Actinomycin d

Actinomycin D is a cytostatic drug obtained from Streptomyces parvulus, approved since December 1, 1966 and available only on prescription. Actinomycin, a red, odorless solid with the molecular formula: C62H86N12O16 belongs to the group of cytotoxic antibiotics (tumor antibiotics). Its antineoplastic effect is mediated by binding to DNA, whereby Actinomycin D inhibits RNA synthesis.

Actinomycin D acts as an intercalator of DNA. It binds strongly but reversibly to DNA and thus interferes with the synthesis of RNA (prevention of RNA polymerase elongation) and consequently with protein synthesis.

Actinomycin D is taken up 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 dosage of 0.7-1.5 mg/m2 body surface area (KOF) occurs 15 minutes after administration. Little actinomycin D is found in red blood cells. Actinomycin D does not cross the blood-brain barrier. 30% of a dose is excreted in urine and feces within one week, 15% in urine alone. The terminal plasma half-life has been determined to be 36 hours. If liver function is impaired, the plasma half-life may be significantly longer than 36 hours. Actinomycin D cannot be absorbed orally due to its strong irritant properties. It is therefore not available as juice or tablets.

Actinomycin D is used for antineoplastic therapy of solid tumors or cancers. It is not currently used for the treatment of leukemias and/or lymphomas. In addition, it is not used as an immunosuppressant in the treatment of autoimmune diseases.

Adults

Ewing's sarcoma: Actinomycin D is used in the treatment of Ewing's sarcoma as part of combination chemotherapy with the cytostatic agents vincristine, adriamycin, and ifosfamide:

Soft tissue sarcoma: Actinomycin D is used in the treatment of soft tissue sarcoma such as rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma and other tumor types as part of combination chemotherapies. Mainly used are: VAI, VAC, VAIA and VACA.

Children and adolescents

Nephroblastoma (Wilms tumor): Actinomycin D is one of the essential cytostatic drugs in the treatment of nephroblastoma (Wilms tumor) in children and adolescents. In particular, the combination of Actinomycin D with vincristine or the combination with vincristine and Adriamycin (doxorubicin) have been shown to be very effective in the control of nephroblastoma.

Ewing's sarcoma: Actinomycin D is used as part of combination chemotherapy with the cytostatic drugs vincristine, adriamycin and ifosfamide: it forms the so-called VAIA block with these cytostatic drugs. The VAIA block can be extended to the EVAIA block by adding etoposide.

Soft tissue sarcomas: Actinomycin D is used in the treatment of soft tissue sarcomas such as rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma and other tumor types as part of combination chemotherapies.

For adults or children, the dosage should not exceed 15 μg/kg body weight per day or 400 - 600 μg/m 2 body surface area per day for five consecutive days when administered intravenously per two-week treatment cycle.

For overweight or edematous patients, the dose should be calculated by body surface area to correspond as closely as possible to lean body mass.

Bone marrow toxicity (leukopenia, thrombocytopenia, anemia). The dose-limiting side effect of Actinomycin D is bone marrow toxicity.

Tissue Irritation: Actinomycin D severely damages skin and soft tissues in undiluted contact. Extravasation may result in severe local necrosis. Pre-irradiation may result in a radiation recall phenomenon.

Nausea, vomiting, loss of appetite: Initial onset occurs 1-6 hours after actinomycin D administration. Duration of nausea and vomiting may last 4-20 hours. Affects > 10% of treated patients. Treatment with antiemetics such as granisetron, tropisetron, ondansetron is indicated.

Infections: Due to leukopenia with associated neutropenia, susceptibility to infections is increased with Actinomycin D therapy. The risk of severe viral infections is increased.

Mucosal damage (mucositis): Damage to the mucous membranes of the mouth, esophagus, and intestines is common. Mucosal damage with diarrhea and pain occurs in 30% of patients treated with Actinomycin D.

Liver Damage (Hepatotoxicity): Actinomycin D may cause damage to the liver. In addition to minor and reversible liver toxicity with increases in transaminases, veno-occlusive disease (VOD) of the liver may occur (Tornesello A et al. 1998). Although VOD is usually reversible, it can progress to fatal acute liver failure. Another complication is hepatopathy-thrombocytopenia syndrome/ HTS (Farruggia P et al. 2011). After previous irradiation of the liver (for example, as part of therapy for right-sided nephroblastoma), the likelihood of life-threatening damage occurring is significantly increased. Actinomycin D application should therefore be avoided for up to two months after irradiation.

Carcinogenicity, Mutagenicity, Embyrotoxicity: Actinomycin D is mutagenic and embryotoxic.

Amenorrhea and Inability to Procreate: Actinomycin D probably inhibits testicular and ovarian function. In females, (secondary) amenorrhea results. In males, azoospermia results.

Dermatologic complications

• Radiation-recall dermatitis in previously irradiated skin areas: Dermatitic reaction following application of Actinomycin D in previously irradiated skin areas.
• Fixed drug reactions that heal under prolonged persistent hyperpigmentation but typically recur after reapplication (Kanwar VS et al 1995). Histologically, interface dermatitis with possible syringometaplasia is seen.
• Multiforme exanthema (see erythema multiforme) has been observed in combination with 5-fluorouracil (Wang S et al 2022).
• Alopecia
• Nail dystrophies

Radiotherapy, halothane, enflurane, isoflurane increase the effect of Actinomycin D.

The simultaneous application of irradiation and Actinomycin D leads to an increase in the effect of Actinomycin D in the irradiated body tissues. A painful dermatitic reaction may develop in the irradiated after Actinomycin D administration. This radiation-recall dermatitis may occur days or even months after irradiation.

When the liver is irradiated (for example, in a right-sided nephroblastoma), damage to the liver occurs more frequently and more severely 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 before Actinomycin D administration, the mucosal damage (mucositis) caused by Actinomycin D is usually more pronounced and severe compared to Actinomycin D administration alone.

Other cytostatic drugs: Other cytostatic drugs may increase the effects and side effects of Actinomycin D.

Pregnancy. Lactation. Vaccinations (live vaccines). The concomitant use of Actinomycin D and radiotherapy is contraindicated.

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Actinomycin D was originally developed as an antibiotic. Actinomycin D was first described in 1949, but because of its toxicity, the antimicrobial indication was not considered. In 1959, the use of Actinomycin D in tumor diseases of children was described.

1. Coppes MJ et al (1997) Cutaneous toxicity following the administration of dactinomycin. Med Pediatr Oncol 29:226-227.
2. Farruggia P et al (2011) Hepatopathy-thrombocytopenia syndrome (HTS) after actinomycin-D therapy: report of three cases and review of the literature. Pediatr Hematol Oncol 28:237-243.
3. Kanwar VS et al (1995) Unusual cutaneous toxicity following treatment with dactinomycin: a report of two cases. Med Pediatr Oncol 24:329-333.
4. Tornesello A et al (1998) Veno-occlusive disease of the liver in right-sided Wilms' tumours. Eur J Cancer 34:1220-1223.
5. Wang S et al (2022) 5-Fluorouracil and actinomycin D lead to erythema multiforme drug eruption in chemotherapy of invasive mole: Case report and literature review. Medicine (Baltimore) 101:e31678