Growth inhibition by diethylstilbestrol and relapse of the Noble rat prostatic tumor

Abstract

アンドロゲン反応性Nobleラット前立腺癌(2Pr121D (1))を用いて, これに種々の量(50～1, 000 μg/kg)のジエルスチルベストロール(DES)を投与した.血清テストステロン値は, すべての実験群において去勢レベルに下降したが, 腫瘍はDESの量が多いほど強く抑制された.腫瘍はDES投与中に再燃を開始し, またDESを中止すると直ちに再燃した.DES投与にて抑制された腫瘍の組織像は, 癌細胞のほとんどが死滅していたが, なお一部にactiveな腫瘍細胞が残存していた.無処置の腫瘍のサイトゾールのdihydrotestosterone (DHT)レセプターは蔗糖密度勾配法, dextrancoated charcoal吸着法, ゲル濾過クロマトグラフィー法にて測定したが, いずれの方法でもサイトゾールDHTレセプターは存在しなかった.しかし核のDHTレセプターを測定するとDHTに対し高親和性結合がみられた.無処置の腫瘍と再燃した腫瘍の核DHTレセプターではsalt-extractable fractionとsalt-resistant fractionのKd. Bmaxはいずれにおいても差はなかった

The response of androgen-sensitive Noble (Nb) rat prostatic adenocarcinoma [2Pr-121D (1)] to varying doses (50 approximately 1, 000 micrograms/kg body weight) of diethylstilbestrol (DES) was investigated and characterized with respect to cytosol and nuclear androgen binding profiles, histology and pattern of relapse. Inhibition of tumor growth was closely related to the dose of DES. Treatment at all but the lowest dose (50 micrograms/kg) initially caused tumor regression, whereas serum testosterone concentrations in all groups, including that receiving the lowest dose, were decreased to castrate levels. Histologically, while extensive cellular destruction was clearly evident at higher doses of DES, some active tumor cells appeared to survive. Tumors eventually relapsed when higher doses of DES were stopped or with the continued administration of low doses. The cytosol dihydrotestosterone (DHT) receptor in this tumor line, as determined by sucrose density gradient, dextran charcoal and Sephadex column methods, was negative. Nuclear binding, however, was positive. Salt-extractable and salt-resistant fractions of nuclei derived from the untreated primary tumor and relapsed tumor following DES treatment contained high affinity androgen receptor. Comparison of binding constants revealed no significant differences. Our findings, based on the Nb rat prostatic tumor model, indicate that DES acts not only by eliminating circulating testosterone, but also by a direct cytotoxic effect on malignant cells. The results also suggest the lack of an apparent relationship between the loss of hormone responsiveness associated with recurrence of prostatic tumor growth and nuclear androgen binding parameters.