By causing pontic regulation and lowering the Sp1 protein, plicamycin (Mith) inhibits the growth of cervical cancer by blocking the DR5/caspase-8/Bid signaling pathway. After 48 hours, plicamycin reduced the proliferation of HEp-2 and KB cells in a concentration-dependent manner. Nuclear condensation and fragmentation were detected using DAPI labeling to qualitatively evaluate cell death. Significant DNA fragmentation is caused by plicamycin when compared to untreated controls [1].

In a xenograft model, the tumorigenic activity of plicamycin (0.2 mg/kg/day) was assessed, and a decrease in tumor mass and volume was noted. The fact that there was no discernible reduction in mouse body weight in the plicamycin-treated group suggests that the toxicity of plicamycin was negligible. In tumor xenografts, plecarmycin also enhanced the number of TUNEL-active cells. The lack of discernible intergroup differences across organs suggests that the plicamycin levels utilized in this investigation did not cause any appreciable systemic toxicity [1].

Absorption, Distribution and Excretion
Radioautography studies with 3H-labeled plicamycin in 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. 67% percent of measured excretion occurs within 4 hours, 75% within 8 hours, and 90% is recovered in the first 24 hours after injection.
It is not known whether plicamycin is excreted in breast milk.
Duration of action: 7 to 10 days with a single dose.
Time to peak effect: 72 hours with a single dose.
Onset of action: When used for hypercalcemia, a reduction in plasma calcium usually occurs within 24 to 48 hours following administration.
Plicamycin is concentrated in the Kupffer cells of the liver, in renal tubular cells, and along formed bone surfaces. It may localize in areas of active bone resorption. Plicamycin also crosses the blood-brain barrier and enters the cerebrospinal fluid (CSF).

Hepatotoxicity
Chemotherapy with plicamycin causes serum enzyme elevations in almost all patients who are treated for more than 1 or 2 days and who are monitored during therapy. Serum ALT, AST and LDH values begin to rise within 3 days of the first infusion and peak within 7 to 10 days at levels of 5 to 500 times the upper limit of the normal range (ULN). The elevations, however, are transient and resolve within 1 to 3 weeks and are rarely associated with symptoms or jaundice. Liver biopsies taken during these episodes usually demonstrate centrolobular necrosis and congestion. With repeated courses, elevations continue to occur generally to the same or lesser degree. A single instance of acute liver failure arising within days of therapy that was suggestive of ischemic hepatitis or sinusoidal obstruction syndrome has been reported in a patient treated with full doses of plicamycin for 4 days for nonmalignant hypercalcemia. Otherwise, the serum enzyme elevations, despite being moderate to severe, are transient and benign.
Likelihood score: A[HD] (well known cause of clinically apparent liver injury with high dose intravenous treatment).

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Protein Binding
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.

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Interactions
Plicamycin-induced hypoprothrombinemia may increase the activity of coumarin- and indandione-derivative anticoagulants and may increase the risk of bleeding in patient receiving heparin or thrombolytic agents; concurrent use is not recommended.
Concurrent use /of nonsteroidal anti-inflammatory drugs, aspirin, dextran, dipyridamole, sulfinpyrazone, or valproic acid/ with plicamycin may increase the risk of hemorrhage because of additive or multiple actions, which may decrease the blood-clotting ability, ie, inhibition of platelet aggregation, by these medications and/or plicamycin combined with induction of hypoprothrombinemia by plicamycin and large dose of aspirin; in addition, the gastrointestinal ulcerative or hemorrhagic potential of aspirin, the nonsteroidal anti-inflammatory drugs, or sulfinpyrazone may increase the risk of hemorrhage in plicamycin-treated patients.
Concurrent use /of other bone marrow depressants, hepatotoxic medications, or nephrotoxic medications/ may increase the potential for toxicity.
Concurrent use /of vitamin D, including calcifediol and calcitriol/ may antagonize the effect of plicamycin when used as a calcium antagonist.

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Non-Human Toxicity Values
LD50 Rat iv 1.74 mg/kg
LD50 Mouse iv 2.14 mg/kg

[1]. Modulation of specificity protein 1 by mithramycin A as a novel therapeutic strategy for cervical cancer. Sci Rep. 2014 Nov 24;4:7162.

[2]. The suppressive role of phytochemical-induced glutathione S-transferase Mu 2 in human urothelial carcinoma cells. Biomed Pharmacother. 2022 Jul;151:113102.

Therapeutic Uses
Mesh Heading: Antibiotics, antineoplastic, fluorescent dyes, nucleic acid synthesis inhibitors, protein synthesis inhibitors
Plicamycin is of limited value in the treatment of neoplastic disease because of its severe toxicity.
Because of low incidence of testicular tumors (est. to be 1% of all tumors), number of cases evaluated is limited.
It has been beneficial in patients with disseminated testicular carcinomas, especially of the embryonal-cell type, but has been largely superseded by other drug regimens, particularly vinblastine, cisplatin, and bleomycin.
For more Therapeutic Uses (Complete) data for MITHRAMYCIN (12 total), please visit the HSDB record page.

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Drug Warnings
It is recommended that plicamycin be administered by intravenous infusion only to hospitalized patients by or under the supervision of a physician experienced in the use of cancer chemotherapeutic agents because of the possibility of severe reactions.
Hemorrhagic syndrome occurs in about 5% of patients who receive no more than 30 ug/kg/day for no more than 10 doses, whereas it is about 12% for higher doses.
BASELINE PLATELET COUNTS, PROTHROMBIN TIME, & BLEEDING TIME SHOULD BE DETERMINED BEFORE THERAPY IS BEGUN. THESE SHOULD BE MONITORED DURING THERAPY & FOR SEVERAL DAYS FOLLOWING LAST DOSE. SIGNIFICANT DECR IN PLATELET COUNT...OR SIGNIFICANT PROLONGATION OF PROTHROMBIN OR BLEEDING TIMES ARE INDICATIONS FOR DISCONTINUING DRUG.
METASTATIC LESIONS IN PATIENTS WITH MIXED PRIMARY TUMORS OF TESTES HAVE BEEN ONLY PARTIALLY REDUCED OR WERE UNAFFECTED... USUALLY, THESE...IDENTIFIED AS TERATOMAS, CHORIOCARCINOMAS, OR SEMINOMAS. USE...IS NOT RECOMMENDED FOR TREATMENT OF METASTASES DUE TO THESE CELL TYPES.
For more Drug Warnings (Complete) data for MITHRAMYCIN (17 total), please visit the HSDB record page.

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Pharmacodynamics
Plicamycin is lethal to Hela cells in 48 hours at concentrations as low as 0.5 micrograms per milliliter of tissue culture medium. Plicamycin has shown significant anti-tumor activity against experimental leukemia in mice when administered intraperitoneally.

C52H76O24

1085.14

1084.472

18378-89-7

163659

Yellow to brown solid powder

1.5±0.1 g/cm3

1169.8±65.0 °C at 760 mmHg

180-183ºC

327.4±27.8 °C

0.0±0.3 mmHg at 25°C

1.640

1.29

11

24

15

76

1940

25

C[C@@H]1[C@H]([C@@H](C[C@@H](O1)O[C@@H]2C[C@@H](O[C@@H]([C@H]2O)C)OC3=CC4=CC5=C(C(=O)[C@H]([C@@H](C5)[C@@H](C(=O)[C@H]([C@@H](C)O)O)OC)O[C@H]6C[C@H]([C@@H]([C@H](O6)C)O)O[C@H]7C[C@H]([C@H]([C@H](O7)C)O)O[C@H]8C[C@]([C@@H]([C@H](O8)C)O)(C)O)C(=C4C(=C3C)O)O)O)O

CFCUWKMKBJTWLW-BKHRDMLASA-N

InChI=1S/C52H76O24/c1-18-29(72-34-14-30(43(58)21(4)68-34)73-33-13-28(54)42(57)20(3)67-33)12-26-10-25-11-27(49(66-9)48(63)41(56)19(2)53)50(47(62)39(25)46(61)38(26)40(18)55)76-36-16-31(44(59)23(6)70-36)74-35-15-32(45(60)22(5)69-35)75-37-17-52(8,65)51(64)24(7)71-37/h10,12,19-24,27-28,30-37,41-45,49-51,53-61,64-65H,11,13-17H2,1-9H3/t19-,20-,21-,22-,23-,24-,27+,28-,30-,31-,32-,33+,34+,35+,36+,37+,41+,42-,43-,44-,45+,49+,50+,51-,52+/m1/s1

(2S,3S)-2-[(2S,4R,5R,6R)-4-[(2S,4R,5S,6R)-4-[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-6-[(2S,4R,5R,6R)-4-[(2S,4R,5S,6R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-8,9-dihydroxy-7-methyl-3,4-dihydro-2H-anthracen-1-one

PA144; mithramycin. US Mithracin. Foreign Mithracine. MTH. A2371; aureolic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~92.15 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (2.30 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (2.30 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)