Similar changes of hypothalamic feeding-regulating peptides mRNAs and plasma leptin levels in PTHrP-, LIF-secreting tumors-induced cachectic rats and adjuvant arthritic rats.

Parathyroid hormone-related protein (PTHrP) is a causative factor of humoral hypercalcemia in malignancy. However, it is difficult to explain the mechanism of anorexia/cachexia with PTHrP secretion in detail. Previously, we demonstrated that the expressions of orexigenic peptides increased and anorexigenic peptides decreased under cachectic conditions in rats carrying tumors secreting PTHrP.

Structure-activity relationships of bioisosteric replacement of the carboxylic acid in novel androgen receptor pure antagonists.

A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of hormone refractory prostate cancer. CH4933468 (32d) with a sulfonamide side chain not only exhibited antagonistic activity with no agonistic activity in the reporter gene assay but also inhibited the growth of bicalutamide-resistant cell lines. This compound also inhibited tumor growth of the LNCaP xenograft in mice dose-dependently.

Structural basis for antibody discrimination between two hormones that recognize the parathyroid hormone receptor.

Parathyroid hormone-related protein (PTHrP) plays a vital role in the embryonic development of the skeleton and other tissues. When it is produced in excess by cancers it can cause hypercalcemia, and its local production by breast cancer cells has been implicated in the pathogenesis of bone metastasis formation in that disease. Antibodies have been developed that neutralize the action of PTHrP through its receptor, parathyroid hormone receptor 1, without influencing parathyroid hormone action through the same receptor.

Crystallization of the receptor-binding domain of parathyroid hormone-related protein in complex with a neutralizing monoclonal antibody Fab fragment.

Parathyroid hormone-related protein (PTHrP) plays an important role in regulating embryonic skeletal development and is abnormally regulated in the pathogenesis of skeletal complications observed with many cancers and osteoporosis. It exerts its action through binding to a G-protein-coupled seven-transmembrane cell-surface receptor (GPCR). Structurally, GPCRs are very difficult to study by X-ray crystallography.

Novel models of cancer-related anemia in mice inoculated with IL-6-producing tumor cells.

We established models of cancer-related anemia in mice from subcutaneous inoculation of two IL-6-producing cancer cell lines, human lung cancer cell line LC-06-JCK and murine colon26 clone 5 colon cancer cells. In both models, elevated levels of IL-6 were detected in sera and hemoglobin levels significantly decreased compared with non-tumor-bearing mice. In the LC-06-JCK model, serum albumin levels also decreased with elevated levels of human IL-6 in sera.

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).

[PTHrP and cancer cachexia].

Parathyroid hormone-related peptide (PTHrP) was discovered to be a causative factor of humoral hypercalcemia of malignancy (HHM) . It also causes cachexia including reduced food intake, body weight loss, and decreased locomotor activity by a mechanism that is independent of hypercalcemia and proinflammatory cytokine actions. PTHrP-induced cachexia is not associated with the repression of orexigenic peptides or induction of anorexigenic peptides ; unexpectedly, the expression of orexigenic peptides was increased and that of anorexigenic peptides was decreased in animals that developed PTHrP-induced cachexia.

Discovery and structure-activity relationships of new steroidal compounds bearing a carboxy-terminal side chain as androgen receptor pure antagonists.

Lead optimization of CH4892280 (4), an androgen receptor (AR) pure antagonist, was investigated. Compounds 6 and 7, which have a carboxylic acid at the end of the side chain at the position 7alpha of dihydrotestosterone (DHT), showed partial agonistic activities in reporter gene assay (RGA). Conversion of the steroidal core structure to 17alpha-methyltestosterone gave compound 14, which showed weak pure antagonistic activity.

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.

Parathyroid hormone-related protein induces cachectic syndromes without directly modulating the expression of hypothalamic feeding-regulating peptides.

Purpose: Parathyroid hormone-related protein (PTHrP) is a causative factor of humoral hypercalcemia of malignancy (HHM) and concurrent anorexia and wasting. Because changes in the expression of hypothalamic feeding-regulating peptides can directly affect appetites and thereby can cause anorexia and wasting, we addressed whether the cachectic syndromes induced by PTHrP rely on the action of hypothalamic feeding-regulating peptides.

Experimental Design: Rats were inoculated with a LC-6 human cancer xenograft that secreted PTHrP, and the mRNA levels of the hypothalamic feeding-regulating peptide genes and serum leptin levels were examined before and after the development of HHM by in situ hybridization histochemistry and ELISA, respectively.

Discovery of 7alpha-substituted dihydrotestosterones as androgen receptor pure antagonists and their structure-activity relationships.

A series of 7alpha-substituted dihydrotestosterone derivatives were synthesized and evaluated for androgen receptor (AR) pure antagonistic activity. From reporter gene assay (RGA), the compound with a side chain containing N-n-butyl-N-methyl amide (19a) showed pure antagonistic activity (IC(50)=340nM, FI(5)>10,000nM), whereas known AR antagonists showed partial agonistic activities. The optimization of 19a led to compound 23 (CH4892280), which showed more potent pure antagonistic activity (IC(50)=190nM, FI(5)>10,000nM).

Capecitabine improves cancer cachexia and normalizes IL-6 and PTHrP levels in mouse cancer cachexia models.

Purpose: To clarify the potential of parathyroid hormone-related protein (PTHrP) and interleukin-6 (IL-6) as cachectic factors in a colon 26 model and the effects of capecitabine on cancer cachexia as determined by plasma levels of IL-6 and PTHrP and body weight loss.

Methods: From two colon 26 sublines-cancer cachectic clone20 and non-cachectic clone5 plasma levels of PTHrP protein and mRNA expression levels in tumor tissues were compared. An IL-6 neutralizing antibody, a PTHrP neutralizing antibody, and capecitabine were administered into mice bearing clone20 and their anticachectic effects evaluated.

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.

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.

Treatment of malignancy-associated hypercalcemia and cachexia with humanized anti-parathyroid hormone-related protein antibody.

Parathyroid hormone-related protein (PTHrP) plays a central role in humoral hypercalcemia of malignancy (HHM), which is one of the most frequent paraneoplastic syndromes. PTHrP produced by the tumor acts through a common PTH/PTHrP receptor to promote bone resorption, inhibit calcium excretion from the kidney, and induce hypercalcemia. Patients with HHM often develop cachexia associated with typical symptoms such as anorexia, malaise, nausea, constipation, polyuria, polydipsia, and confusion.