Radiosensitization of the rats' rhabdomyosarcoma R 1 by chloronitroimidazole compound--P40 dependent on radiation dose in fractionated radiotherapy.

The radiosensitizing effectiveness of 1-(2-hydroxy-3-methoxy-propyl)-2-chloro-4-nitroimidazole (P40) dependent on various fractionated schedules was tested in the rat solid tumor, rhabdomyosarcoma R 1. P40 combined conventional fractionation of gamma rays exerted no radiosensitizing effect measured as local control and growth delay as well. In contrary, the significant sensitization has been noticed when nontoxic doses of the nitroimidazole were combined with higher (3.7 Gy) doses of radiation. Low toxicity of P40 is encouraging for further experimental studies.

Chloronitroimidazoles as radiosensitizers of hypoxic cells in vitro.

Some results of the first more complex studies in vitro on radio-sensitizing efficiency, cytotoxicity and reactivity with blood-thiols of a series of 4- or 5-nitroimidazoles substituted in the 5, 4 or 2 position with chlorine are presented. The derivatives of 4-nitroimidazole substituted in 5 position ("ortho" position) with Cl show higher radiosensitizing efficiency than one may expect from their reduction potential, E1/2. At the same time they are extremely toxic, especially for aerobic cells. It is considered that high biological activity of ortho-substituted 4-nitroimidazoles is connected with their considerable chemical reactivity towards thiols and suppression of those natural protective compounds in the cells. The corresponding 5-nitro isomers are about tenfold weaker sensitizers, and simultaneously much less cytotoxic, either in aerobic or in hypoxic conditions. The chloro-4(5)-nitroimidazoles nonsubstituted at N-1 and ionizable in aqueous solution are relatively weaker at the same time less toxic radiosensitizers. It is evaluated that potential application in radiotherapy may have those chloronitroimidazoles which show low aerobic cytotoxicity, moderate radiosensitizing ability and no reactivity towards thiols. On the basis of the study in vitro, we have selected such a compound: 1-methyl-2-chloro-4-nitroimidazole (P13) for screening in vivo.

2-Chloro-4-nitroimidazole radiosensitizers of hypoxic tumor cells in vivo.

The transplantable rhabdomyosarcoma in WAG/Rij rats was used to test the in vivo effectiveness of 1-methyl-2-chloro-4-nitroimidazole (P13) and its analog 1-(2-hydroxy-3-methoxy-propyl)-2-chloro-4-nitroimidazole (P40) as tumor-cell radiosensitizers after their i.p. administration at low doses. The results indicate that both compounds administered repeatedly at nontoxic concentrations (70-150 mg/kg body wt.) in combination with moderate fractional doses of irradiation (3.7 Gy) enhance the radiation effect on tumors. The local control of tumors on the 210th day in all experimental groups has been higher than in the control ones. In the case of P40 administered in the maximal dose, the increment in local control is statistically significant (p less than 0.05). The regrowth delay has also been longer after treatment with radiosensitizers. In the course of treatment we did not observe any symptoms of neurotoxicity of the compounds. The mean body weight of rats during the administration of compounds remained on the level of control rats whose tumors were irradiated only.

Radiosensitizing ability and cytotoxicity of some 5(4)-substituted 2-methyl-4(5)-nitroimidazoles.

Radiosensitizing efficiency and cytotoxicity of three 2-methyl-4(5)-nitroimidazoles substituted with electron-withdrawal groups -NO2, -Cl and -OCH3 in 5(4)-position ("ortho" position) have been evaluated in vitro on V 79-379 A cells under aerobic as well as under hypoxic conditions. It has been established that 2-h incubation of cells at 37 degrees C in the presence of increasing (up to 2 mM) concentration of the compounds causes a moderate cytotoxicity for P7(2-methyl-5(4)-chloro-4(5)-nitroimidazole) and P5(2-methyl-4,5-dinitroimidazole). Cytotoxicities of these compounds are much stronger under hypoxic than under aerobic conditions. The compound P9(2-methyl-5(4)-methoxy-4(5)-nitroimidazole) is practically completely nontoxic. The radiosensitizing efficiency of P5, P7, and P9 at 2 mM concentration expressed by ER (enhancement ratio) equals 1.75, 1.57 and 1.14 respectively. A discussion regarding the features of electron-affinity, cytotoxicity and radiosensitizing ability of the compounds studied is presented.