Discovery of an orally-active nonsteroidal androgen receptor pure antagonist and the structure-activity relationships of its derivatives.

The 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethylthiohydantoin derivatives which have carboxy-terminal side chains were synthesized and their agonistic/antagonistic activities against androgen receptor (AR) measured. Among them, compound 13b showed antagonistic activity (IC50=130 nM) with no agonistic activity even at 10000 nM. This compound exhibited significant metabolic stability and oral antiandrogenic activity (ED50=7 mg/kg).

Involvement of cyclooxygenase-2 in the tumor site-dependent production of parathyroid hormone-related protein in colon 26 carcinoma.

It has been shown that in the mouse colon 26 tumor model, tumors grown in the subcutis (subcutis colon 26) caused early onset of cachectic syndromes, whereas those in the liver (liver colon 26) did not. Both interleukin (IL)-6 and parathyroid hormone-related protein (PTHrP) were involved in the development of cachectic syndromes in this tumor model. However, whether expression of PTHrP and IL-6 is differently regulated in the tumor microenvironment is unclear.

Humanized monoclonal antibody against parathyroid hormone-related protein suppresses osteolytic bone metastasis of human breast cancer cells derived from MDA-MB-231.

Background: Parathyroid hormone-related protein (PTHrP) has been implicated in bone metastasis. However, the effects on bone metastasis of blocking the PTHrP function have not been tested in the clinic. Here, the effects of a humanized anti-PTHrP monoclonal antibody (mAb) on bone metastasis in a human xenograft model are shown.

Identification of a novel, orally bioavailable estrogen receptor downregulator.

Tamoxifen has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer, but its partial agonist activity is considered to limit the efficacy, and cause tumor flare and endometrial cancer. Fulvestrant, on the other hand, binds and degrades ER, thereby acting as a pure anti-estrogen without partial agonist activity. However, due to its low oral bioavailability, fulvestrant has to be intramuscularly administered to patients, which limits the convenience of the drug, and causes pain and inflammation at the site of injection.

Increased renal calcium reabsorption by parathyroid hormone-related protein is a causative factor in the development of humoral hypercalcemia of malignancy refractory to osteoclastic bone resorption inhibitors.

Purpose: Bisphosphonate and calcitonin lower blood calcium in humoral hypercalcemia of malignancy (HHM) by suppressing osteoclastic bone resorption, but repeated administration of these drugs often leads to relapse. In this study, we examined the roles of parathyroid hormone-related protein (PTHrP) in the development of bisphosphonate- and calcitonin-refractory HHM.

Experimental Design: Nude rats bearing the LC-6 JCK tumor xenograft (LC-6 rats) exhibited high bone turnover and HHM.

Parathyroid hormone-related protein (PTHrP) as a causative factor of cancer-associated wasting: possible involvement of PTHrP in the repression of locomotor activity in rats bearing human tumor xenografts.

Nude rats bearing the LC-6-JCK human lung cancer xenograft displayed cancer-associated wasting syndrome in addition to humoral hypercalcemia of malignancy. In these rats, not only PTHrP but also several other human proinflammatory cytokines, such as IL-6, leukemia-inducing factor, IL-8, IL-5 and IL-11, were secreted to the bloodstream. Proinflammatory cytokines induce acute-phase reactions, as evidenced by a decrease of serum albumin and an increase in alpha1-acid glycoprotein.

Generation of a humanized monoclonal antibody against human parathyroid hormone-related protein and its efficacy against humoral hypercalcemia of malignancy.

A humanized monoclonal antibody against parathyroid hormone-related protein (PTHrP) was generated from the mouse monoclonal antibody raised against the peptide corresponding to the N-terminal 34 amino acids of the human PTHrP [(PTHrP(1-34)]. The humanized antibody interacted with the PTHrP(1-34) with a kD value of 1.90 x 10(-10) M, and the epitope resides between the amino acids 20 and 30 of the PTHrP.