Plicamycin (mithramycin)

Direct tubular epithelial toxicity affecting both proximal and distal segments impairs electrolyte handling, producing electrolyte wasting and, with cumulative exposure, frank acute tubular necrosis and a rising creatinine. Superimposed on this, its potent inhibition of osteoclastic bone resorption lowers serum calcium and phosphate, so the electrolyte picture reflects both the renal tubular lesion and the antiresorptive effect. Toxicity is cumulative and increases with repeated dosing and with pre-existing renal impairment.

Hypocalcemia (sometimes symptomatic), hypophosphatemia and hypokalemia with a rising creatinine; frequently accompanied by hepatotoxicity and a hemorrhagic diathesis (thrombocytopenia and clotting-factor effects), which together limited the drug's use.

With repeated / cumulative dosing (days to weeks).

Aureolic-acid antitumor antibiotic that binds GC-rich DNA in the minor groove (in a magnesium-dependent fashion), displacing Sp1-family transcription factors and inhibiting RNA and protein synthesis. It also potently inhibits osteoclastic bone resorption, the basis of its historical use for hypercalcemia. Historically used for testicular germ-cell tumors and hypercalcemia of malignancy / Paget disease.

Discontinue for renal dysfunction; correct electrolyte derangements including hypocalcemia (calcium repletion) and provide supportive care. Bisphosphonates (and later denosumab) have entirely replaced plicamycin for hypercalcemia owing to its nephrotoxicity and hemorrhagic toxicity.