Autophagy; cell cycle (IC50 = 0.4 nM); DNA repair (IC50 = 0.42 μM)

Actinomycin D inhibits BrdU incorporation at 80 nM, which significantly reduces SMC proliferation. Using a flowcytometric analysis, the G1-phase arrest provides more evidence for this. Actinomycin D suppresses the levels of focal adhesion kinase (FAK), proliferating cell nuclear antigen (PCNA), and Raf protein expression. Actinomycin D is found to increase extracellular signalregulated kinases (Erk) involved in cell-cycle arrest.[1]

Actinomycin D is active in two distinct mouse models that are typified by either an unmutated B-cell receptor or inactive p53 function, both of which are recognized adverse prognostic factors in CLL. Actinomycin D targets the survival proteins TOSO, BCL2, and MCL1.[3]

Actinomycin D is co-incubated for three hours at thirty degrees Celsius with a reaction mixture that has the following contents: 120 mg of a whole-cell extract of HeLa cells, 70 mM KCl, 0.4 mM of dGTP, dCTP, dATP, and digoxygenylated-dUTP in reaction buffer that has 40 mM Hepes-KOH (pH 7.6), 5 mM MgCl₂, 0.5 mM Dithiotreitol, 2 mM EGTA, 10 mM phosphocreatine, 50 mg/mL creatine phosphate, and 360 mg/mL of bovine serum albumin combined. DNA damage is identified during this reaction, and neosynthesized DNA fragments replace the removed patches. Digoxygenylated-dUMPs are integrated during this DNA synthesis. Three washes halt the DNA repair reaction.

Actinomycin D at different doses is incubated at 37°C after cultured SMC are starved for 24 hours. 18 to 24 hours are spent on drug treatment. Since actinomycin D dissolves in 0.1% DMSO, DMSO-containing vehicle control is also provided.

Mice: For more than nine generations, the original Eμ-TCL1a transgenic mice have been backcrossed to C57BL/6 mice.The Eμ-TCL-1 transgenic mice's tumor cells are engrafted into C57BL/6 wild-type mice. Mice are regularly given blood from the tail vein, which is then subjected to flow cytometry analysis to determine the percentage of CD5+/CD19+ cells in the peripheral blood. Treatment is initiated when 40–60% of the tumor cells in the peripheral blood are present. IV injections of actinomycin D (0.06 mg/kg over 10 days) are administered every day.

Absorption, Distribution and Excretion
poorly absorbed from gastrointestinal tract
Dactinomycin is poorly absorbed from the GI tract. The drug is extremely irritating to tissues and, therefore, must be administered iv.
Dactinomycin is rapidly distributed into tissues, with high concentrations in bone marrow and nucleated cells, including granulocytes and lymphocytes. The drug appears to cross the blood-brain barrier poorly, if at all.
Plasma protein binding /of dactinomycin/ is 5%.
Dactinomycin apparently crosses the placenta. It is not known if dactinomycin is distributed into milk.
For more Absorption, Distribution and Excretion (Complete) data for DACTINOMYCIN (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
hepatic
Dactinomycin appears to be only slightly metabolized; small amounts of monolactones of the drug have been detected in the urine.

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Biological Half-Life
36 hours
The terminal plasma half-life for radioactivity was approximately 36 hours.
The terminal elimination half life of actinomycin D is 36 to 48 hours.

Hepatotoxicity
Chemotherapy with dactinomycin in combination with other agents is associated with serum enzyme elevations in a high, but variable proportion of patients depending upon the dose, other agents used as well as the frequency of monitoring and criteria used to define elevations. The ALT elevations are usually asymptomatic and transient and may resolve without dose modification. In many instances, it is difficult to attribute the liver test abnormalities to dactinomycin, because of the exposure to other potentially hepatotoxic agents.
Dactinomycin can also cause a distinctive form of clinically apparent liver injury referred to as hepatopathy-thrombocytopenia syndrome (HTS) that can be severe and even fatal. This syndrome appears to be due to sinusoidal obstruction, but there may also be an element of direct hepatic and bone marrow injury. In large studies, between 1% and 5% of children with cancer treated with regimens including dactinomycin developed acute hepatic injury and thrombocytopenia suggestive of HTS. The syndrome is more common in younger children and with higher doses of dactinomycin. The time to onset is typically within 3 to 6 weeks after the initial dose, often arising 5 to 10 days after the 2nd or 3rd course of cyclic chemotherapy with dactinomycin. The onset of symptoms is sudden, and children characteristically present with right upper quadrant pain or tenderness, hepatomegaly, liver test abnormalities and signs of excessive bleeding such as epistaxis or bruising. Serum aminotransferase levels are markedly elevated (10 to 100 times ULN) early in the course, but fall rapidly and can be normal within 7 to 14 days. The platelet count is generally less than 25,000/μL and also resolves rapidly. Serum alkaline phosphatase is typically normal and bilirubin levels are minimally elevated, except if the course is progressive and fatal. Serum ammonia and INR may also be raised, and ascites often develops during the acute syndrome. The overall pattern of injury resembles acute hepatic necrosis, and liver histology shows centrolobular necrosis and evidence of sinusoidal obstruction. Recovery is rapid and usually complete.
Likelihood score: C (Probable cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of dactinomycin during breastfeeding. Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. The manufacturer recommends that breastfeeding be discontinued during dactinomycin therapy and for 14 days after the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
5%

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Interactions
Radiation treatment, cyclophosphamide, or vincristine incr response to dactinomycin.
Dactinomycin may raise the concentration of blood uric acid; dosage adjustment of antigout agents may be necessary to control hyperuricemia and gout; allopurinol may be preferred because of risk of uric acid nephropathy with uricosuric antigout agents.
Leukopenic and/or thrombocytopenic effects of dactinomycin may be increased with concurrent or recent therapy /with blood dyscrasia-causing medications/ if these medications cause the same effects; dosage adjustment of dactinomycin, if necessary, should be based on blood counts.
Concurrent use with dactinomycin may potentiate the effects of /other bone marrow depressants or radiation therapy/ including gastrointestinal toxicity, bone marrow depression, and erythema and tanning of the skin; lower doses of each are recommended. Dactinomycin alone may reactivate erythema from previous radiation therapy.
For more Interactions (Complete) data for DACTINOMYCIN (10 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 7200 ug/kg
LD50 Rat ip 100 ug/kg
LD50 Rat iv 460 ug/kg
LD50 Rat sc 800 ug/kg
For more Non-Human Toxicity Values (Complete) data for DACTINOMYCIN (6 total), please visit the HSDB record page.

[1]. J Biomed Sci . 2005;12(3):503-12.

[2]. Carcinogenesis . 1997 Dec;18(12):2441-5.

[3]. Leukemia . 2012 Dec;26(12):2508-16.

Therapeutic Uses
Antineoplastic; Anti-Bacterial Agents; Nucleic Acid Synthesis Inhibitors; Protein Synthesis Inhibitors
Dactinomycin, as part of a combination chemotherapy and/or multi-modality treatment regimen, is indicated for the treatment of Wilms' tumor, childhood rhabdomyosarcoma, Ewing's sarcoma and metastatic, nonseminomatous testicular cancer. /Included in US Product label/
Dactinomycin is indicated as a single agent, or as part of a combination chemotherapy regimen, for the treatment of gestational trophoblastic neoplasia. /Included in US Product label/
Dactinomycin, as a component of regional perfusion, is indicated for the palliative and/or adjunctive treatment of locally recurrent or locoregional solid malignancies. /Included in US Product label/
For more Therapeutic Uses (Complete) data for DACTINOMYCIN (7 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ COSMEGEN (Dactinomycin for Injection) should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.
/BOXED WARNING/ This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Avoid exposure during pregnancy. Due to the toxic properties of dactinomycin (eg, corrosivity, carcinogenicity, mutagenicity, teratogenicity), special handling procedures should be reviewed prior to handling and followed diligently. Dactinomycin is extremely corrosive to soft tissue. If extravasation occurs during intravenous use, severe damage to soft tissues will occur. In at least one instance, this has led to contracture of the arms.
COSMEGEN is a toxic drug and very careful and frequent observation of the patient for adverse reactions is necessary. These reactions may involve any tissue of the body, most commonly the hematopoietic system resulting in myelosuppression. As such, live virus vaccines should not be administered during therapy with COSMEGEN. The possibility of an anaphylactoid reaction should be borne in mind.
Pt may ... become more susceptible to infections due to suppression of normal immune mechanisms. If dactinomycin is given at or about time of infection with chickenpox, severe generalized disease, which is sometimes fatal, may occur.
For more Drug Warnings (Complete) data for DACTINOMYCIN (24 total), please visit the HSDB record page.

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Pharmacodynamics
Generally, the actinomycins exert an inhibitory effect on gram-positive and gram-negative bacteria and on some fungi. However, the toxic properties of the actinomycins (including dactinomycin) in relation to antibacterial activity are such as to preclude their use as antibiotics in the treatment of infectious diseases. Because the actinomycins are cytotoxic, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumor implant. This cytotoxic action is the basis for their use in the treatment of certain types of cancer. Dactinomycin is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis.

C62H86N12O16

1255.43

1254.628

C, 59.32; H, 6.90; N, 13.39; O, 20.39

50-76-0

457193

Orange to red solid powder

1.4±0.1 g/cm3

1386.0±65.0 °C at 760 mmHg

251-253 °C

792.1±34.3 °C

0.0±0.3 mmHg at 25°C

1.656

Streptomyces

-4.03

5

18

8

90

3030

10

O=C(C1=C(N)C(C(C)=C2OC3=C(N=C21)C(C(N[C@@H]4C(N[C@@H](C(C)C)C(N5[C@](CCC5)([H])C(N(C)CC(N(C)[C@@H](C(C)C)C(O[C@@H]4C)=O)=O)=O)=O)=O)=O)=CC=C3C)=O)N[C@@H]6C(N[C@@H](C(C)C)C(N7[C@](CCC7)([H])C(N(C)CC(N(C)[C@@H](C(C)C)C(O[C@@H]6C)=O)=O)=O)=O)=O

RJURFGZVJUQBHK-IIXSONLDSA-N

InChI=1S/C62H86N12O16/c1-27(2)42-59(84)73-23-17-19-36(73)57(82)69(13)25-38(75)71(15)48(29(5)6)61(86)88-33(11)44(55(80)65-42)67-53(78)35-22-21-31(9)51-46(35)64-47-40(41(63)50(77)32(10)52(47)90-51)54(79)68-45-34(12)89-62(87)49(30(7)8)72(16)39(76)26-70(14)58(83)37-20-18-24-74(37)60(85)43(28(3)4)66-56(45)81/h21-22,27-30,33-34,36-37,42-45,48-49H,17-20,23-26,63H2,1-16H3,(H,65,80)(H,66,81)(H,67,78)(H,68,79)/t33-,34-,36+,37+,42-,43-,44+,45+,48+,49+/m1/s1

2-amino-4,6-dimethyl-3-oxo-1-N,9-N-bis[(3R,6S,7R,10S,16S)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propan-2-yl)-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]phenoxazine-1,9-dicarboxamide

DACT; ACTD; actinomycin C1; actinomycin D; actinomycin I1; actinomycin IV; actinomycin X 1; actinomycinthrvalprosarmeval; dactinomycine; meractinomycin; actinomycin D; Actinomycin C1; Actinomycin IV; Meractinomycin; 50-76-0; Cosmegen; Actinomycin I1; US brand names: Cosmegen; Lyovac.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

DMSO : ≥ 27 mg/mL (~21.5 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (1.66 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 20.8 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: 2.08 mg/mL (1.66 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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.)