Swanson Steven M, Christov Konstantin
Department of Medicinal Chemistry & Pharmacognosy, Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612-7231, USA.
Anticancer Res. 2003 Jul-Aug;23(4):3207-13.
An early full-term pregnancy is protective against mammary cancer in both humans and rodents. Treating rats with two hormones of pregnancy, estradiol and progesterone, for 5 weeks renders the rat mammary glands refractory to carcinogenesis. Our objectives was to determine if a shortened regimen (3 weeks) would be as effective as the 5-week regimen and to determine if the mammary gland was vulnerable to carcinogenic insult during the hormone treatments. We also examined cancers that survived the chemopreventive regimen to see if those tumors were particularly aggressive compared to control tumors (i.e., less differentiated, estrogen receptor alpha (ER alpha)-negative or harbored mutations in Ha-ras). In the first experiment, Lewis rats were injected with N-methyl-N-nitrosourea (MNU, 50 mg/kg) at 50 days of age. At 60 days of age, the rats were either mated and allowed to nurse their young for 3 weeks, treated with hormone vehicle for 5 weeks, or 17 beta-estradiol (E, 20 micrograms) and progesterone (P, 4 mg) 5 times per week for 3 or 5 weeks. All the rats exposed to MNU but not estradiol and progesterone developed multiple mammary cancers. Pregnancy reduced multiplicity to 0.40 cancers/rat. Treatments of estradiol and progesterone for 3 or 5 weeks reduced cancer multiplicity and increased latency to a similar degree as pregnancy. Mammary cancers from each group displayed a similar spectra of histologic class, estrogen receptor alpha (ER alpha) content and Ha-ras mutation status. In the second experiment, 50-day-old rats were treated for five weeks with either estradiol and progesterone or vehicle as above beginning at 60 days of age and treated with MNU at 50, 64, 78 or 92 days of age. In each case, estradiol and progesterone treatments resulted in significantly reduced mammary tumor frequency. These results demonstrate that a three-week regimen of estradiol and progesterone can protect the mammary gland from chemically-induced carcinogenesis even when carcinogen exposure occurs concomitant with estradiol and progesterone stimulation.
早期足月妊娠对人类和啮齿动物的乳腺癌具有保护作用。用两种妊娠激素雌二醇和孕酮对大鼠进行5周的治疗，可使大鼠乳腺对致癌作用产生抗性。我们的目标是确定缩短疗程（3周）是否与5周疗程一样有效，并确定在激素治疗期间乳腺是否易受致癌性损伤。我们还检查了在化学预防疗程后存活的癌症，以观察这些肿瘤与对照肿瘤相比是否具有特别的侵袭性（即分化程度较低、雌激素受体α（ERα）阴性或携带Ha-ras基因突变）。在第一个实验中，50日龄的Lewis大鼠注射N-甲基-N-亚硝基脲（MNU，50mg/kg）。60日龄时，将大鼠交配并让其哺育幼崽3周，用激素载体治疗5周，或每周5次给予17β-雌二醇（E，20μg）和孕酮（P，4mg），持续3周或5周。所有暴露于MNU但未接受雌二醇和孕酮治疗的大鼠都发生了多发性乳腺癌。妊娠将癌症多发性降低至0.40个癌症/大鼠。雌二醇和孕酮治疗3周或5周可使癌症多发性降低，并使潜伏期延长至与妊娠相似的程度。每组的乳腺癌在组织学类型、雌激素受体α（ERα）含量和Ha-ras突变状态方面表现出相似的谱型。在第二个实验中，50日龄的大鼠从60日龄开始，用雌二醇和孕酮或上述载体进行5周治疗，并在50、64、78或92日龄时用MNU治疗。在每种情况下，雌二醇和孕酮治疗均导致乳腺肿瘤发生率显著降低。这些结果表明，即使在致癌物暴露与雌二醇和孕酮刺激同时发生时，为期3周的雌二醇和孕酮疗程也能保护乳腺免受化学诱导的致癌作用。
