Occurrence of hypercalcemia and leukocytosis with cachexia in a human squamous cell carcinoma of the maxilla in athymic nude mice: a novel experimental model of three concomitant paraneoplastic syndromes.

Abstract

Hypercalcemia and leukocytosis may occur in conjunction as paraneoplastic syndromes associated with malignant disease. Here we describe a human squamous cell carcinoma of the maxilla that was associated with hypercalcemia and leukocytosis, and also cachexia. The primary tumor was surgically removed and established in permanent cell culture. When either primary tumors or cultured tumor cells were inoculated into nude mice, the nude mice developed the same paraneoplastic syndromes as those which occurred in the patient from whom the tumor was originally derived. The plasma calcium was increased two and one-half-fold and the WBC count 30-fold, and the body weight was decreased by 45% in tumor-bearing animals. Each of these paraneoplastic syndromes was alleviated by surgical excision of the tumor, indicating that the paraneoplastic syndromes were due to a factor or factors produced by the primary tumor. The development of each of these paraneoplastic syndromes in nude mice correlated positively with the other two syndromes. We examined the organs of tumor-bearing mice and found striking histopathologic abnormalities in the bones, spleen, and liver, but no infiltration with tumor cells. The bones showed marked evidence of osteoclastic bone resorption. This model of a human tumor associated with the hypercalcemia-leukocytosis paraneoplastic syndrome, together with cachexia, should make it possible to determine the mechanisms responsible for these paraneoplastic syndromes and their relationship to each other.

Herbimycin A, a pp60c-src tyrosine kinase inhibitor, inhibits osteoclastic bone resorption in vitro and hypercalcemia in vivo.

“…Furthermore, herbimycin A inhibited the capacity of mature osteoclasts to form pits on dentine slices and suppressed bone resorption in organ cultures of fetal rat long bones. More importantly, we found that herbimycin A decreased and prevented rhIL-la-or tumor-induced hypercalcemia, both of which are associated with increased osteoclastic bone resorption in vivo (14,15 None of the currently available inhibitors of bone resorption are entirely satisfactory. Estrogens have only been used effectively in postmenopausal females and the mode of action ofestrogen remains unclear.…”

“…Ca2" was determined using a calcium pH analyzer (model 634; Corning, Medfield, MA) as described ( 15). Body weight of animals was measured (Lum-O-Gram; Ohaus Scale Corporation, Florham Park, NJ).…”

Inhibition of osteolytic bone metastasis of breast cancer by combined treatment with the bisphosphonate ibandronate and tissue inhibitor of the matrix metalloproteinase-2.

“…Cells (1 ϫ 10 5 ) were suspended in 0.1 ml of PBS and injected into the left heart ventricle of 4-wk-old, female BALB/c-nu/nu mice (Harlan Industries, Houston, TX) with 27-gauge needle under the anesthesia with pentobarbital (0.05 mg/gram). Animals were kept in our animal facilities for 4 to 7 wk as described (17). Weight of animals and excised tumors was determined by using a digitalized weigher (Lum-O-Gram ™ ; Ohaus Scale Corporation, Florham Park, NJ).…”

Identification of a Novel Bone/Calcium Metabolism-regulating Factor in Porcine Pancreas

“…Purification of PPE-Initial steps of the purification were described earlier (2,3). Crude PPE was run through a DE-52 column (Whatman Labsales) (4.8 ϫ 60 cm, Kontes) equilibrated with 0.1 M Tris-HCl, pH 7.5.…”

“…Recently, we have found that systemic administration of extracts of the porcine pancreas (PPE) 1 that have been prepared according to the methods described by Takaoka et al (1) reproducibly decrease blood ionized calcium (Ca 2ϩ ) concentrations in normal mice and inhibit bone resorption, which is stimulated by parathyroid hormone (PTH), interleukin-1␣, prostaglandin E 2 , tumor necrosis factor, transforming growth factor ␣, and 1,25-dihydroxyvitamin D 3 (1,25D 3 ) in organ cultures of fetal rat long bones (2). Inhibition of bone resorption by PPE was associated with inhibition of osteoclast formation (3).…”