A comparison of the physiological effects of RSU1069 and RB6145 in the SCCVII murine tumour.

The physiological and therapeutic effects of the bioreductive agent RSU1069 (80 mg/kg i.p.) and its prodrug RB6145 (240 mg/kg i.p.) were investigated in the SCCVII tumour. Using laser Doppler flowmetry it was found that RSU1069 produced a significant 30% reduction in tumour blood flow 30 min after administration, while RB6145 had no effect. Tumour oxygenation, measured with an Eppendorf oxygen electrode, was unchanged by either agent except for a reduction in values less than 2.5 mmHg at 30 min after injection. Neither agent significantly altered tumour energy metabolism, assessed by 31P magnetic resonance spectroscopy. Both agents significantly increased tumour glucose content by a factor of 1.6-1.7 at 30 min after injection, but had no effect on glucose-6-phosphate or lactate levels. Tumour growth was significantly delayed by heating (42.5 degrees C, 60 min), and although neither RSU1069 nor RB6145 alone had any effect on tumour growth they produced a similar enhancement of the tumour response to heat. The therapeutic effects are consistent with the known conversion in vivo of one third of the pro-drug RB6145 to its active product RSU1069, however the physiological effects of the two agents in the SCCVII tumour are not identical.

[1]  P. Workman,et al.  Pharmacokinetic contribution to the improved therapeutic selectivity of a novel bromoethylamino prodrug (RB 6145) of the mixed-function hypoxic cell sensitizer/cytotoxin α-(1-aziridinomethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069) , 2004, Cancer Chemotherapy and Pharmacology.

[2]  C. Grau,et al.  Relationship between tumour oxygenation, bioenergetic status and radiobiological hypoxia in an experimental model. , 1995, Acta oncologica.

[3]  C. Thiemermann,et al.  Induction of hypoxia in experimental murine tumors by the nitric oxide synthase inhibitor, NG-nitro-L-arginine. , 1994, Cancer research.

[4]  R. Durand,et al.  Modulation of tumor hypoxia by conventional chemotherapeutic agents. , 1994, International journal of radiation oncology, biology, physics.

[5]  P. Vaupel,et al.  Stable bioenergetic status despite substantial changes in blood flow and tissue oxygenation in a rat tumour. , 1994, British Journal of Cancer.

[6]  P. Kristjansen,et al.  Biochemical and physiological changes induced by nicotinamide in a C3H mouse mammary carcinoma and CDF1 mice. , 1992, International journal of radiation oncology, biology, physics.

[7]  M. Horsman,et al.  Tumor blood flow changes induced by chemical modifiers of radiation response. , 1992, International journal of radiation oncology, biology, physics.

[8]  J. Brown,et al.  Pharmacological modification of tumor blood flow: lack of correlation between alteration of mean arterial blood pressure and changes in tumor perfusion. , 1992, International journal of radiation oncology, biology, physics.

[9]  G. Adams,et al.  Oral (po) dosing with RSU 1069 or RB 6145 maintains their potency as hypoxic cell radiosensitizers and cytotoxins but reduces systemic toxicity compared with parenteral (ip) administration in mice. , 1991, International journal of radiation oncology, biology, physics.

[10]  B. Teicher,et al.  Effect of pH, oxygenation, and temperature on the cytotoxicity and radiosensitization by etanidazole. , 1991, International journal of radiation oncology, biology, physics.

[11]  I. Stratford,et al.  Induction of tumour hypoxia by FAA and TNF: interaction with bioreductive drugs. , 1991, International journal of radiation biology.

[12]  J. Overgaard,et al.  The use of blood flow modifiers to improve the treatment response of solid tumors. , 1991, Radiotherapy and Oncology.

[13]  M. Trotter,et al.  Drug induced perturbations in tumor blood flow: therapeutic potential and possible limitations. , 1991, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[14]  G. Adams,et al.  Dual-function 2-nitroimidazoles as hypoxic cell radiosensitizers and bioreductive cytotoxins: in vivo evaluation in KHT murine sarcomas. , 1990, Radiation research.

[15]  P. Vaupel,et al.  Tumor tissue oxygenation as evaluated by computerized-pO2-histography. , 1990, International journal of radiation oncology, biology, physics.

[16]  G. Adams,et al.  Synthesis and evaluation of alpha-[[(2-haloethyl)amino]methyl]-2- nitro-1H-imidazole-1-ethanols as prodrugs of alpha-[(1-aziridinyl)methyl]-2- nitro-1H-imidazole-1-ethanol (RSU-1069) and its analogues which are radiosensitizers and bioreductively activated cytotoxins. , 1990, Journal of medicinal chemistry.

[17]  G. Adams,et al.  Bioreductive drugs and the selective induction of tumour hypoxia. , 1990, British Journal of Cancer.

[18]  J. Overgaard,et al.  Improved Treatment of Tumours in vivo by Combining the Bioreductive Drug RSU-1069, Hydralazine and Hyperthermia , 1990 .

[19]  G. Adams,et al.  Selective Activation of Drugs by Redox Processes , 1990, NATO ASI Series.

[20]  J. Overgaard,et al.  Hydralazine-induced enhancement of hyperthermic damage in a C3H mammary carcinoma in vivo. , 1989, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[21]  Y. Shibamoto,et al.  Microangiographic and histologic analysis of the effects of hyperthermia on murine tumor vasculature. , 1988, International journal of radiation oncology, biology, physics.

[22]  C. Streffer,et al.  Effects on intermediary metabolism in mouse tissues by Ro-03-8799. , 1987, British Journal of Cancer.

[23]  A. P. Shepherd,et al.  Evaluation of an infrared laser-Doppler blood flowmeter. , 1987, The American journal of physiology.

[24]  D. Chaplin,et al.  The effect of hydralazine on the tumor cytotoxicity of the hypoxic cell cytotoxin RSU-1069: evidence for therapeutic gain. , 1987, International journal of radiation oncology, biology, physics.

[25]  A. Horwich,et al.  A toxicity and pharmacokinetic study in man of the hypoxic-cell radiosensitiser RSU-1069. , 1986, The British journal of radiology.

[26]  I. Stratford,et al.  The differential cytotoxicity of RSU 1069: cell survival studies indicating interaction with DNA as a possible mode of action. , 1986, British Journal of Cancer.

[27]  G. Adams,et al.  RSU 1069, a nitroimidazole containing an aziridine group. Bioreduction greatly increases cytotoxicity under hypoxic conditions. , 1986, Biochemical pharmacology.

[28]  G. Adams,et al.  RSU 1069, a 2-nitroimidazole containing an alkylating group: high efficiency as a radio- and chemosensitizer in vitro and in vivo. , 1984, International journal of radiation oncology, biology, physics.

[29]  G. Adams,et al.  Radiation sensitization and chemopotentiation: RSU 1069, a compound more efficient than misonidazole in vitro and in vivo. , 1984, British Journal of Cancer.

[30]  J. R. Stewart,et al.  In vivo cytotoxicity of misonidazole and hyperthermia in a transplanted mouse mammary tumor. , 1983, Radiation research.

[31]  D. Hirst,et al.  Enhancement of CCNU cytotoxicity by misonidazole: possible therapeutic gain. , 1982, British Journal of Cancer.

[32]  K. C. George,et al.  Effect of hyperthermia on cytotoxicity of the radiosensitizer Ro-07-0582 in a solid mouse tumour. , 1977, British Journal of Cancer.

[33]  N. Bleehen,et al.  Interaction of hyperthermia and the hypoxic cell sensitizer Ro-07-0582 on the EMT6 mouse tumour. , 1977, British Journal of Cancer.