Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Miscellaneous Anticancer Drugs: 

  • Dactinomycin (actinomycin D; Cosmegen)

     

    • Dactinomycin (Cosmegen)

     

    • Overview:

      • Actinomycins are antibiotic metabolites that have been isolated from Streptomyces.⁷

        • Historically, dactinomycin was the first antibiotic demonstrated to exhibit anticancer properties.

          • Selman Waksman, credited with discovering these antibiotics in Actinomyces antibioticus, received the Nobel Prize in medicine (1951) for this work.

            • Selman Waksman, Ph.D.

              Attribution: This figure corresponds to Figure 1 in reference 10. (Woodruff HB Selman A. Waksman, Winner of the 1952 Nobel Prize for Physiology or Medicine. Appl Environ Microbiol 80(1) 2-8 (2014).) "Professor Selman Waksman with graduate student H. Boyd Woodruff. Laboratory photograph during the studies leading to the discovery of actinomycins, 1940. Administration Building, School of Environmental and Biological Sciences (SEBS), Rutgers University. (Special Collections in University Archives, Rutgers University Libraries)". https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911012/

        • Actinomycin-D (Cosmegen) has proven useful in treating both choriocarcinoma and pediatric sarcomas.⁸ 

          • Dactinomycin is also been shown important in treating Wilms tumor, rhabdomyosarcoma and Ewing sarcoma.

          • Dactinomycin is also active in NPM1-mutated AML (Acute Myeloid Leukemia).⁸

            • Nucleophosmin NPM1 (a.k.a. nucleolar phosphoprotein B23 or numatrin) gene mutations represent the most frequent acquired abnormalities in acute myeloid leukemia (AML).¹¹ 

              • NPM1 Protein¹²

                Attribution:  Emw "Structure of the NPM1 protein.  Bases on Pymol rendering of PDB  2p1b." Emw [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)]. https://commons.wikimedia.org/wiki/File:Protein_NPM1_PDB_2p1b.png

       

      • Absorption, Distribution, Biotransformation, Excretion:

        • Dactinomycin is administered by the intravenous (IV) route of administration.¹

        • In children the volume of distribution (Vd) ranges from about 60 to about 700 L, consistent with substantial extravascular distribution.⁹ 

        • Dactinomycin does not cross the blood-brain barrier.

        • Dactinomycin is subject to very limited hepatic metabolism.⁹ 

          • Dactinomycin is excreted in the urine and bile and exhibits a terminal plasma half-life (t_½) of about 36 hours.¹

            • About 30% of a parent compound can be recovered in urine and feces within about one week.⁹

      • Mechanism of Action:

        • Dactinomycin is a DNA intercalator, binding to double-helical DNA.¹ 

          • This binding accounts for the drug's biological effects and cytotoxic activity.

            • The planar phenoxazone rain fits (intercalates) between adjacent guanine-cytosine pairs in DNA.

              • In addition, the polypeptide chains position themselves in the minor groove of the DNA helix.

              • This dactinomycin-DNA complex is sufficiently thermodynamically stable to block DNA transcription by RNA polymerase.¹

              • Dactinomycin: DNA Binding¹³

                Figure attribution:  reference 13 The pentapeptide lactone (circled in red) binds to residues located in the DNA minor groove by means of both hydrogen and hydrophobic bonding. The actinosin aromatic portion is flat, allowing ready intercalation between guanosine and cytosine residues on a single DNA strand. The p-benzoquinoneimine component (lower right side of the molecule) is associated with metabolism by NADPH/CYP 450 reductase, associated with additional single-strand DNA breaks and free radical generation.13

               

              • Dactinomycin is categorized as one of the most potent antitumor drugs, effective in inhibiting rapidly dividing normal and neoplastic cells.¹

      • Clinical Uses:

        • The principal clinical use of dactinomycin is treating rhabdomyosarcoma and Wilms tumor in children.¹ 

          • When used in the treatment of Wilms tumor dactinomycin in combination with other modalities including surgery, radiation therapy, vincristine and cyclophosphamide chemotherapy may be curative.¹ 

        • Dactinomycin is also important in treating Ewing sarcoma.⁷

         

      • Toxicities/Adverse Effects:^1,13

        • Early-onset toxicities due to dactinomycin administration include:

          • Nausea

          • Anorexia

          • Vomiting.

        • Hematopoietic suppression (with pancytopenia) may develop within a week following therapy completion.

          • Myelosuppression is a common side effect and is often the dose-limiting toxic reaction.

            • The low point with respect to white blood cell and platelet levels occurs in the 8-15 day period following dactinomycin administration.⁸

        • Dactinomycin is a significant vesicant with extravasation associated with substantial tissue damage.

          • "Full thickness skin necrosis presenting 48h following chemotherapy extravasation."¹⁴

            "Full thickness skin necrosis presenting 48h following chemotherapy extravasation."9 Attribution: (Ioannis Goutos) Goutos I CogswellLK Giel H Extravasation Injuries: a review.  The Journal of Hand Surgery [European Volume] 2014, Vol 38E(8) 808-818. https://www.researchgate.net/publication/259629745_Extravasation_injuries_A_review

        • Dermatological effects of dactinomycin include:

          • Alopecia

          • Erythema

          • Desquamation

          • Increased inflammation/pigmentation in concurrently and previously irradiated regions.

        • Previous radiotherapy:⁸

          • Since dactinomycin is associated with radiosensitization, inflammatory reactions at previously irradiated locations may occur.

            • Clinically, these reactions may sometimes be serious particularly if lungs are involved.

            • Such symptoms may be mitigated by corticosteroid administration.

        • Oral mucosal ulcerations are frequently encountered along with proctitis, glossitis, lip inflammation (cheilitis).^1,13

        • Dactinomycin administration is associated with increases in liver enzymes.

          • A more severe hepatotoxicity with characteristics of venoocculsive pathology has been noted in some children treated for Wilms tumor.

            • Venoocculsive disease associated with either chemotherapy or bone marrow transplantation may be more appropriately referred to as "sinusoidal obstruction syndrome."¹²