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 Plicamycin

MedKoo Code#:  100740

Name:  Plicamycin

CAS#:  18378-89-7 　 Synonym:  aureolic acid; mithramycin. US brand name: Mithracin. Foreign brand name: Mithracine. Abbreviation: MTH. Code names: A-2371; PA-144   IUPAC/Chemical name: (2S,3S)-3-((1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl)-2-(((2S,4R,5R,6R)-4-(((2S,4R,5R,6R)-4-(((2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-6-(((2S,4R,5R,6R)-4-(((2S,4R,5S,6R)-4,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8,9-dihydroxy-7-methyl-3,4-dihydroanthracen-1(2H)-one

Chemical structure:

Theoretical analysis:

Chemical Formula: C52H76O24 Exact Mass: 1084.47265 Molecular Weight: 1085.14 Elemental Analysis: C, 57.56; H, 7.06; O, 35.39 m/z: 1084.47265 (100.0%), 1085.47601 (56.2%), 1086.47936 (15.5%), 1086.47690 (4.9%), 1087.48272 (2.8%), 1087.48025 (2.8%)

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plicamycin is an antibiotic isolated from the bacterium Streptomyces plicatus with antineoplastic activity. Plicamycin, also known as mithramycin, binds to the minor groove of DNA at GC-rich sites, resulting in inhibition of RNA synthesis; this agent also inhibits mRNA expression, resulting in a reduction in protein synthesis. In addition, plicamycin may inhibit bone resorption by down regulating transcription of c-src, an oncogene involved in bone metabolism and resorption. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Mithracin (plicamycin) is a yellow crystalline compound which is produced by a microorganism, Streptomyces plicatus. Mithracin is available in vials as a freeze-dried, sterile preparation for intravenous administration. Each vial contains 2500 mcg (2.5 mg) of Mithracin with 100 mg of mannitol and sufficient disodium phosphate to adjust to pH 7. After reconstitution with sterile water for injection, the solution has a pH of 7. The drug is unstable in acid solutions with a pH below 4. Mithracin is an antineoplastic agent. It has an empirical formula of C 52 H 76 O 24

CLINICAL PHARMACOLOGY

Although the exact mechanism by which Mithracin 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 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. 

Mithracin shows potent cytotoxicity against malignant cells of human origin (Hela cells) growing in tissue culture. Mithracin is lethal to Hela cells in 48 hours at concentrations as low as 0.5 micrograms per milliliter of tissue culture medium. Mithracin 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.

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