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Tamoxifen Development

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The timer of tamoxifen otherwise known by brand names such as novadex or its original compound id ici46474 is one that switches back to the 1950s it is a derivative of triphenylethylene that demonstrated hormone altering effects specifically on estrogen this led to a new pathway of drug discovery that would revolutionize the treatment of breast cancer with the

Combination of cyclophosphamide methotrexate and fluorosil chemotherapy tamoxifen initiated the greatest decline in case fatality throughout the 1980s but what makes moxman special first it is considered a first in-class drug the first selective estrogen receptor modulator or serm and it enabled the specific targeting of er positive cancers second is that due to

The difficulty of treating this cancer the revolution in treatment and significant impact on mortality resulted in ici limited pharmaceuticals division being presented with the queen’s award for technological achievement by the lord lieutenant of chester shire on july 6 1978 3 a unique fact about tamoxifen is that as you will see as we walk through the timeline

Tamoxifen was initially targeted as a contraceptive not an anti-cancer drug and the intention almost led to ici pharmaceuticals scrapping the development altogether once ici 46474 was not to found to have ovulation inhibiting properties it was only through the protestive resignation of its head scientist arthur walpole the development was picked up again and thank

God it was in the late 1950s there was a surge in the research and development of a novel class of anti-estrogen compounds as a potential for a morning after contraceptive pill at the time imperial chemical industries ici pharmaceuticals and arthur walpole a reproductive endocrinologist led a team in hopes of developing this new class of contraceptive in 1962 a

Canvassing walpole’s research team named dora richardson was developing derivatives based on a triphenyl ethylene molecule and synthesized the world’s first compound with the name ici4647 which would then later become tamoxifen originally tamoxifen was intended as an estrogen inhibitor however during later later drug testing trials it was found that tamoxifen

Had no efficacy as no estrogen inhibitor on the contrary it stimulated ovulation in women the further development of tamoxifen was abandoned by ici pharmaceuticals as a futile effort as previously mentioned however research team leader arthur warpole insisted that ici46474 could be a potential therapeutic for a breast cancer subsequently ici 46474 was trialled as

A breast cancer therapeutic and proved to have efficacy in stopping cancer cell growth and proliferation unlike conventional drug discovery processes the target for tamoxifen was not selected first in contrast it was discovered it was found the principle mechanism of action of tamoxifen is mediated by its binding to the urethra and receptor and the blocking of

The proliferative actions of estrogen however it is also suggested the anti-proliferative action of tamoxifen is the induction of the synthesis of the cytokine transforming growth factor b by tamoxifen which acts as a negative autocrine regulatory molecule following the synthesis of triphenylethylene derivatives by dora richardson the compounds including ici46474

Or tamoxifen underwent lead identification tamoxifen has a geometric cyst isomer compound nine ici-47699 following analysis it was identified that these two isomers had opposing actions with tamoxifen demonstrating antioestrogenic activity and compound ici-47699 having anoestrogenic activity considering the nature of the product tamoxifen emerged as the lead

Compound and moved forwards tamoxifen was then developed into a citrate form for better pharmaceutical kinetic profile however differing to conventional drug design no optimization or alterations were done to the original structure the drug then moved into pre-clinical trials ici pharmaceuticals performed a number of pre-clinical terrorism studies using a range

Of species and whilst rat infants initially demonstrated kinky ribs these symptoms eventually resolved following birth all other species studied found that tamoxifen was safe and that the terragin seemingly to religion effect seen in rats was due to restriction of the uterine growth and therefore making tamoxifen not a true terragin studies on toxicology under

Glp conditions were conducted using a number of species including rats mice rabbits dogs monkeys and sheep and found to be non-toxic across all species these studies were also performed for more than six months organ damage studies were also conducted using pigtail monkeys where changes in the reproductive cycle most closely resemble humans the compound was found

To be non-harmful the mechanism of action of tamoxifen was not known when clinical trials were initially conducted instead following the christie hospital clinical trials studies attempted to evaluate ici 46474’s mechanism of action resulting in strides in 1973 by worchester foundation in animal tumor models particularly the dnba induced mammary carcinoma model

These studies fully describe the anti-tumor activity of ici-46474 in vivo reproductive studies were also performed on this compound with compound ici-46474 being found to be most effective in terminating early pregnancy in rats on the fourth day after mating it therefore supported the hypothesis proposed by ballpal and harper in that compound ici-46474 prevents

Implantation in rats by counteracting the e-western surge on day four however despite the success in rat models the relevance to humans who do not experience this oestrogen surge was questioned rather anti-estrogens like tamoxifen in fact improved the fertility by inducing ovulation in sub-fertile humans so much of the drug development was not relevant the

First collaborative clinical trials took place from 1967 to 1971. ici began planning a trial with compound tamoxifen for the induction of ovulation in amaranic women rather than as a contraceptive as the results had been shown to not be relevant for humans however as a mechanism of action was at this time unknown it caused fears for fetal malformation despite

Its lack of teratogenic effects in animal experiments the lack of terroristicity was considered as not enough of a safeguard to constitute moving it to human trials because of this they believe that the first woman to undergo the trial should be often an abortion in the case that there was a terror geratogenic effect and to complicate this even more the existence

Of the 1967 abortion act would severely limit the number of women that could be selected so whilst they tried to plant around these complications they still need to do therapeutic study to find the safe dopage range for use in contraceptive trials and the approval for this was obtained from the csm in 1969 the compound was approved for treatment of anovalation or

Mineralia associated with high levels of endogenous estrogen and for the treatment of breast cancer in 30 menopausal and postmenopausal women for the clinical trial regarding the treatment of an ovulation or menorahia tamoxifen was found to be capable of inducing ovulation rather than suppressing ovulation in women despite the positive results in pre-clinical rat

Studies but there were better and more exciting results in the breast cancer trials at the christie hospital despite the goal of testing ic46474 as a contraceptive they found that the treatment of ici-46474 was just as effective as traditional estrogen and androgen hormone treatments and also had no toxicity and was well tolerated even at the highest oral dose of

10 milligrams the team was very excited by the results the first trial but the company ici was not as enthusiastic they told the team they were supposed to be looking for a contraceptive not an anti-cancer agent the development of the department also felt that it was hopeless however the csm granted the company permission to prolong and extend the trials on the

Basis of positive clinical results by the end of 1970 60 patients had been admitted to christie breast cancer trial and of 40 of the 40 women who had been on the trial for more than 10 weeks all had shown measurable and marked tumor regression the clinicians carrying out the trial doctors told him coal also reported reported how impressed they were with the absence

Of toxicity and the low incidence of any side effects so the previous clinical trial testing of ici46474 as a cancer treatment at the christie hospital was really decisive and made a huge impact it confirmed the anti-anti-estrogens could be used to treat breast cancer and this catalyzed further studies to test anti-adressions in animal tumor models these studies

Were started first started in 1973 at the worchester foundation for experimental biology using the ndmba-induced rat mammary carcinoma model this model was considered state-of-the-art because no other hormone-dependent models were available for study there was also another study at the tenoves institute for cancer research in cardiff which also used the dmba

Induced rat mammary carcinoma model for the study of anti-tumor actions of ici-46474 these studies fully described the anti-tumor activity of the anti-estrogen in vivo which was also very convenient as efficacy of tamoxifen was being established widely in breast cancer clinical trials as well the study of cancer as a broad treatment was demonstrated throughout

The 1970s with tamoxifen showing clinical applicability in multitude of studies and consistently demonstrating reduced incidence with low toxic side effects it also became prevalent as a preventative method in healthy women for those at risk of breast cancer as it notably decrease incidence of breast cancer the final point in our dog discovery timeline is

Registration and post marketing surveillance the pattern for ici-46474 was applied for in 1962 and approved in 1965 however its patent protection was repeatedly denied in the u.s until the 1980s due to unknown reasons since then there are patterns involving compounds that are derivatives of tamoxifen new processes for preparation of toxins and the use of tamoxifen

In the treatment for specific diseases drug registration currently there are two types of tamoxifen drugs in the market novodex which is an oral tablet form of tamoxifen which was approved by the tga in 1977 in sultamox an oral solution of tamoxifen which was approved by the tga in 2005. in australia tamoxifen has quite a late entry into the market novadex only

Obtained tga approval recently in 2016 and was entered into the australian registry of therapeutic goods not long after post-marketing surveillance since approval by the committee of the safety medicines in the uk in 1973 and by the food and drug administrations in the u.s in 1977 for the treatment of breast cancer tamoxifen has shown good safety and efficacy

It is now available in more than 110 countries around the world as a first-line endocrine therapy for the treatment of breast cancer

Transcribed from video
Tamoxifen Development By Jordy Sobczak