Treatments using adnrogen gonadtropin blockers - any knowledge anybody?

[R.B.]

Has anybody heard of any treatments using blocking of androgens / Gonadotropins etc.

Result comments etc.

RB

Regular Article

British Journal of Cancer (1999) 79, 631-636.
doi:10.1038/sj.bjc.6690099

Medroxyprogesterone acetate inhibits interleukin 6 secretion from KPL-4 human breast cancer cells both in vitro and in vivo: a possible mechanism of the anticachectic effect

J Kurebayashi1, S Yamamoto1, T Otsuki2 and H Sonoo1

1Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan

2Department of Hygiene, Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan



Correspondence to: J Kurebayashi, Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan

Received 2 March 1998; revised 27 May 1998; accepted 28 May 1998



Interleukin 6 (IL-6) is a multifunctional cytokine. Recent reports suggest that circulating IL-6 secreted from tumour cells plays an important role in cancer-induced cachexia. Medroxyprogesterone acetate (MPA) has been used as an endocrine therapeutic agent for patients with breast cancer. It has been suggested that MPA decreases serum IL-6 levels and preserves the bodyweight of patients with advanced breast cancer. However, the mechanisms of action responsible for the anticachectic effect of MPA have not been elucidated. Therefore, the effects of MPA on IL-6 secretion were studied both in vitro and in vivo using a human breast cancer cell line, KPL-4, which secretes IL-6 into medium and induces cachexia when injected into female nude mice. MPA (10-1000 nM) dose-dependently decreased basal IL-6 secretion into medium, and also suppressed tumour necrosis factor (TNF-alpha)-induced IL-6 secretion. Both basal and TNF-alpha-induced IL-6 mRNA levels were dose-dependently lowered by MPA. Moreover, intramuscular injections of MPA (100 mg kg-1 twice a week) into nude mice bearing KPL-4 transplanted tumours significantly decreased serum IL-6 levels without affecting tumour growth and preserved the bodyweight of recipient mice. These findings suggest that suppression of IL-6 secretion from tumour cells, at least in part, causes the anticachectic effect of MPA.
© 1999 Cancer Research Campaign

Keywords: interleukin 6; cachexia; medroxyprogesterone acetate; breast





Research article
.
The progestational and androgenic properties of medroxyprogesterone acetate: gene regulatory overlap with dihydrotestosterone in breast cancer cells
Radhika P Ghatge , Britta M Jacobsen , Stephanie A Schittone and Kathryn B Horwitz
University of Colorado Health Sciences Center, Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, Denver, Colorado, USA

Breast Cancer Research 2005, 7:R1036-R1050 doi:10.1186/bcr1340

Published 2 November 2005

Abstract

Introduction

Medroxyprogesterone acetate (MPA), the major progestin used for oral contraception and hormone replacement therapy, has been implicated in increased breast cancer risk. Is this risk due to its progestational or androgenic properties? To address this, we assessed the transcriptional effects of MPA as compared with those of progesterone and dihydrotestosterone (DHT) in human breast cancer cells.

Method

A new progesterone receptor-negative, androgen receptor-positive human breast cancer cell line, designated Y-AR, was engineered and characterized. Transcription assays using a synthetic promoter/reporter construct, as well as endogenous gene expression profiling comparing progesterone, MPA and DHT, were performed in cells either lacking or containing progesterone receptor and/or androgen receptor.

Results

In progesterone receptor-positive cells, MPA was found to be an effective progestin through both progesterone receptor isoforms in transient transcription assays. Interestingly, DHT signaled through progesterone receptor type B. Expression profiling of endogenous progesterone receptor-regulated genes comparing progesterone and MPA suggested that although MPA may be a somewhat more potent progestin than progesterone, it is qualitatively similar to progesterone. To address effects of MPA through androgen receptor, expression profiling was performed comparing progesterone, MPA and DHT using Y-AR cells. These studies showed extensive gene regulatory overlap between DHT and MPA through androgen receptor and none with progesterone. Interestingly, there was no difference between pharmacological MPA and physiological MPA, suggesting that high-dose therapeutic MPA may be superfluous.

Conclusion

Our comparison of the gene regulatory profiles of MPA and progesterone suggests that, for physiologic hormone replacement therapy, the actions of MPA do not mimic those of endogenous progesterone alone. Clinically, the complex pharmacology of MPA not only influences its side-effect profile; but it is also possible that the increased breast cancer risk and/or the therapeutic efficacy of MPA in cancer treatment is in part mediated by androgen receptor.