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Paraneoplastic Syndrome of Hypercalcemia and Leukocytosis Caused by Squamous Carcinoma Cells (T3M-1) Producing Parathyroid Hormone-related Protein, Interleukin 1, and Granulocyte Colony-stimulating Factor^{1 ,2}

Institute of Clinical Endocrinology, Tokyo Women's Medical College, Kawada-cho 8-1, Shinjuku-ku, Tokyo 162 [K. Sa., K. K., I. H., T. T., K. Sh.]; Research Institute of the Foundation for Growth Science in Japan [K. Sa., Y. F., T. T., K. Sh.], Shinjuku-ku, Tokyo; Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo [S. A., K. T.]; The Third Department of Internal Medicine, University of Tokyo [H. M., T. O., F. T.], Hongo, Bunkyo-ku, Tokyo; and The First Department of Internal Medicine, Medical Center of the Saitama Medical School [Y. K.], Saitama, Japan

Previously we reported that a clonal squamous cell carcinoma cell line (T3M-1) derived from a lower jaw cancer of a patient with marked leukocytosis and hypercalcemia produced factors containing a potent bone-resorbing activity (BRA) (M_r 15,000–20,000) and a colony-stimulating activity. To elucidate the pathogenesis of this humoral hypercalcemia, BRA and colony-stimulating activity in both the conditioned medium and cells were characterized.

The conditioned medium, when eluted at neutral pH, contained colony-stimulating activity and thymocyte proliferation-stimulating activity, the latter of which comigrated with BRA. Upon elution with acetic acid (pH 2.0), the conditioned medium contained no interleukin 1-like activity but potent parathyroid hormone-like activity, which comigrated with BRA. Northern blot hydridization analysis revealed that T3M-1 cells produced constitutively mRNA for parathyroid hormone-related protein and granulocyte colony-stimulating factor. Furthermore, primer extension analysis revealed that the cells also produced mRNA for interleukin 1(IL-1).

Since parathyroid hormone-related protein and IL-1 (osteoclast-activating factor) synergistically increase the concentration of serum calcium, and since IL-1 (hemopoietin 1) potentiates granulocyte colony-stimulating factor-induced granulocytopoiesis, we speculate that parathyroid hormone-related protein, granulocyte colony-stimulating factor, and IL-1 are synergistically involved in a paraneoplastic syndrome of hypercalcemia and leukocytosis, at least in some patients with solid tumors.

¹ Part of this work was presented at the 59th Meeting of the Japan Endocrine Society, Nagasaki, October 1986; the IXth International Conference on Calcium-regulating Hormones and Bone Metabolism, Nice, France, October 1986; and at the 61st Meeting of the Japan Endocrine Society, July 1988.

² This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan (No. 61570563); a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan (62-26); a research grant from the Foundation for Growth Science in Japan (especially donations from Toshiko Sato); a research grant for bone-regulating peptides from Chugai Pharmaceutical Co.; and the Kato Memorial Fund for Nambyou Research.

³ Recipient of "Morning Star Award" of the Japan Endocrine Society. To whom requests for reprints should be addressed.

Received 5/23/88. Revised 4/ 7/89. Accepted 5/17/89.