Bleomycin--mode of Action with Particular Reference to the Cell Cycle

Over the last four years, investigations into the mechanism of interaction between bleomycin and DNA have been pursued at a rapid pace. This is, no doubt, because of the potential of bleomycin as a tool for molecular biology. It seems likely that the precise nature of the interaction between Fe(II), oxygen and bleomycin will be elucidated in the near future together with the nature of the binding between the complex and DNA. More information on the mechanism of strand scission including the involvement of free radical mechanisms and sequence specificity may also be expected. In contrast to this picture of rapid progress at the molecular level, interest in studies of bleomycin action at the cellular level appears to have waned. This is despite the fact that most of the important questions which have been raised regarding effects of the drug on cell cycle progression, the possibility of a selective action on on-cycling cells and the nature of 'recovery from potentially-lethal damage' remain unresolved. There is no doubt that, for most cell types, bleomycin produces a block at the early G2 stage of the cell cycle. There is considerable doubt, however, as to how many of the cells blocked for a significant period remain clonogenically viable. This question is amenable to being answered using a vital DNA stain, such as Hoechst 33342, and cell sorting but this does not appear to have been done. The relationship between G2 blockage and repair of DNA damage has also not been resolved. Neither has the question of whether or not DNA breaks which remain unrepaired are different in nature from the majority of repairable lesions. The data on the relative sensitivity of exponential and plateau phase cells are conflicting and their in vivo significance unclear. Well designed experiments to examine the bleomycin sensitivity of those cells in solid tumors which survive radiation treatment could help to answer this question. Evidence that the phenomenon of 'recovery from potentially lethal damage' is therapeutically-exploitable is mainly lacking. It would be of great relevance to known whether or not the effect can be observed in normal tissues. However, the evidence that the effect is not simply an artefact of clonogenic assay procedures is scanty and this possibility must be borne in mind.(ABSTRACT TRUNCATED AT 400 WORDS)