Charged particle cytogenetics: effects of LET, fluence, and particle separation on chromosome aberrations

Induced rearrangements of chromosomes, disrupting the orderly sequence and/or separation of the genetic material, are responsible for a significant proportion of cellular lethality, genetic mutation, and, as has become increasingly apparent in recent years, human cancer. The quantitative observation of chromosomal aberrations induced by ionizing radiations led early to the realization that as linear energy transfer (LET) increased, curvilinear dose responses became increasingly linear. Those few studies that examined aberrations as a function of LET found that the optimally effective LET was about 100 keV per micrometer, results consistent with those observed for other end points. The majority of chromosomal aberrations originate from molecular interaction between pairs of lesions (misrepair), with differences in sensitivity to aberration induction through the cell cycle. In Chinese hamster V-79 cells for all LET values studied, aberrations are most frequent in G2, then G1, then S phase of the cell cycle. The variation in sensitivity through the cell cycle changes from a factor of about 5 for 10 keV/micron particles to about 3 for 80 keV/micron particles. In the G2 phase a curvilinear dose response (G1 and S being linear) is found for all LETs occurring at fluences where there are substantial distances (greater than or equal to 3 micron) between particles. It is possible that for this one phase of the cell cycle a saturation of repair capabilities occurs as a function of both fluence and LET. When cells were irradiated with associated charged particles (molecular ions) it was found that even when two particles were separated by distances of less than 100 nm their effect was much less than one particle of twice the LET (the equivalent of 0 distance separation). This implies that the vast majority of molecular interactions which result in chromosomal aberrations occur as a consequence of interaction between damaged sites formed only a few nanometers from each other. It is clear that an analysis of chromosomal aberrations produced by charged particles can provide considerable insight into basic radiobiological mechanisms and into the organization of the mammalian genome.