Mithramycin impairs the release of 45Ca from bone induced by prostaglandin E2 or multiple myeloma sera. Implications for a novel means of local tumor control.
Some tumors release factors able to activate host osteoclasts. Mithramycin at sub-tumoricidal doses inhibits the release of calcium 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 prelabelled with 45Ca were cultured in the presence of 10(-7) M prostaglandin E2, sera from normal individuals, or from patients with multiple myeloma. Additional samples preincubated for 3 h with 1 microgram/ml of mithramycin, were washed before culture. Compared with controls, prostaglandin E2 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-labelled 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 prostagladins 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.
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D009101:Multiple Myeloma / Q000378:metabolism*; D010010:Osteoclasts / Q000502:physiology; D008926:Plicamycin / Q000009:adverse effects*; D011458:Prostaglandins E / Q000494:pharmacology*; D051381:Rats
D011458:Prostaglandins E; D008926:Plicamycin; D002118:Calcium