8 Extraordinary tumor control in phase I trial of concurrent tirapazamine cisplatin and radiotherapy for far advanced head and neck cancer

Peters, L.J.; Rischin, Danny; Hicks, Richard J.; Hughes, Peter; Sizeland, Andrew

doi:10.1016/s0360-3016(99)90026-3

Cited by 12 publications

(14 citation statements)

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“…Melting points were determined on an Electrothermal 2300 melting point apparatus. NMR spectra were obtained on a Bruker Avance 400 spectrometer at 400 MHz for 1 H and 100 MHz for 13 C spectra. Spectra were obtained in CDCl3, unless otherwise specified, and are referenced to Me4Si.…”

Section: Methodsmentioning

confidence: 99%

“…A solution of chloride 17 (3.0 g, 16.5 mmol) in DCM (50 mL) was added to a stirred solution of 2-(aminoethoxy)ethanol (28) (2.49 mL, 24.8 mmol) and Et3N (3.45 mL, 24.8 mmol) in DCM (80 mL) and the solution stirred at 20 °C for 16 h. The solvent was evaporated and the residue purified by chromatography, eluting with 40% EtOAc/DCM, to give 1-oxide 29 (2.62 g, 63%) as a yellow powder: mp (DCM/EtOAc) 131-131.5 °C; 1 H NMR δ 8.25 (dd, J ) 8.7, 1.2 Hz, 1 H, H-8), 7.68 (ddd, J ) 8.4, 7.2, 1.5 Hz, 1 H, H-6), 7.57 (d, J ) 8.4 Hz, 1 H, H-5), 7.28 (ddd, J ) 8.7, 7.2, 1.3 Hz, 1 H, H-7), 6.02 (br s, 1 H, NH), 3.74-3.80 (m, 6 H, 3 × CH2O), 3.64-3.67 (m, 2 H, CH2N), 2.71 (t, J ) 5.9 Hz, 1 H, OH); 13 C NMR δ 158.9, 149.7, 135.5, 130.9, 126.4, 124.9, 120.4, 72.4, 69.5, 61.7, 41.9. Anal.…”

Section: N-(2-{2-[(14-dioxido-124-benzotriazin-3-yl)amino]-ethoxy}eth...mentioning

confidence: 99%

“…A solution of MCPBA (1.57 g, 6.4 mmol) in DCM (50 mL) was added dropwise to a stirred solution of carbamate 31 (1.85 g, 5.3 mmol) in DCM (100 mL) and NaHCO3 (0.89 g, 10.6 mmol), and the mixture was stirred at 20 °C for 6 h. The suspension was filtered through Celite, the solvent evaporated, and the residue purified by chromatography, eluting with a gradient (0-5%) of MeOH/(40-0%) EtOAc/DCM, to give (i) starting material 31 (926 mg, 50%) and (ii) 1,4-dioxide 32 (702 mg, 40%) as a red solid: mp (EtOAc) 139-140 °C; 1 13 C NMR δ 156.0, 149.8, 138.5, 135.9, 130.6, 129. 5, 121.6, 117.4, 79.4, 70.3, 68.9, 41.3, 40.3, 28.3 (3); MS m/z 366 (MH + , 40%), 350 ( 5) 310 (20); HRMS calcd for C16H24N5O5 (MH + ) m/z 366.1777, found 366.1767.…”

Section: -{[2-(2-tert-butyloxycarbamoylethoxy)ethyl]amino}-124-benzot...mentioning

confidence: 99%

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DNA-Targeted 1,2,4-Benzotriazine 1,4-Dioxides: Potent Analogues of the Hypoxia-Selective Cytotoxin Tirapazamine

et al. 2003

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Tirapazamine (TPZ, 1,2,4-benzotriazin-3-amine 1,4-dioxide) is a bioreductive hypoxia-selective cytotoxin, currently in phase II/III clinical trials in combination with radiotherapy and with cisplatin-based chemotherapy. We have prepared a series of 1,2,4-benzotriazine 1,4-dioxide (BTO) analogues of TPZ where a DNA-targeting chromophore is attached at the 3-position via a flexible linker. DNA binding affinity was modified through variation of the chromophore or the pK(a) of the linker chain. The association constants (K(DNA)) for calf thymus DNA ranged from 1 x 10(2) to 5.6 x 10(5) M(-1) (ionic strength of 0.01 M). DNA binding affinity was dependent on the presence of a positive charge, either in the linker chain or in the chromophore, and (for a series of 4-acridine carboxamide chromophore analogues) correlated strongly with linker chain pK(a). The efficacy of these BTOs in killing aerobic and hypoxic mouse SCCVII tumor cells in vitro was determined by clonogenic survival. Cytotoxicity was measured as the concentration required to reduce plating efficiency to 10% of controls (C(10)), and the hypoxic cytotoxicity ratio (HCR) for each BTO was calculated as C(10)(aerobic)/C(10)(hypoxic). BTOs bearing a positive charge showed increased hypoxic cytotoxicity (1.5-56-fold) compared to TPZ and mostly modest HCRs (8-51), but some excellent (>167 and 400) values. There was a strong correlation between K(DNA) and hypoxic cytotoxicity but no correlation between K(DNA) and HCR. Cytotoxicity in HT-29 human colon carcinoma cells, determined using IC(50) assays, showed similar relationships with a correlation between K(DNA) and hypoxic cytotoxicity but no correlation between K(DNA) and HCR. In this cell line, a higher proportion of compounds (7 of 11) had HCRs greater than or equal to that of TPZ. The data confirm that DNA targeting is a useful concept for increasing potency while maintaining hypoxic selectivity and provide a direction for the further development of DNA-targeted analogues of TPZ.

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Section: Methodsmentioning

confidence: 99%

Section: N-(2-{2-[(14-dioxido-124-benzotriazin-3-yl)amino]-ethoxy}eth...mentioning

confidence: 99%

Section: -{[2-(2-tert-butyloxycarbamoylethoxy)ethyl]amino}-124-benzot...mentioning

confidence: 99%

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DNA-Targeted 1,2,4-Benzotriazine 1,4-Dioxides: Potent Analogues of the Hypoxia-Selective Cytotoxin Tirapazamine

et al. 2003

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“…In a phase I study, concurrent tirapazamine, cisplatin, and radiation therapy was associated with a higher-than-expected locoregional control rate in patients with stage IV head and neck cancer [94]. After a median follow-up of 21 months, 10 of the 16 treated patients were alive without locoregional disease, and an additional four patients were alive with either locoregional recurrence or only distant metastases [94]. The combination of tirapazamine plus cisplatin-based chemotherapy is being evaluated through phase III clinical studies in patients with stage IIIB and IV NSCLC (Cisplatin and Tirapazamine Against Previously Untreated Lung Tumors [CATAPULT] I and II) [95].…”

Section: Hypoxic-cell Selective Agentsmentioning

confidence: 99%

“…A recent phase I/II study demonstrated that a combination of tirapazamine plus cisplatin does not delay subsequent radiation therapy in patients with locally advanced cervical cancer; preliminary evidence of rapid and prolonged complete responses was noted [86]. In a phase I study, concurrent tirapazamine, cisplatin, and radiation therapy was associated with a higher-than-expected locoregional control rate in patients with stage IV head and neck cancer [94]. After a median follow-up of 21 months, 10 of the 16 treated patients were alive without locoregional disease, and an additional four patients were alive with either locoregional recurrence or only distant metastases [94].…”

Section: Hypoxic-cell Selective Agentsmentioning

confidence: 99%

Impact of Tumor Hypoxia and Anemia on Radiation Therapy Outcomes

et al. 2002

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Local recurrence remains a major obstacle to achieving cure of many locally advanced solid tumors treated with definitive radiation therapy. The microen-vironment of solid tumors is hypoxic compared with normal tissue, and this hypoxia is associated with decreased radiosensitivity. Recent preclinical data also suggest that intratumoral hypoxia, particularly in conjunction with an acid microenvironment, may be directly or indirectly mutagenic. Investigations of the prognostic significance of the pretreatment oxygenation status of tumors in patients with head and neck or cer-vical cancer have demonstrated that increased hypoxia, typically designated in these studies as pO 2 levels below 2.5-10 mm Hg, is associated with decreased local tumor control and lower rates of disease-free and overall survival. Hypoxia-directed therapies in the radiation oncology setting include treatment using hyperbaric oxygen, fluosol infusion, carbogen breathing, and electron-affinic and hypoxic-cell sensitizers. These interventions have shown the potential to increase the effectiveness of curative-intent radiation therapy, demonstrating that the strategy of overcoming hypoxia may be a viable and important approach. Anemia is common in the cancer population and is suspected to contribute to intratu-moral hypoxia. A review of the literature reveals that a low hemoglobin level before or during radiation therapy is an important risk factor for poor locoregional disease control and survival, implying that a strong correlation could exist between anemia and hypoxia (ulti-mately predicting for a poor outcome). While having a low hemoglobin level has been shown to be detrimental, it is unclear as to exactly what the threshold for "low" should be (studies in this area have used thresholds ranging from 9-14.5 g/dl). Optimal hemoglobin and pO 2 thresholds for improving outcomes may vary across and within tumor types, and this is an area that clearly The Oncologist 2002;7:492-508 www.TheOncologist.com The Oncologist ® LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Discuss the prognostic significance of intratumoral hypoxia and low hemoglobin levels in patients receiving curative-intent radiation for head and neck or cervical cancer. 2. Describe the potential relationship between anemia and intratumoral hypoxia in patients with solid tumors. 3. List possible interventions for improving intratumoral oxygenation and radiosensitivity in the radiation oncology setting. Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

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Tumor Radiation Biology

Brown

Graves

2014

Comprehensive Biomedical Physics

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8 Extraordinary tumor control in phase I trial of concurrent tirapazamine cisplatin and radiotherapy for far advanced head and neck cancer

Cited by 12 publications

References 0 publications

DNA-Targeted 1,2,4-Benzotriazine 1,4-Dioxides: Potent Analogues of the Hypoxia-Selective Cytotoxin Tirapazamine

DNA-Targeted 1,2,4-Benzotriazine 1,4-Dioxides: Potent Analogues of the Hypoxia-Selective Cytotoxin Tirapazamine

Impact of Tumor Hypoxia and Anemia on Radiation Therapy Outcomes

Tumor Radiation Biology

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