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In vivo testing of hypoxic radiosensitizers using the KHT murine tumour assayed by the lung-colony technique
Abstract:
The KHT transplantable tumour of C3H mice has been used as a model tumour for the invivo study of hypoxic cell sensitizers. Eleven sensitizers comprising four nitrofuran five nitrobenzene and two nitroimidazole derivatives, which have been shown to be effective on hypoxic mammalian cells in vitro, have been investigated. Two of these compounds, metronidazole (2-methyl-5-nitroimidazole-1 ethanol) and tinidazole (ethyl [2-(2'-methyl-5'-nitro-1'-imidazolyl) ehtyl] sulfone), showed signs of hypoxic cell-sensitization in vivo when given systemically by intraperitoneal injections. In addition, preliminary testing of the nitrobenzene NDPP (P-NITRO-3-DIMETHYL-PROPRIOPHENONE HYDROCHLORIDE) INDICATED THAT WHEN IT WAS INJECTED DIRECTLY INTO THE TUMOUR AND IRRADIATION WAS COMPLETED WITHIN TEN MINUTES AFTER INJECTION, APPRECIABLE SENSITIZATION WAS OBTAINED. More detailed studies indicated that both metronidazole at 1,500 mg/kg and tinidazole at 750 mg/kg given intraperitoneally gave an enhancement ratio of 1-5 for a chronically hyopix cell population in this solid tumour in air-breathing mice. Measures of plasma levels of metronidazole and enhancement ratios obtained in the present in vivo system seem in relative agreement with the in vitro and in vivo results of others.
Insights
Metronidazole and tinidazole demonstrated hypoxic cell sensitization in vivo within a mouse tumor model. Direct tumor injection of NDPP also showed promising sensitization effects, supporting their potential as radiosensitizers.
Area of Science:
- Oncology
- Radiotherapy
- Pharmacology
Background:
- The KHT transplantable tumor in C3H mice serves as a model for studying hypoxic cell sensitizers.
- Hypoxic cells in tumors are resistant to radiation therapy, necessitating the development of effective sensitizing agents.
Purpose of the Study:
- To investigate the in vivo efficacy of eleven chemical sensitizers on hypoxic tumor cells.
- To evaluate nitroimidazole derivatives, metronidazole and tinidazole, as systemic radiosensitizers.
- To assess the preliminary efficacy of NDPP when directly injected into tumors.
Main Methods:
- Eleven sensitizers, including nitrofuran, nitrobenzene, and nitroimidazole derivatives, were tested.
- Systemic intraperitoneal injections were used for metronidazole and tinidazole.
- Direct intratumoral injection was employed for NDPP, followed by irradiation within ten minutes.
Main Results:
- Metronidazole and tinidazole showed significant hypoxic cell sensitization in vivo.
- An enhancement ratio of 1.5 was observed for both metronidazole (1,500 mg/kg) and tinidazole (750 mg/kg) in chronically hypoxic cells.
- Direct intratumoral injection of NDPP resulted in appreciable sensitization.
Conclusions:
- Metronidazole and tinidazole are effective in vivo hypoxic cell sensitizers when administered systemically.
- Direct intratumoral administration of NDPP shows potential for radiosensitization.
- The findings align with previous in vitro and in vivo studies on these sensitizers.