Padilla G M, Yacullo R C, Padilla J J, Payne B, Petrow V
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
Biochem Cell Biol. 1990 Oct;68(10):1181-8. doi: 10.1139/o90-175.
We had previously reported that 6-methylene progesterone, an inhibitor of 5 alpha-reductase, the enzyme which converts testosterone to dihydrotestosterone, markedly inhibited growth of the androgen-dependent Dunning R3327-H rat prostatic tumors. We now find that the progesterone derivatives melengestrol acetate (MGA) and megestrol acetate (MA) inhibit both the androgen-dependent (Dunning R3327-H) and the androgen-independent (Dunning R3327-AT3) prostatic tumors. Growth of the AT3 tumors was suppressed by approximately 53% after 9 days of daily s.c. injections with MGA at 10 mg/kg body weight. MGA also caused a 54% weight reduction of the ventral prostate and a 53% reduction of the seminal vesicles. Adrenal weights were reduced by 42%. A 24-day oral treatment with MGA (at approximately 15-17 mg/(kg.day)) inhibited AT3 tumor growth by 59% and caused a weight reduction in the following tissues: prostate (46%), seminal vesicles (19%), testes (12%), and adrenals (52%). Under the same protocol, MA inhibited AT3 tumor growth by 32% and reduced the weight of the ventral prostate by 49% and the weight of the adrenals by 18%, but had no effect on the seminal vesicles and testes. The extent of the MGA-induced prostatic regression was accompanied by cytological changes similar to those effected by 6-methylene progesterone, i.e., shrinking of the acinar epithelium. The AT3 tumors in MGA-treated rats displayed a limited degree of apoptosis. Atrophy of the adrenal cortex and lowered plasma levels of corticosterone and dihydroepiandrosterone were also observed. A therapeutic role for MGA and MA against androgen-independent prostatic neoplasms in man is forecast by these observations.
我们之前曾报道，6-亚甲基孕酮是一种5α-还原酶（将睾酮转化为二氢睾酮的酶）的抑制剂，可显著抑制雄激素依赖性的邓宁R3327-H大鼠前列腺肿瘤的生长。我们现在发现，孕酮衍生物醋酸甲地孕酮（MGA）和醋酸甲羟孕酮（MA）可抑制雄激素依赖性（邓宁R3327-H）和雄激素非依赖性（邓宁R3327-AT3）前列腺肿瘤。每天以10mg/kg体重皮下注射MGA 9天后，AT3肿瘤的生长被抑制了约53%。MGA还使腹侧前列腺重量减轻了54%，精囊重量减轻了53%。肾上腺重量减轻了42%。以约15-17mg/（kg·天）的剂量口服MGA进行24天治疗，可使AT3肿瘤生长抑制59%，并使以下组织重量减轻：前列腺（46%）、精囊（19%）、睾丸（12%）和肾上腺（52%）。在相同方案下，MA使AT3肿瘤生长抑制32%，腹侧前列腺重量减轻49%，肾上腺重量减轻18%，但对精囊和睾丸没有影响。MGA诱导的前列腺消退程度伴随着类似于6-亚甲基孕酮所引起的细胞学变化，即腺泡上皮细胞萎缩。接受MGA治疗的大鼠的AT3肿瘤显示出有限程度的细胞凋亡。还观察到肾上腺皮质萎缩以及血浆皮质酮和脱氢表雄酮水平降低。这些观察结果预示着MGA和MA对人类雄激素非依赖性前列腺肿瘤具有治疗作用。
