Actinomycin D.

Structural formula
General
Non-proprietary name	Actinomycin D.
other names	Dactinomycin; ACTO-D; ACTD; Dactinomycin D.; Oncostatin K; Actinomycin IV; Meractinomycin; Actinomycin 7; 2-Amino-4,6-dimethyl-3-oxo- N , N '-bis [(3 R , 6 S , 7 R , 10 S , 16 S ) 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] nonadec-6-yl] phenoxazin-1,9- dicarboxamide ( IUPAC ) ;
Molecular formula	C 62 H 86 N 12 O 16
Brief description	red, odorless solid
External identifiers / databases
EC number	200-063-6
ECHA InfoCard	100,000,058
PubChem	457193
ChemSpider	10482167
DrugBank	DB00970
Wikidata	Q186127
Drug information
ATC code	L01 DA01
Drug class	Cytostatic
Mechanism of action	DNA - intercalator
properties
Molar mass	1255.42 g mol −1
Physical state	firmly
Melting point	241.5–243 ° C (decomposition)
solubility	heavy in water (40 g l −1 at 10 ° C)
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances danger
H and P phrases	H: 300
	P: 301 + 310 + 330
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Pharmacological information
Mode of administration	intravenous (iv)
Bioavailability	oral administration not possible (toxic).
metabolism	insignificant.
Interactions	radiotherapy	Effect of actinomycin D
	Halothane , enflurane , isoflurane	Effect of actinomycin D
	Other cytotoxic drugs	Effect of actinomycin D
excretion	Urine & stool: 30% of the substance within 1 week of administration.
Incompatibility	Benzyl alcohol	Precipitation.
	Filgrastim (G-CSF)	Precipitation.
	Riboflavin	Precipitation.
Clinical information
Indication (s)	children	Nephroblastoma (Wilms tumor), soft tissue sarcoma, Ewing sarcoma, rhabdomyosarcoma
Indication (s)	Adults	Ewing's sarcoma, soft tissue sarcoma, testicular carcinoma, chorionic carcinoma, Kaposi's sarcoma
Side effects	Veno-occlusive liver disease (VOD). Nausea . Vomiting . Anorexia . Leukopenia ( neutropenia ). Thrombopenia . Anemia . Mucositis (pain, diarrhea ). Alopecia skin irritation (especially after radiation)
Contraindication (s)	Pregnancy . Lactation . Vaccinations ( live vaccines ). Simultaneous use of actinomycin D and radiation therapy is contraindicated.
Admission status
	Germany	United States	EU
Approval date	1st December 1966	October 12, 1964	--. - .----
status	Pharmacy only. Prescription only.

Actinomycin D or Dactinomycin (trade names Lyovac-Cosmegen , Cosmegen (EU); manufacturer: MSD ) is a cytostatic agent used to treat cancer . It belongs to the group of cytotoxic antibiotics (also called tumor antibiotics ). Its antineoplastic effects are mediated by binding to DNA , where actinomycin D inhibits RNA synthesis .

Origin and manufacture

Actinomycin D, from the group of actinomycins , is a peptide - antibiotic from Streptomyces parvulus . It consists of two cyclic peptides linked by an oxidized phenoxazine unit.

Mechanism of action

Actinomycin D acts as an intercalator for DNA. In a simple comparison, this means that actinomycin D blocks the DNA zip fastener so that it cannot be opened. Normal use of the DNA is not possible without opening. All cells that contain DNA are affected by the effects of actinomycin D. Only the brain cells and cells of the spinal cord are protected from the effects of actinomycin D by the blood-brain barrier . This also means that cancers of the brain and spinal cord cannot be treated with actinomycin D.

In low dosages Actinomycin D inhibits DNA-dependent RNA synthesis by intercalation (Mounting and crosslinking) of guanine - nucleotides of the DNA. The asymmetric phenoxazone plays an important role in the addition of actinomycin D to the DNA, because this component binds specifically to the sites of the DNA that are rich in guanine and cytosine nucleotides (GC-rich). By binding to the DNA, the DNA-dependent RNA polymerase is blocked: The formation of mRNA does not occur and protein production decreases. At higher doses, actinomycin D also inhibits DNA replication . The activity of the DNA polymerase is blocked here. There are connections within a single strand of DNA, between two strands of DNA, and between DNA and proteins.

Actinomycin D is not tied to a specific phase of the cell cycle . However, there is experimental evidence in human leukemia cell lines that actinomycin D is particularly active in the S and G2 phases of the cell cycle. From this it was concluded that topoisomerase II might have a role in actinomycin D activity.

Pharmacokinetics

Actinomycin D is absorbed by bone marrow cells and tumor cells after intravenous administration. Actinomycin D can also be detected in other internal organs and tissues. The median peak concentration of 25.1 ng / ml at a dose of 0.7–1.5 mg / m ² body surface area (BSA) occurs 15 minutes after administration. Little actinomycin D is found in red blood cells. Actinomycin D does not cross the blood-brain barrier. Efficacy in the brain or central nervous system is therefore very unlikely. The median duration of exposure is 2.67 mg / l × min (range 1.12–4.90 mg / l × min). The maximum concentration (Cmax) and the Area Under Curve ( AUC ) depend on the dose. The AUC is higher in patients weighing less than 40 kg, which may correlate with a higher risk of toxicity. Actinomycin D is bound to plasma protein by approximately 5%.

30% of a dose is excreted in the urine and stool within one week, 15% in the urine alone. The terminal plasma half-life has been determined to be 36 hours. In the case of functional impairment of the liver, the plasma half-life can be significantly longer than 36 hours. Actinomycin D cannot be ingested orally due to its highly irritating properties. It is therefore not available as juice or tablets.

Interactions

Irradiation: The simultaneous application of radiation and actinomycin D leads to an increase in the effectiveness of actinomycin D in the irradiated body tissues. The irradiated skin may be reddened and painful after administration of actinomycin D. This also happens if there is insufficient time between the irradiation and actinomycin D administration. When the liver is irradiated (for example in the case of a right-sided nephroblastoma), damage to the liver occurs more frequently and more seriously than with actinomycin D treatment alone. The same applies to the mucous membranes of the mouth, esophagus and intestines. If parts of these mucous membranes have been irradiated prior to actinomycin D administration, the mucosal damage ( mucositis ) caused by actinomycin D is usually more pronounced and more severe than when actinomycin D is administered alone.

Inhalation narcotics: The simultaneous use of halogenated inhalation anesthetics such as halothane , isoflurane and enflurane leads to an increase in the effectiveness of actinomycin D. The mechanism for this has not been clarified.

Other cytotoxic drugs: Other cytotoxic drugs can increase the effects and side effects of actinomycin D.

application areas

Actinomycin D is used for the antineoplastic therapy of solid tumors or cancers.

It is currently not used to treat leukemia and / or lymphoma . In addition, it is also not used as an immunosuppressant in the treatment of autoimmune diseases . However, there is evidence that actinomycin D may be beneficial in CLL.

Adults

Ewing's sarcoma: Actinomycin D is used in the treatment of Ewing's sarcoma as part of a combination chemotherapy with the cytostatic agents vincristine, adriamycin and ifosfamide: Together with these cytostatic agents, it forms the VAIA block, which has proven to be effective in the treatment of Ewing's sarcoma. The VAIA block can be expanded to the EVAIA block by adding etoposide. The VACA block is also effective: Here the ifosfamide has been exchanged for cyclophosphamide.

Soft tissue sarcoma: Actinomycin D is used in the treatment of soft tissue sarcomas such as rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma and other types of tumors as part of combination chemotherapy. Essentially, the combination chemotherapies correspond to those used in Ewing's sarcoma, especially VAI , VAC , VAIA and VACA.

Children and young people

Nephroblastoma (Wilms tumor): Actinomycin D is one of the essential cytostatic agents in the treatment of nephroblastoma (Wilms tumor) in children and adolescents. Its effectiveness in nephroblastoma has been repeatedly proven in several international studies. In particular, the combination of actinomycin D with vincristine or the combination with vincristine and adriamycin ( doxorubicin ) have proven to be very effective in combating nephroblastoma.

Ewing's sarcoma: Actinomycin D was used in the EICESS 92 protocol in the treatment of Ewing's sarcoma as part of a combination chemotherapy with the cytostatic agents vincristine, adriamycin and ifosfamide: with these cytostatic agents it forms the VAIA block, which has proven to be effective in the treatment of Ewing's sarcoma Has. The VAIA block can be expanded to the EVAIA block by adding etoposide. The VACA block is also effective: Here the ifosfamide has been exchanged for cyclophosphamide.

The current (2006) standard treatment in Europe according to the Euro-EWING 99 therapy optimization study provides for treatment with actinomycin D in postoperative chemotherapy (after removal of the tumor). Actinomycin D is always administered as part of the VAC (vincristine, actinomycin D, cyclophosphamide) and VAI blocks (vincristine, actinomycin D, ifosfamide). Actinomycin D must not be administered in parallel with radiation therapy because of the increase in the side effects of radiation therapy.

Soft tissue sarcomas: Actinomycin D is used in the treatment of soft tissue sarcomas such as rhabdomyosarcoma , leiomyosarcoma , synovial sarcoma and other types of tumors as part of combination chemotherapy. Essentially, the combination chemotherapies correspond to those used in Ewing's sarcoma, especially VAIA and VACA. In addition, VAC (vincristine, actinomycin D and cyclophosphamide) is used as a standard treatment with good response rates. For soft tissue sarcomas with a favorable risk profile (stage I and favorable histology = tumor type), treatment with vincristine and actinomycin D alone is effective.

Side effects

Bone marrow toxicity ( leukopenia , thrombopenia , anemia ): The dose-limiting side effect of actinomycin D is bone marrow toxicity. The action of actinomycin D hampers and suppresses blood formation. After administration of actinomycin D, thrombopenia and leukopenia in particular result. The nadir (low point in the number of blood cells) occurs 1 to 2 weeks after administration. The bone marrow and blood formation recover after actinomycin D administration within 2 to 3 weeks. Actinomycin D does not accumulate in red blood cells ( erythrocytes ), which are DNA-free, but the damage occurs in the development stage of the erythrocytes in the bone marrow , where they still contain DNA.

Tissue irritation: Actinomycin D is highly toxic. In the event of undiluted contact with skin and soft tissue, it damages them severely. In the event of (unintentional and unwanted) administration into the connective tissue next to the vein, severe skin and connective tissue reactions can occur: Depending on the amount or dose of actinomycin D used, the affected tissue can die ( necrosis ). This side effect is particularly serious if the affected area has previously been irradiated. Even if the irradiation was completed weeks ago, irradiated tissue can react irritated after actinomycin D administration ( radiation recall phenomenon).

Due to its toxicity, the regulations for handling cytostatics must be strictly observed. Contact with actinomycin D should be avoided wherever possible. This also applies to inhalation of powder or contact of actinomycin D with the eyes. Skin or eyes contaminated with actinomycin D should be flushed immediately with water or saline for 15 minutes.

Nausea, vomiting, loss of appetite: The first appearance occurs 1–6 hours after actinomycin D administration. With appropriate psychological conditioning, vomiting and nausea can occur more quickly . The duration of nausea and vomiting after actinomycin D administration can last 4–20 hours. This side effect is common (affects more than 10% of treated patients). Treatment (ideally prophylactic) with antiemetics such as granisetron , tropisetron , ondansetron is indicated.

Infections: Due to the leukopenia with associated neutropenia, the susceptibility to infections is increased during treatment with actinomycin D. It is easier to bacterial and mycotic (fungal) infections. These can be minor, but most often they are more serious infections such as pneumonia and urinary tract infections . The immune defense can be so weakened by the leukopenia that blood poisoning ( sepsis ) by bacteria, fungi or viruses can occur. These are life threatening.

The lymphopenia that comes with leukopenia increases the risk of serious viral infections .

Damage to the mucous membrane (mucositis): Actinomycin D causes severe damage to the mucous membranes in the mouth, esophagus and intestines. The characteristics of the damage to the mucous membrane ( mucositis ) are pain (sometimes only controllable using morphine ) and diarrhea . The latter can also be bloody if severely damaged. Damage to the mucous membrane with diarrhea and pain occurs in 30% of all patients treated with actinomycin D, so this side effect is very common. With simultaneous anemia and impaired liver function with subsequent coagulation disorders , bloody diarrhea can result in severe (dangerous) bleeding ; this is rare.

Liver damage (hepatotoxicity): Actinomycin D can damage the liver. In addition to minor and reversible liver damage with an increase in transaminases as a sign of the toxic effect on the liver cells, venous occlusive liver disease ( veno-occlusive disease; VOD ) of the liver can occur. In this case, the hepatic veins , especially the smaller ones, thrombose for a reason that has not been definitively established and subsequently cause severe damage to the liver. Although this VOD is reversible, in not a few cases veno-occlusive liver disease can result in fatal acute liver failure .

In particular, if the liver has been irradiated beforehand (for example as part of the therapy for a right-sided nephroblastoma ), the likelihood of life damage occurring is significantly increased. In the case of nephroblastoma (on the right side, side of the liver), actinomycin D should not be administered for up to two months after irradiation.

Carcinogenicity, mutagenicity, embyrotoxicity: Actinomycin D has been shown to be mutagenic and embryotoxic . It changes the genetic material and damages unborn life. It is also a carcinogen: Actinomycin D can cause cancer.

Amenorrhea and infertility: Actinomycin D is very likely to inhibit testicular and ovarian function, although it has not been studied explicitly. In women, the inhibition of ovarian function results in (secondary) amenorrhea (loss of menstrual bleeding). In men, the sperm are either severely damaged or absent ( azoospermia ).

Historical

Actinomycin D was first described in 1949. The description of a controlled synthesis as the basis for industrial production was published in 1959. In 1959 the first study was published which looked at the use of actinomycin D in childhood tumors. Giulio D'Angio first described how actinomycin D increased the effect of X-rays. In the same year, the teratogenic effects of actinomycin D were also described. Actinomycin D was first used in lymphoma (reticulosarcoma) in 1959.

Actinomycin D was originally developed as an antibiotic. Due to its pronounced toxicity, it could not be used to treat bacterial infections.

Web links

Actinomycin D Monograph from the BC Cancer Agency Free access. Status: 1994
US package insert Actinomycin D. Status: June 2005 ( Memento from December 1, 2007 in the Internet Archive )

Individual evidence

↑ ^a ^b ^c ^d ^e Entry on dactinomycin in the GESTIS substance database of the IFA , accessed on January 23, 2020(JavaScript required) .
↑ ABDA database (as of June 11, 2008) of DIMDI
↑ Delepierre M. et al. Reassessment of structural characteristics of the d (CGCG) 2: actinomycin D complex from complete 1H and 31P NMR. J Biomol Struct Dyn. 1989 Dec; 7 (3): 557-589. PMID 2627299
^ Wu MH, Yung BY Cell cycle phase-dependent cytotoxicity of actinomycin D in HeLa cells. Eur J Pharmacol . 1994 Apr 4; 270 (2-3): 203-212. PMID 8039550
↑ Veal GJ et al. of United Kingdom Children's Cancer Study Group, Pharmacology Working Group. Pharmacokinetics of dactinomycin in a pediatric patient population: a United Kingdom Children's Cancer Study Group Study. Clin Cancer Res . 2005 Aug 15; 11 (16): 5893-5899. PMID 16115931
↑ O. Merkel, N. Wacht, E. Sifft, T. Melchardt, F. Hamacher, T. Kocher, U. Denk, JP Hofbauer, A. Egle, M. Scheideler, M. Schlederer, M. Steurer, L. Kenner, R. Greil: Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic . In: Leukemia . 26, No. 12, December 2012, pp. 2508-2516. doi : 10.1038 / leu.2012.147 . Retrieved April 1, 2014.
↑ EURO-EWING-99 study kinderkrebsinfo.de
↑ Dalgliesch CE, Todd AR Actinomycin. Nature . 1949 Nov 12; 164 (4176): 820. PMID 15395378
↑ Katz E., Goss WA Controlled biosynthesis of actinomycin with sarcosine. Biochem J . 1959 Nov; 73: 458-465. PMID 14404788
↑ Tan CT et al. The effect of actinomycin D on cancer in childhood. Pediatrics. 1959 Oct; 24: 544-561. PMID 13836792
↑ D'Angio GJ et al. Potentiation of x-ray effects by actinomycin D. Radiology. 1959 Aug; 73: 175-177. PMID 13813586
↑ Tuchmann-Duplessis H, Mercier-Parot L. Apropos of the teratogenic action of actinomycin. CR Seances Soc Biol Fil. 1959; 153: 1697-1700. PMID 13839737
↑ Shiba S. Studies on the therapy of reticulosarcoma (-tosis) with actinomycin. Acta Unio Int Contra Cancrum. 1959; 15 (Suppl 1): 264-266. PMID 14445951

[GESTIS-1] Entry on dactinomycin in the GESTIS substance database of the IFA , accessed on January 23, 2020(JavaScript required) .

[DIMDI-2] ABDA database (as of June 11, 2008) of DIMDI

[ACTOD2-3] Delepierre M. et al. Reassessment of structural characteristics of the d (CGCG) 2: actinomycin D complex from complete 1H and 31P NMR. J Biomol Struct Dyn. 1989 Dec; 7 (3): 557-589. PMID 2627299

[ACTOD3-4] Wu MH, Yung BY Cell cycle phase-dependent cytotoxicity of actinomycin D in HeLa cells. Eur J Pharmacol . 1994 Apr 4; 270 (2-3): 203-212. PMID 8039550

[ACTOD1-5] Veal GJ et al. of United Kingdom Children's Cancer Study Group, Pharmacology Working Group. Pharmacokinetics of dactinomycin in a pediatric patient population: a United Kingdom Children's Cancer Study Group Study. Clin Cancer Res . 2005 Aug 15; 11 (16): 5893-5899. PMID 16115931

[6] O. Merkel, N. Wacht, E. Sifft, T. Melchardt, F. Hamacher, T. Kocher, U. Denk, JP Hofbauer, A. Egle, M. Scheideler, M. Schlederer, M. Steurer, L. Kenner, R. Greil: Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic . In: Leukemia . 26, No. 12, December 2012, pp. 2508-2516. doi : 10.1038 / leu.2012.147 . Retrieved April 1, 2014.

[7] EURO-EWING-99 study kinderkrebsinfo.de

[ACTOD5-8] Dalgliesch CE, Todd AR Actinomycin. Nature . 1949 Nov 12; 164 (4176): 820. PMID 15395378

[ACTOD6-9] Katz E., Goss WA Controlled biosynthesis of actinomycin with sarcosine. Biochem J . 1959 Nov; 73: 458-465. PMID 14404788

[ACTOD7-10] Tan CT et al. The effect of actinomycin D on cancer in childhood. Pediatrics. 1959 Oct; 24: 544-561. PMID 13836792

[ACTOD8-11] D'Angio GJ et al. Potentiation of x-ray effects by actinomycin D. Radiology. 1959 Aug; 73: 175-177. PMID 13813586

[ACTOD9-12] Tuchmann-Duplessis H, Mercier-Parot L. Apropos of the teratogenic action of actinomycin. CR Seances Soc Biol Fil. 1959; 153: 1697-1700. PMID 13839737

[ACTOD10-13] Shiba S. Studies on the therapy of reticulosarcoma (-tosis) with actinomycin. Acta Unio Int Contra Cancrum. 1959; 15 (Suppl 1): 264-266. PMID 14445951