Lasofoxifene (CP-336,156), a novel selective estrogen receptor modulator,in preclinical studies |
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Authors: | H Z Ke T A Brown D D Thompson |
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Institution: | (1) Osteoporosis Research, Mail Stop 8118W-216, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA |
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Abstract: | Estrogen replacement therapy is reported to reduce the incidence of vertebral fractures in postmenopausal women, however,
its compliance is limited because of side effects and safety concerns. Estrogen’s side effects on breast and uterine tissues
leading to the potential increased risk of uterine and breast cancer limit widespread estrogen usage. Thus, there is a significant
medical need for a therapy that protects against postmenopausal bone loss but is free of estrogen’s negative effects on reproductive
tissues. Selective estrogen receptor modulators (SERMs) have been investigated as an alternative to hormone replacement therapy.
One such compound, raloxifene, has been approved for the prevention and treatment of osteoporosis.
Lasofoxifene (LAS), a new, nonsteroidal, and potent SERM, is an estrogen antagonist or agonist depending on the target tissue.
LAS selectively binds with high affinity to human estrogen receptors. In ovariectomized (OVX) rat studies, LAS prevented the
decrease in femoral bone mineral density, tibial and lumbar vertebral trabecular bone mass at an ED100 of about 60 μg/kg/day. LAS inhibited the activation of trabecular and endocortical bone resorption and bone turnover in tibial
metaphyses and diaphyses, and lumbar vertebral body in OVX rats. In addition, LAS decreased total serum cholesterol, inhibited
body weight gain and increased soleus muscle weight in OVX rats. Similarly, LAS prevented bone loss induced by orchidectomy
or aging in male rats by decreasing bone resorption and bone turnover while it had no effect in the prostate. Further, LAS
decreased total serum cholesterol in intact aged male rats or in orchidectomized male rats. Synergestic skeletal effects were
found with LAS in combination with bone anabolic agents such as prostaglandin E2 (PGE2), parathyroid hormone (PTH) or a growth hormone secretagoue (GHS) in OVX rats. In combination with estrogen, LAS inhibited
the uterine stimulating effects of estrogen but did not block the bone protective effects of estrogen. In immature and aged
female rats, LAS did not affect the uterine weight and uterine histology. In OVX adult female rats, LAS slightly but significantly
increased uterine weight. These results demonstrated that LAS produced effects on the skeleton indistinguishable from estrogen
in female and male rats. However, unlike estrogen, LAS had little effect on uterine weight and cellular proliferation of uterus
in female rats. In preclinical anti-tumor studies, LAS inhibited human breast cancer growth in mice bearing MCF7 tumors, prevented
NMU-induced mammary carcinomas and possessed chemotherapeutic effects in NMU-induced carcinomas in rats.
Therefore, we conclude that LAS possesses the antiestrogenic effects in breast tissue and estrogenic effects in bone and serum
cholesterol, but lacks estrogen’s side effects on uterine tissue. These data support the therapeutic potential of LAS for
the prevention and treatment of postmenopausal bone loss and mammary carcinomas in humans. |
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