Mithramycin Impairs the Release of 45Ca from Bone Induced by Prostaglandin E2 or Multiple Myeloma Sera

Abstract

Some tumors release factors able to activate host osteoclasts. Mithramycin at subtumoricidal doses inhibits the release of Ca mediated by osteoclasts. If invasion of bone by a cancer requires activation of these cells, their intermittent blockade might impede the development of metastases to bone or their local extension. Fetal rat bones prelabeled with 45Ca were cultured in the presence of 10-7 M prostaglandin E2 [PGE2], sera from normal individuals or from patients with multiple myleoma. Additional samples preincubated for 3 h with 1 .mu.g/ml mithramycin were washed before culture. Compared with controls, PGE2 stimulated the release of 45Ca by 28% (5 experiments) and mithramycin inhibited release by 15% (3 experiments). Preexposure to this cytotoxic antibiotic before culture with PGE2 reduced the augmented release. Sera from 4 patients with multiple myeloma were incubated with 45Ca-labeled bones, some pretreated with mithramycin. An additional 29% release of 45Ca (4 experiments) was prevented by mithramycin. These results are consistent with the hypothesis that augmented release of 45Ca due to stimulatory factors such as prostaglandins or factors in sera from patients with multiple myeloma can be partially inhibited by pretreatment with mithramycin. Possibly, intermittent blockade of host osteoclasts can impair formation of metastases to bone by cancers dependent upon their activation for this event, or reduce the extent of local invasion by established metastases. Modifying the behavior of a cancer by altering the host-response to factors which it releases represents a potential alternative to cytotoxic chemotherapy.