Parathyroid hormone-related protein as a potential target of therapy for cancer-associated morbidity.

Abstract

Proinflammatory cytokines are involved in the genesis of cancer-associated cachexia. Parathyroid hormone-related protein (PTHrP) is the causative agent in humoral hypercalcemia of malignancy (HHM) and is frequently secreted from various kinds of solid tumors as well as from adult T-cell leukemia/lymphoma. PTHrP, like PTH, acts on PTH receptor type 1 (PTH1R). Activation of PTH1R may lead to stimulation of secretion of proinflammatory cytokines. It is expected, therefore, that PTHrP constitutes a key factor in the activation of the proinflammatory and cachectogenic cytokine network and consequently in the development of cachexia in patients with cancer. Two groups of cancer-bearing patients of similar clinical backgrounds were enrolled. Plasma concentrations of PTHrP and cytokines were measured with immunoradiometric assay and radioimmunoassay, respectively. Cancer tissues from patients with HHM were transplanted into nude mice or nude rats. The effects of humanized antihuman PTHrP antibody were examined. In clinical studies, Group B patients (with elevated plasma PTHrP), compared with Group A patients (with normal plasma PTHrP), tended to exhibit higher plasma levels of tumor necrosis factor (TNF)-alpha (P = 0.13), interleukin (IL)-5 (P = 0.08), and IL-8 (P = 0.08), and had significantly higher levels of IL-6 (P = < or =0.01). The levels of TNF-alpha and IL-6 correlated with those of PTHrP. In animal studies, the antibody caused a prompt and sustained decline in serum calcium. This response was accompanied by improvements in food intake, drinking, body weight gain, and general behavior. It also ameliorated the suppression of serum ADH. When those effects were compared with those induced either by bisphosphonate or calcitonin, it turned out that not all of the beneficial effects of the antibody were directly correlated with the depression of blood calcium. PTHrP is a promising molecular target for the development of a novel mode of treatment for patients with cancer-associated morbidity.