Effects of Mitomycin C on Human Chromosomes

Mitomycin C (MC) is a chemically reactive antibiotic derived from Streptomyces caespitosus. The drug selectively inhibits DNA synthesis (2, 15, 29, 34, 39, 40, 43, 44, 49) and degrades cellular DNA but does not affect the synthesis of R N A or protein (31, 33, 40). MC induces bacteriophage production in lysogenic bacteria (23, 29), increases the rate of genetic recombination among mutant forms orE. coil (15, 47, 49), and possesses anti tumor activity (15, 47). In tissue culture systems, MC inhibits mitosis, reduces cell viability, and produces nuclear disorganization and giant cells (21, 32). Several models for the mechanism of MC activity have been suggested. Reich et el. proposed that MC acts through the scission of the DNA strands, thereby preventing replication (33). This implies that the template competence of the DNA is destroyed (31). ~[he depolymerization of DNA and the accumulation of acid-soluble fragments implicates the DNA polymerase system as a possible target of MC activity (33, 34). Recently, Iyer and Szybalski suggested that the primary action of MC is the "cross-linking" of the complementary strands of the DNA molecule and that the degradation of DNA may be of a secondary nature (16). The effects of MC on plant chromosomes have been previously noted. Merz (26) reported that chromatid breaks in the heterochromatic regions of Vicia ]abe root tip chromosomes were induced by MC. Matsuura et el. (24, 25) observed no breaks after MC treatment of Trillium kamschaticum; however, MC treatment followed by x-ray greatly increased the frequency of chromosome breaks involved in exchanges. Because MC has a profound effect on DNA synthesis and because another Streptomyces-derived antimicrobial agent (streptonigrin) caused nonrandom breakage of human chromosomes (3, 4), the present study was undertaken. The experiments to be described demonstrate that MC preferentially produces breaks and rearrangements in the paracentric secondary constrictions of chromosomes 1, 9, and 16. M A T E R I A L S A N D M E T H O D S