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A Laboratory Evaluation of 1,4-Dimethyl-1,4-diphenyl-2-tetrazene (Centrazene), a Carcinostatic Compound

( Department of Metabolic Chemotherapy, Lederle Laboratories, American Cyanamid Company, Pearl River, New York)

The biological properties of 1,4-dimethyl-1,4-diphenyl-2-tetrazene (centrazene), a new anti-neoplastic compound which is not an alkylating agent, were described and compared with those of thioTEPA. Short-term studies demonstrated that both centrazene and thioTEPA inhibited the growth of 72j mammary adenocarcinoma growing in C3H mice. ThioTEPA produced concurrent bone marrow damage, and its effects were directly related to dosage. In contrast, the anti-tumor effects of centrazene did not appear related to dosage, nor was there any measurable evidence of bone marrow damage.

The effects of centrazene and thioTEPA upon the survival of C3H mice bearing a transplantable (72j) or spontaneous mammary tumor were compared by oral, subcutaneous, and intraperitoneal routes of administration. Both thioTEPA and centrazene prolonged the survival of mice bearing transplantable 72j mammary adenocarcinoma; however, the longest survivals were obtained with centrazene treatment. Only centrazene significantly prolonged the survival of mice bearing spontaneous tumors.

In contrast to the results obtained with mammary tumors, centrazene did not prolong the survival of mice bearing S-180, 6C3HED lymphosarcoma, or Harding-Passey melanoma or of rats bearing the Walker 256 carcinosarcoma.

Parenteral administration of centrazene produced optimum survival effects at daily doses ranging from 5.6 mg/kg (72j mammary adenocarcinoma) to 16.8 mg/kg (spontaneous mammary tumors). In diet experiments optimum survivals were obtained only when tumor-bearing mice consumed much higher daily doses of centrazene (about 2000 mg/kg body weight). This suggested that the compound was poorly absorbed orally or else inactivated in the digestive tract.

The weight gain and mortality of normal C3H mice were unaffected by subcutaneous doses of centrazene as high as 2000 mg/kg given daily for 10 days. In contrast, rats given subcutaneous doses of this compound ranging from 2000 to 0.4 mg/kg daily for 10 days showed various degrees of mortality and growth inhibition.

Received 9/28/63.