David A. Karnofsky memorial lecture. Thoughts on chemical therapy

Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time

“…Importantly, treatment near menopause was ineffective, and therefore, tumor responsiveness was related to the duration of estrogen deprivation. In 1970, Alexander Haddow commented that "the extraordinary extent of tumor regression observed in perhaps 1% of postmenopausal cases [with oestrogen] has always been regarded as of major theoretical importance, and it is a matter for some disappointment that so much of the underlying mechanisms continues to elude us" (4). High-dose estrogen therapy using diethylstilbestrol (DES) remained the standard of care for the treatment of metastatic breast cancer in postmenopausal women for 30 y (1950s to late 1970s in the United States).…”

“…A recent study in patients whose breast cancer had responded but then failed AI treatment (28) showed that low-dose E 2 treatment (6 mg daily) would produce the same clinical benefit as high-dose E 2 (30 mg daily) but with fewer toxic side effects. Thus, laboratory observations with low doses of estrogen treatment translate to clinical practice, and a mechanism is now emerging to explain the original observations by Haddow (3,4). The goal of future translational research is to discover molecular mechanisms to amplify the estrogen-induced apoptotic trigger.…”

Proven value of translational research with appropriate animal models to advance breast cancer treatment and save lives: the tamoxifen tale

“…first validation of an antitumour response in animal models and then a clinical trial. Sir Alexander Haddow FRS discovered [20] that high dose synthetic oestrogen treatment could produce a 30% response rate in breast cancer patients more than 5 years after their menopause [21]. This was the first chemical therapy to treat any cancer successfully and was proven in clinical trials.…”

“…This cascade of knowledge answered the question 'how can oestrogen stimulate breast cancer growth (which is the basis of all successful anti-oestrogenic therapy for the past 40 years [32]) but also cause apoptosis as a breast cancer therapy [22,23]'. It is animal models that aided the understanding of 'Haddow's paradox' [21] …”

Estrogen-Induced Apoptosis in Breast Cancer Cells: Translation to Clinical Relevance

“…However, the molecular mechanisms of the anticancer action of estrogen remained elusive. In 1970 Haddow (Haddow 1970) was not enthusiastic about the overall prospects of chemical therapy of breast cancer, he felt that it was important that safer less toxic "estrogens" were developed that might extend therapeutic use. There were clues that deciphering the mysteries of endocrine therapy, such as unknown mechanisms of tumor regression after high-dose estrogen therapy, which could be of major benefit for patient's treatment.…”