Tamoxifen resistance, and possible ways to prevent it (scientific study)

[AnotherUser]

TweetCheck this out. May be of interest. I don't know if tamoxifen resistance is a huge concern in the length of time that we use tend to use it, but it may be worth looking at, as the article suggests a possible solution. And one other thing: To you bastards who said that tamoxifen (Nolvadex) can't act as an estrogen agonist (this was a long time back), up yours You're wrong. Here's a link to the article too:

https://journals.endocrinology.org/er...erc0100265.htm

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New approaches to the understanding of Tamoxifen action and resistance.
L M Berstein1, H Zheng1, W Yue1, J-P Wang1, A E Lykkesfeldt2, F Naftolin3, N Harada4, M Shanabrough5 and R J Santen6
Lab. Oncoendocrinology, Petrov Research Institute of Oncology, St. Petersburg, Russia
1Div. Endocrinology and Metabolism, University of Virginia, Charlottesville, Virginia, USA
2Dept. Tumor Endocrinology, Institute of Cancer Biology, Copenhagen, Denmark
3Dept. Obstetr. Gynecol., Yale Univ. School Med., New Haven, CT, USA.
4Dept. Biochemistry, Fujita Health University School of Medicine, Toyoake, Japan

(Requests for offprints should be addressed to R J Santen)

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Abstract
Tamoxifen (TAM) provides an effective agent for treatment of hormone dependent breast cancer but resistance uniformly ensues upon continued use. Additional studies are required to define more precisely the mechanisms involved in development of resistance. We conducted systematic experimental and clinical studies based on the hypothesis that tumors exposed to tamoxifen long term may develop resistance by becoming hypersensitive to its estrogenic effects. These investigations uncovered new features of the tamoxifen resistance (TR) phenomenon and identified possible means for its prevention and/or elimination. Initially we confirmed that TR may be divided into two subtypes, primary and acquired resistance, and that these differ by certain important characteristics including the level of the possible involvement of adaptive and genetic components. Then we distinguished at least three consequent stages of this phenomenon: stage I when TAM behaves as an antiestrogen, stage II with development of increased sensitivity to the agonistic (pro-estrogenic) properties of TAM and stage III with an adaptive increase in sensitivity to estradiol (E2). During this evolutionary process, as shown in vitro, MAP kinase and aromatase activities increase. The time frame of the increase in MAPK activity as a rule outpaces the increase in aromatase activity during the course of the development of TR. This may occur as a response to estrogen deprivation or interruption of the process of estrogen signaling and can be one of the promoting factors of increased aromatase activation. On the other hand, the chronology of these events indicates that changes in the MAPK-cascade can be more important for the early steps of the development and maintenance of the TAM-resistant state. Changes in local estrogen production/sensitivity to E2 are perhaps essential for the later steps of this phenomenon.

We have explored the use of a growth factor blocking agent to abrogate the adaptive changes in sensitivity. Farnesylthiosalicylic acid (FTS), an inhibitor of GTP-Ras binding to its membrane acceptor site, reduces the increase in number of MCF-7 cells induced by long term TAM treatment. It also decreases MAPK activity in TAM-treated MCF-7 cells and in established TAM-resistant cell lines. Alone or in combination with letrozole (presumably, through the influence on MAPK pathway) FTS exerts moderate inhibitory effects on aromatase activity in estrogen-deprived or estrogen-exposed MCF-7 cells. Taken together, our observations suggest that FTS is a "candidate drug" for the treatment of TR. Both the adaptive and genetic types of resistance may be amenable to this approach. Our studies underline the possible importance of starting the treatment/prevention of TR early on. From our clinical studies using immunohistochemistry, there is a rather strong rationale to include as a predisposing factor in the development of TR the increase in MAP kinase and aromatase activities in human primary breast tumors.

In summary, data obtained during the course of this project may be considered as evidence supporting the principle that processes resulting in responses to TAM as an agonist and the development of estrogen hypersensitivity of breast cancer cells could potentially be mechanistically linked.

[prolangtum]

TweetI wonder how long "continued use" is considered to be

[nox]

TweetI didn't see any mention of regular cells. I think this only applies to tumors.

[scorpion]

TweetThis study clearly does not involve Male subjects first off, and as mentioned above was specific to tumorerous cells....

Given this what benefit do you feel this study has for Male AS users of tamox? [this is not a flame it is a serious question]

[prolangtum]

Tweetgyno on males can become tumerous..

[scorpion]

Tweet

gyno on males can become tumerous..

LMFAO that right I guess they could...but come on...is that the benefit of this study???

[AnotherUser]

Tweettumor cells are quite similar to regular cells. Most are regular cells with abnormal growth. I will say that it MAY not be relevent to normal cells, but it very well may be. And I believe it is... Also, the mention of this not involving male subjects... do you really think male cells are that different from female cells? The difference is one lousy chromosome. 1 out of 46. Male cells function the same as female cells, they just develop differently (ie, gonads in males are testes, in females develops into ovaries). Somatic cells however are almost identical.