Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Recordati Rare Diseases, Immeuble Le Wilson, 70 avenue du Général de Gaulle, 92800 Puteaux, France
Mode of action: Cosmegen inhibits the proliferation of cells by forming a stable complex with DNA and interfering with DNA-dependent RNA synthesis.
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 tumour implant. This cytotoxic action is the basis for their use in the palliative treatment of certain types of cancer.
Results of a study in patients with malignant melanoma indicate that dactinomycin (3H actinomycin D) is minimally metabolised, is concentrated in nucleated cells and does not penetrate the blood brain barrier. Approximately 30% of the dose was recovered in urine and faeces in one week. The terminal plasma half-life for radioactivity was approximately 36 hours.
The international Agency on Research on Cancer has judged that dactinomycin is a positive carcinogen in animals. Local sarcomas were produced in mice and rats after repeated subcutaneous or intraperitoneal injection. Mesenchymal tumours occurred in male F344 rats given intraperitoneal injections of 50 micrograms per kg, two to five times per week for 18 weeks. The first tumour appeared at 23 weeks.
Dactinomycin has been shown to be mutagenic in a number of test systems in vitro and in vivo, including human fibroblasts and leucocytes, and HELA cells. DNA damage and cytogenetic effects have been demonstrated in the mouse and the rat.
Adequate fertility studies have not been reported, although, an increased incidence of infertility following treatment with other antineoplastic agents has been reported.
Cosmegen has been shown to cause malformations and embryotoxicity in the rat, rabbit and hamster when given in doses of 50-100 micrograms per kg intravenously (three to seven times the maximum recommended human dose).
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