inhibition of SR 4233 reduction was seen with erythromycin or cyclosporin A which act as substrates/inhibitors for Cyp3a-type enzymes, but inhibition was seen with p-nitrophenol and tolbutamide which are substrates for Cyp2el- and Cyp2c-type enzymes, respectively (11% and 25% inhibition in induced microsomes) [20].
• Our preliminary study has also shown that a hypoxic cytotoxin, tirapazamine, increases ER expression in breast cancer xenografts [27].
• Tirapazamine cytotoxicity for neuroblastoma is p53 dependent [28].
• The survival of phi X174 was evaluated as an index of drug damage and from this we conclude that SR 4233 induces pH-dependent DNA damage in E coli, which is recognized and repaired primarily by the uvrC gene product and by the exonuclease III and endonuclease III gene products [29].
• The molecular basis and mechanisms of action of combining classic cytotoxic agents (e.g. platinum-containing drugs, taxanes, etc.) and novel agents (e.g. tirapazamine, EGFR inhibitors and other targeted agents) with radiotherapy will be examined [30].

Analytical, diagnostic and therapeutic context of SR 4233

• The data suggest that SR 4233 has considerable promise as an adjunct to standard radiotherapy [31].
• Because tirapazamine is currently undergoing clinical trials, application of this procedure could provide an early indicator of tumors likely to contain hypoxic, susceptible cells and also the extent of the response [17].
• Use of the comet assay to identify cells sensitive to tirapazamine in multicell spheroids and tumors in mice [17].
• Tirapazamine (SR 4233), a benzotriazine di-N-oxide, a potent and selective killer of hypoxic cells, is currently in Phase I clinical trials with the expectation that it will be combined with radiation therapy [32].
• Tirapazamine (TPZ) is a hypoxia-selective bioreductive drug currently in Phases II and III clinical trials with both radiotherapy and chemotherapy [15].

References