Testing of New Hypoxic Cell Sensitizers in Vivo

• Published in: Radiation research 1982-07, Vol.91 (1), p.186-198
• Main Authors: Stone, Helen B., Sinesi, Mark S.
• Format: Article
• Language: English
• Subjects: Animals; Dosage; Drug Evaluation, Preclinical; Etanidazole; Female; Hypoxia; Irradiation; Mammary Neoplasms, Experimental - radiotherapy; Mice; Mice, Inbred C3H; Misonidazole - analogs & derivatives; Misonidazole - therapeutic use; Misonidazole - toxicity; Neurotoxicity; Nitroimidazoles - therapeutic use; Nitroimidazoles - toxicity; Oxygen; Radiation sensitizing agents; Radiation-Sensitizing Agents - therapeutic use; Radiation-Sensitizing Agents - toxicity; Radiotherapy; Sensitization; Sensitizing; Tumors
• ISSN: 0033-7587; 1938-5404
• DOI: 10.2307/3575826

We tested five agents as potential sensitizers of hypoxic cells in vivo in mammary tumors in C3H mice in comparison with misonidazole. The ${\rm LD}_{50/2}$ for desmethylmisonidazole was 2.7 mg/g body wt, compared to 1.3 for misonidazole. It was as effective in reducing the ${\rm TCD}_{50}$ of MDAH-MCa-4 as were equitoxic doses of misonidazole. The ${\rm LD}_{50/2}$ of SR-2508 was 3.3 mg/g and was as effective a sensitizer as misonidazole. Ro 07-0741 was more toxic, with an ${\rm LD}_{50/2}$ of 0.6 mg/g, but was as effective as misonidazole at equitoxic doses. NP-1 was also more toxic than misonidazole (${\rm LD}_{50/2}=0.4\ {\rm mg}/{\rm g}$) but was a less effective sensitizer. Rotenone, which causes sensitization by inhibiting cellular respiration, thus increasing the diffusion distance of oxygen, was extremely toxic (${\rm LD}_{50/2}=0.003\ {\rm mg}/{\rm g}$), and systemic respiratory inhibition and the radioprotective effects of the dimethyl sulfoxide used to dissolve it rendered it totally ineffective as a sensitizer in vivo.