Clinical Applications of Mifepristone (RU486) and Other Antiprogestins Assessing the Science and Recommending a Research Agenda (1993) / Chapter Skim
Currently Skimming:
B9. Antiprogestins and the Treatment of Breast Cancer
B9. Antiprogestins and the Treatment of Breast Cancer
Pages 210-228
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 210... ...
, focuses on evidence that progesterone also has proliferative actions in the breast; on the role of synthetic progestins in breast cancer treatment; and on the preliminary data showing that progesterone antagonists may be powerful new tools for the management of metastatic breast cancer because they block the local effects of endogenous progesterone on breast cell proliferation. The reader is also referred to the excellent general review on progestin regulation of cell proliferation by Clark and Sutherland (1990~.
|
From page 211... ...
increases the mitotic index of normal human breast ductal ep~hebum maintained in intact athym~ nude Mae Janus and Welsch' 1984~. In facL ~auvais~a~is and colleagues (Compel et ala 1986; Hauvais~a~~ et ala 1986)
|
From page 212... ...
PROGESTERONE AND BREAST CANCER A discussion of the role of progestins in breast cancer must distinguish between their effects on carcinogenesis and their role in regulating proliferation of established cancers. Progestin Agonists and Tumor Induction Progestin agonists have been shown to be carcinogenic or to increase the incidence of spontaneous mammary tumors in dogs and mice (Frank et al., 1979; Lanari et al., 1986, 1989; Nagasawa et al., 1988; Kordon et al., 1990~.
|
From page 213... ...
Progestin Agonists and Growth of Established Tumors Carcinogen-induced rat mammary tumors are a major model for in viva studies of progestin-regulated growth (Welsch, 1985~. Following ovariectomy, progesterone alone is usually unsuccessful in preventing regression of established tumors.
|
From page 214... ...
However, the mechanisms underlying the actions of intermediate and high doses of progestin agonists in breast cancer regression remain unclear when compared to their proliferative actions at physiologic doses. Although some studies suggest that Pit-negative tumors respond just as well as do Pit-positive tumors (implying that progesterone receptors are not involved)
|
From page 215... ...
What is the explanation for the paradox that both antiprogestins and high-dose progestin agonists inhibit the growth of breast cancers? Human Breast Cancer Cell Lines Two Pit-positive human breast cancer cell lines that are phenotypically different have served as the major models for studies of growth regulation by antiprogestins.
|
From page 216... ...
R 5020 appears to have dual proliferative/ antiproliferative effects, depending on the dose that is tested, and the antiproliferative doses produce growth stasis. By contrast, RU 486 is more purely antiproliferative even at low doses, and it can produce growth regression.
|
From page 217... ...
Although the majority of studies using cell culture models ascribe growth-inhibitory properties to progestins and to antiprogestins through direct effects involving Pits, contradictory results have also been reported. Given the fact that at physiological levels, progesterone is believed to be mitogenic in the normal breast (see above)
|
From page 218... ...
Since adrenal weights are unchanged by RU 486, participation of the antiglucocorticoid effects in the antitumor activity is considered to be unlikely (Schneider et al., 1989~. This is supported by studies in human breast cancer cell lines, where the inhibitory effects of RU 486 cannot be rescued by dexamethasone (Bardon et al., 1985~.
|
From page 219... ...
A similar trend was observed with NMUinduced rat mammary tumors (Michna et al., 1989a, b; Schneider et al., 1989~. However, lack of comparative metabolic and pharmacokinetic data on the two antiprogestins in rats and mice makes these quantitative differences uninterpretable at present.
|
From page 220... ...
, although maintenance of high sustained blood levels of the drug is likely to be important. PROGESTIN RESISTANCE The emergence of hormone-resistant cells eventually reduces the effectiveness of all therapies in advanced breast cancer, and progestin agonists or antagonists are unlikely to be exceptions.
|
From page 221... ...
and of human breast cancer cell lines (Graham et al., 1992~. Factors or treatments that lead to the selection and expansion of Pit-poor or Pit-negative populations would in the long run produce progestin resistance.
|
From page 222... ...
However, nothing is known about the pattern of mitosis in breast cancer cells during the normal menstrual cycle. Obtaining such data is important, and it should be possible to analyze the mitotic patterns of tumors taken from cycling patients.
|
From page 223... ...
However, while it is always preferable to ask biological questions using clinical tissues, much of the work on the mechanisms of the mitogenic actions of progestins and progestin antagonists will require well-controlled studies using organ-cultured human breast tumors, human breast cancer cell lines, and human tumors implanted into nude mice.
|
From page 224... ...
Growth stimulation of T47D human breast cancer cells by the anti-progestin RU 486. Endocrinology 124:2642-2644, 1989.
|
From page 225... ...
Difference between R 5020 and the antiprogestin RU 486 in antiproliferative effects on human breast cancer cells. Breast Cancer Research and Treatment 10:37, 1987.
|
From page 226... ...
Multihormonal regulation of the progesterone receptor in MCF-7 human breast cancer cells: Interrelationships among insulin, insulin-like growth factor-I, serum, and estrogen. Etldocrinology 126:891, 1990.
|
From page 227... ...
The effects of glucocorticoids and progesterone on hormone-responsive human breast cancer in long-term tissue culture. Cancer Research 36:4602, 1976.
|
From page 228... ...
Genetic instability and the development of steroid hormone insensitivity in cultured T47D human breast cancer cells. Cancer Research 48:4340, 1988.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.