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Insight into cancer, one of the principal scourges of modern man, has increased slowly but steadily over the years. Epidemiologists concur that most human malignancies are caused, at least in part, by environmental determinants over which an individual can exercise some control; in principle then, the disease is preventable to some extent (10). In practice, however, the goal of cancer prevention by large-scale efforts to minimize exposure to the causal agents would seem to be unattainable, as judged by societal experience with two major ‘life-style‚ factors, habitual tobacco usage and sunbathing. Although an ultimate aim is to develop other more socially acceptable prevention strategies, there exists in the interim a requirement for improved diagnostic techniques and more rational treatment protocols. Each of these approaches to cancer control will almost certainly necessitate clearer understanding of the fundamental mechanisms underlying the etiology and pathogenesis of the disease.

Insight into cancer, one of the principal scourges of modern man, has increased slowly but steadily over the years. Epidemiologists concur that most human malignancies are caused, at least in part, by environmental determinants over which an individual can exercise some control; in principle then, the disease is preventable to some extent (Doll and Peto, 1981). In practice, however, the goal of cancer prevention by large-scale efforts to minimize exposure to the causal agents would seem to be unattainable, as judged by societal experience with two major ‘life-style’ factors, habitual tobacco usage and sunbathing. Although an ultimate aim is to develop other more socially acceptable prevention strategies, there exists in the interim a requirement for improved diagnostic techniques and more rational treatment protocols. Each of these approaches to cancer control will almost certainly necessitate clearer understanding of the fundamental mechanisms underlying the etiology and pathogenesis of the disease.

SUMMARY A re-analysis of the metabolic fate of ultraviolet light (u.v.)-induced cyclobutyl pyrimidine dimers in the DNA of dermal fibroblasts from patients with different genetic forms of xeroderma pigmentosum (XP), a rare cancer-prone skin disorder, has provided new insight into the mode of dimer repair in normal human cells. When DNA isolated from post-u.v. incubated cultures was subjected to enzymic photoreactivation (PR) to probe dimer authenticity, single-strand scissions were produced in the damaged DNA of incubated XP group A and D cells, but not in DNA from XP group C cells or normal controls. Since enzymic PR treatment ruptures only the cyclobutane ring, these results suggested that in dimer excision-defective XP group A and D strains, the intradimer phosphodiester bond may have been cleaved without site restoration. Such a cleavage event had not previously been detected; the possibility that this reaction may be an early step in the normal excision-repair process is supported by the observed release of free thymidine (dThd) and its monophosphate (TMP), but not of thymine, upon photochemical reversal of the dimer-containing excision fragments isolated from post-u.v. incubated normal cells. The combined number of dThd and TMP molecules released was equal to ≈80% of the number of dimers photoreversed; for such release to occur, the dimer must both be at one end of an excised fragment and contain an internal phosphodiester break. Taken together, these data lead us to propose a novel model for dimer repair in human cells in which hydrolysis of the intradimer phosphodiester linkage precedes the concerted action of a generalized ‘bulky lesion-repair complex’ involving conventional strand incision/lesion excision/repair resynthesis/strand ligation reactions.

Retrospective studies of cancer incidence in AT families suggest that the major detrimental impact of the AT gene on the health of the general population stems from its disease-predisposing potential in heterozygotes. The absence of a definitive marker for routine identification of such carriers, however, has previously precluded direct validation of this predicted effect of AT heterozygosity. We demonstrate that chronic gamma-ray exposure, because it expands the difference in radiation cytotoxicity between normal and heterozygotic strains compared to acute dose delivery, may point the way to development of a reliable laboratory diagnostic procedure for identification of carriers of a defective AT gene.

Comparative effects of decay of DNA-bound 125I, of gamma-radiation and of tritiated water on survival of the proliferative ability of cultured cells were examined. The results confirm a previous report that cells frozen to -196 degrees C in the presence of 2M glycerol have lost a considerable proportion of their intracellular water. The data also suggest that the fraction of the lethal damage caused by deposition of radiation energy in intracellular water close to the DNA is greater for gamma-radiation than for the decay of DNA-bound 125I. Inherited differences in the sensitivity of untransformed fibroblasts from individual humans to ionizing radiations and other DNA-damaging agents are being explored. The ratios of the sensitivities of various cell lines to particular agents can vary several-fold. Thus the RBE of various radiations is affected not only by the irradiation conditions and the water content of the cells but also by inherited abnormalities in the DNA repair systems in human cells.

Micrococcus radiodurans possesses an exonuclease (orthophosphoric diester phosphohydrolase EC 3.1.4.1) bound to its cell surface. Exposure to ionizing radiation causes release of this activity into the surrounding medium; less than 10% remains cell associated after 400 krad dose (sublethal). This enzyme is not normally excreted. The extent of release is a function of total ionizing radiation dose only, and is independent of dose rate or temperature. This enzyme is not involved in the postirradiation DNA degradation that accompanies repair in this organism. A 5′-nucleotidase also located in the cell envelope is not released under these conditions. Since only a small amount of the total cell protein is released, an initial enzyme purification of about 150-fold could be achieved relative to crude extracts.

The effect of liquid-holding after γ and uv irradiation was investigated in three different strains of Schizosaccharomyces pombe: the haploid wild type $972\ {\rm h}^{-}$ , the diploid ${\rm h}^{-}/{\rm h}^{-}$ and the radiation-sensitive strain UVS-1 ${\rm h}^{-}$ . It was found that the diploid strain is only slightly more resistant to inactivation by both γ and uv irradiation compared to the haploid wild type. For liquid-holding experiments various non-nutrient solutions were examined and two which yielded minimal spontaneous cell death were chosen as favorable for all subsequent studies. These experiments have shown that: (i) the haploid wild type exhibited negative liquid-holding effect (NLHE) after γ irradiation, similar to that reported previously for uv irradiation; (ii) the diploid strain showed NLHE after both γ and uv irradiation; the rate of NLHE, for a given dose, was similar to that for the haploid strain; (iii) for both haploid an...