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Although the exact mechanism by which Mithracin (plicamycin) causes tumor inhibition is not yet known, studies have indicated that this compound forms a complex with deoxyribonucleic acid (DNA) and inhibits cellular ribonucleic acid (RNA) and enzymic RNA synthesis. The binding of Mithracin (plicamycin) to DNA in the presence of Mg + + (or other divalent cations) is responsible for the inhibition of DNA-dependent or DNA-directed RNA synthesis. This action presumably accounts for the biological properties of Mithracin (plicamycin) .
Mithracin (plicamycin) shows potent cytotoxicity against malignant cells of human origin (Hela cells) growing in tissue culture. Mithracin (plicamycin) is lethal to Hela cells in 48 hours at concentrations as low as 0.5 micrograms per milliliter of tissue culture medium. Mithracin (plicamycin) has shown significant anti-tumor activity against experimental leukemia in mice when administered intraperitoneally.
Plicamycin may lower serum calcium levels; the exact mechanism (or mechanisms) by which the drug exerts this effect is unknown. It appears that plicamycin may block the hypercalcemic action of pharmacologic doses of vitamin D. It has also been suggested that plicamycin may lower calcium serum levels by inhibiting the effect of parathyroid hormone upon osteoclasts. Plicamycin's inhibition of DNA-dependent RNA synthesis appears to render osteoclasts unable to fully respond to parathyroid hormone with the biosynthesis necessary for osteolysis. Decreases in serum phosphate levels and urinary calcium excretion accompany the lowering of serum calcium concentrations.
Radioautography studies 1 with 3 H-labeled plicamycin in C3H mice show that the greatest concentrations of the isotope are in the Kupffer cells of the liver and cells of the renal tubules. Plicamycin is rapidly cleared from the blood within the first 2 hours and excretion is also rapid. Sixty-seven percent of measured excretion occurs within 4 hours, 75% within 8 hours, and 90% is recovered in the first 24 hours after injection. There is no evidence of protein binding, nor is there any evidence of metabolism of the carbohydrate moiety of the drug to carbon dioxide and water with loss through respiration. Plicamycin crosses the blood-brain barrier; the concentration found in brain tissue is low but it persists longer than in other tissues. The experimental results in animals correlate closely with results achieved in man. 2
ANIMAL PHARMACOLOGY AND TOXICOLOGY
In mice the average intravenous LD 50 of Mithracin (plicamycin) is 2,000 mcg/kg of body weight. When administered orally, it is not toxic to mice even at doses 100 times greater than the intravenous LD 50 . In rats the average intravenous LD 50 of Mithracin (plicamycin) is 1,700 mcg/kg of body weight. It is not toxic to rats when administered orally at doses 17 times greater than the intravenous LD 50 . In dogs and monkeys Mithracin (plicamycin) is essentially non-toxic when administered intravenously for 24 days at daily doses as high as 50 and 24 mcg/kg of body weight, respectively. However, at higher doses of 100 mcg/kg/day intravenously it is lethal to dogs and monkeys. Signs of toxicity in dogs and monkeys included anorexia, vomiting, listlessness, melena, anemia, lymphopenia, elevated alkaline phosphatase, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase values, hypochloremia, and azotemia. Dogs also showed marked thrombocytopenia, hyponatremia, hypokalemia, hypocalcemia, and decreased prothrombin consumption. Necropsy findings consisted of necrosis of lymphoid tissue and multiple generalized hemorrhages. Mithracin (plicamycin) was only mildly irritating when injected intramuscularly in rabbits and subcutaneously in guinea pigs. Histologic evidence of inhibition of spermatogenesis was observed in a substantial number of male rats receiving doses of 0.6 mg/kg/day and above. This preclinical finding of selective drug effect constituted the scientific rationale for clinical trials in testicular tumors.
Treatment of Patients with Inoperable Testicular Tumors: In a combined series of 305 patients with inoperable testicular tumors treated with Mithracin (plicamycin) , 33 patients (10.8%) showed a complete disappearance of tumor masses and an additional 80 patients (26.2%) responded with significant partial regression of tumor masses. The longest duration of a continuing complete response is now over 8 1 / 2 years. The therapeutic responses in this series of patients have been summarized by type of testicular tumor in the accompanying table.
RESULTS IN 305 TESTICULAR TUMOR CASES BY TUMOR TYPE
|TYPE OF TESTICULAR
Mithracin (plicamycin) may be useful in the treatment of patients with testicular tumors which are resistant to other chemotherapeutic agents. Prior radiation therapy or prior chemotherapy did not alter the response rate with Mithracin (plicamycin) . This suggests that there is no significant cross resistance between Mithracin (plicamycin) and other chemotherapeutic agents.
Treatment of Patients with Hypercalcemia and Hypercalciuria: A limited number of patients with hypercalcemia (range: 12.0-25.8 mg%) and patients with hypercalciuria (range 215-492 mg/day) associated with malignant disease were treated with Mithracin (plicamycin) . Hypercalcemia and hypercalciuria were promptly reversed in all patients. In some patients, the primary malignancy was of non-testicular origin.
Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.
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