Effects of diazoxide‐induced reversible diabetes on chemically induced autochthonous mammary carcinomas in sprague‐dawley rats

Abstract

The effect of oral administration of diazoxide on rats bearing mammary carcinomas induced by dimethylbenzanthracene (7,12-DMBA) or methylnitrosourea (MNU) was investigated. Administration of 300 mg/kg diazoxide caused mild reversible diabetes with maximum glucose levels of 305 +/- 74 (control: 119 +/- 12) mg/dl and related insulin levels of 15 +/- 5 (control: 24 +/- 11) microU/ml after 4 hr in tumor-bearing animals. Following the same dose of diazoxide a more than 90% inhibition of tumor growth was observed in 7,12-DMBA- and MNU-induced autochthonous rat mammary carcinomas as well as remission of the median total tumor volume per group in 7,12-DMBA-induced lesions. Frequently, onset of remissions and median remission duration proved to be dose-dependent in 7,12-DMBA-induced mammary carcinoma and, with the exception of the median remission duration, in MNU-induced tumors too. After cessation of diazoxide application, 30% rebound responses were observed in 7,12-DMBA-induced tumors of animals that had had a first remission due to diazoxide. Application of insulin (2 IU per rat) together with diazoxide (300 mg/kg) reversed the tumor-inhibiting effect of diazoxide in MNU-induced tumors. The diazoxide effect might in part be due to a decrease in the percentage of proliferating cells caused by insulin depletion as indicated by a lower amount of cells in S-phase, as measured by DNA-flow cytometry. Marked toxicity was observed after effective doses of diazoxide; the experiments indicate that induction of reversible diabetes might be a useful tool in the treatment of hormone-dependent mammary carcinoma.

Insulin and Diazoxide for Treatment of Cancer

“…Thus, in spite of a mild antiandrogen action [23], the antitumor effect of diazoxide is probably due to its anti-insulin action. An additional mechanism of diazoxide to explain effects on tumor growth might be the elevating effect of diazoxide on cyclic adenosine-3':5'monophosphate-(cAMP)-levels [7]; cAMP and its analogues can inhibit growth of human breast and colon cancer cell lines [34]. However, our own preliminary findings showed a paradoxical decrease of cAMP levels in experimental mammary tumors treated with diazoxide.…”

“…In experimental breast cancer, diazoxide induced remissions in up to 93% of the animals. As a charac teristic of hormonal treatment, withdrawal of the drug at the end of remission was followed by a rebound response leading to a second reduction of tumor size in about 30% of the animals [7]. Diazoxide had no influence on tumor growth in vitro, and its in vivo effect was completely abolished by additional treatment with insulin [7].…”

“…As a charac teristic of hormonal treatment, withdrawal of the drug at the end of remission was followed by a rebound response leading to a second reduction of tumor size in about 30% of the animals [7]. Diazoxide had no influence on tumor growth in vitro, and its in vivo effect was completely abolished by additional treatment with insulin [7]. Thus, in spite of a mild antiandrogen action [23], the antitumor effect of diazoxide is probably due to its anti-insulin action.…”

“…The non-diuretic benzothiadiazine diazoxide induces a reversi ble decrease of insulin levels and leads to remissions of DMBA-and MNU-induced rat tumors [7], A combined ther apy of DMBA-induced mammary carcinomas with tamoxifen and diazoxide yielded a prolongation of remission duration by about 50% at two different tamoxifen dosages, while medroxy progesterone acetate and diazoxide led to increased remis sion rates, but shortened remission durations [10]. Growth stimulation of human MCF-7 mammary carcinoma cells by insulin simultaneously elevates the sensitivity of these cells to methotrexate [1].…”

Diazoxide for Lowering Insulin Levels in Breast Cancer Patients

“…The effect of diazoxide on cancer growth was first examined in DMBA‐induced mammary carcinomas of the rat [3]. In a nontoxic dose, diazoxide led to a remission rate of 82%.…”