A clinically important group of anticancer drugs are certain cytotoxic antibiotics that inhibit DNA and/or RNA synthesis by complexing with DNA via an interposing reaction called intercalation. The process is now understood to be one by which the planar, poly-cyclic portions of some drugs can "slide" into the double helical DNA structure in a horizontal manner by interposing between the base layers of DNA, which are stacked at distances of 3.36 A above each other. Interactions between the purine and pyrimidine bases and the flat, aromatic portions of the intruder molecule are primarily van der Waals. Additional binding forces for particular drugs may include hydrogen bonding between certain groups on the drug molecules and on the DNA bases as well as ionic interactions.
A prominent and intensely studied antibiotic is actinomycin, which is also known as actinomycin D (Cosmogen®). It consists of a phenoxazone ring bonded to two identical cyclical pentapeptides (Fig. 4-18). The phenoxazone ring system intercalates between two successive G = C base pairs of DNA, resulting in a deformed RNA template. DNA transcription along this template is crippled since the polymerase cannot now move along it. Thus RNA chain elongation is now inhibited. In addition, hydrogen bonding exists between the NH2 group of guanosine and the threonine C = O function.
Actinomycin is particularly effective in the treatment of Wilm's tumor in the kidney (of children) and, as a member of combination protocols, against adult Ewing's and Kaposi's sarcoma. This agent is also useful in MTX-resistant choriocarcinoma. The drug is cell-cycle specific in the S and G, phase.
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