Inhibition of DNA excision repair and the repair of X-ray-induced DNA damage by cytosine arabinoside and hydroxyurea.
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Aphidicolin↗
Biomedical subjects
R J Fram
Publications and source records attributed to R J Fram.
Mismatch repair of cis-diamminedichloroplatinum(II)-induced DNA damage.
Because cytotoxicity by an alkylating agent such as N-methyl-N'-nitrosoguanidine is markedly increased in adenine methylase-deficient dam-3 Escherichia coli, it was of interest to assess whether mismatch repair was similarly important in the repair of DNA damage induced by cis-diamminedichloroplatinum(II) (CDDP). The results demonstrate that after exposure to 5-40 microM CDDP, dam-3 E. coli are 2-15-fold more sensitive to the cytotoxic effects of this agent. Further, dam-3 mutL451 E. coli deficient in mismatch repair was as resistant as wild type. trans-Diamminedichloroplatinum(II) treatment did not cause marked increments in cytotoxicity in dam-3 E. coli compared to wild type. The rate of excision of platinum was significantly reduced in dam-3 E. coli compared to wild type, demonstrating that differences in the repair of CDDP-induced DNA damage underlie enhanced cytotoxicity by this agent. Lastly, mutagenesis by CDDP was abrogated in umuDC- E. coli, showing that this gene product mediates mutagenesis by this agent.
Cell Survival↗
The effect of inhibitors of DNA synthesis on DNA repair.
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Alkylating Agents↗
Lethal effects of 1-beta-D-arabinofuranosylcytosine incorporation into deoxyribonucleic acid during ultraviolet repair.
We have previously demonstrated that 1-beta-D-arabinofuranosylcytosine (ara-C) incorporates into leukemic cell DNA and that the extent of this incorporation correlates significantly with loss of clonogenic survival. These studies have now been extended by monitoring the incorporation of ara-C in DNA undergoing repair of UV-induced damage. The present studies have been performed using human foreskin diploid fibroblasts that undergo density-dependent growth arrest. The results demonstrate that ara-C incorporates specifically into DNA undergoing repair of damage by UV light. The extent of ara-C incorporation in AG1522 DNA during UV repair correlates significantly (p less than 0.0006) with cell lethality. These findings confirm that incorporation of ara-C into DNA undergoing either semiconservative or unscheduled DNA synthesis results in lethal cellular events. The present findings may provide the experimental basis for the development of new therapeutic approaches using ara-C in combination with agents that damage DNA.
Cell Survival↗
Clinical, pathologic and immunologic features of patients with non-Hodgkin's lymphoma in a leukemic phase. A retrospective analysis of 34 patients.
A retrospective review of 34 patients with non-Hodgkin's lymphoma and a leukemic phase was undertaken. The median survival after onset of a leukemic phase was 30 months for patients with nodular poorly differentiated lymphocytic lymphoma which was significantly longer than 19 months for diffuse poorly differentiated lymphocytic lymphoma, and 2 months for diffuse histiocytic and undifferentiated lymphoma. Clinical features of patients with diffuse histologies that contributed to a poor prognosis included advanced stage of disease as well as age. Underlying lymph node histology also defined features of the leukemic phase which included duration, peak leukocyte count, and in some instances, distinctive morphologic characteristics of circulating malignant cells. Although small sample size did not permit definitive correlations of immunological subtype and survival, heterogeneity was noted, suggesting that clearer stratification of these patients with immunologic techniques may be useful in assessing prognosis in future investigations.
Adult↗
Accumulation of leukemic cell DNA strand breaks with adriamycin and cytosine arabinoside.
Adriamycin (doxorubicin) and cytosine arabinoside (Ara-C) induce single strand DNA breaks and DNA fragmentation. In view of the therapeutic efficacy of adriamycin in combination with Ara-C in the treatment of human acute non-lymphocytic leukemia, we have attempted to assess the accumulation of DNA strand breaks and DNA fragmentation with these agents by alkaline elution analysis. Although a less than additive enhancement was noted for the elution of pulse labelled, replicating DNA, the results demonstrate an additive effect of adriamycin and Ara-C on the elution of pre-labelled L1210 murine leukemia DNA.
Animals↗
The spectrum of genitourinary abnormalities in patients with cryptorchidism, with emphasis on testicular carcinoma.
A spectrum of genitourinary abnormalities occur in patients with cryptorchidism; the most important is the enhanced susceptibility to developing testis cancer. While the etiologic basis for developing testis cancer in cryptorchid patients remains controversial, failure of normal testicular development--testicular dysgenesis--may underlie carcinogenesis in the cryptorchid testis. This report reviews these associations as well as the characteristics of testis cancer in the cryptorchid testis and the evidence supporting early orchiopexy.
Adolescent↗
DNA strand breaks caused by inhibitors of DNA synthesis: 1-beta-D-arabinofuranosylcytosine and aphidicolin.
We have used alkaline elution analysis to determine whether strand breaks are detectable in L1210 DNA labeled during and prior to 1-beta-D-arabinofuranosylcytosine (ara-C) exposure. The results demonstrate that ara-C enhances elution of previously synthesized DNA as well as replicating DNA. ara-C induced dose-dependent strand breaks when DNA was labeled prior to drug exposure. In contrast, simultaneous exposure of cells to tritiated thymidine and drug resulted in maximal elution rates with 10(-6) M ara-C. These findings are compared to those obtained with aphidicolin, another inhibitor of DNA synthesis, which unlike ara-C is not incorporated into the DNA strand. These results suggest that both ara-C and aphidicolin increase DNA elution rates by impairing DNA synthesis. The different dose-dependent patterns during replicative DNA synthesis may result from the incorporation of ara-C in the DNA strand.
Animals↗
Genetic control of ligand-induced events in B lymphocytes.
The early cycle of events which follows the binding of anti-Ig ligands to the surface Ig molecules of B lymphocytes was compared in several inbred strains of mice. Kinetic differences were found in the rate of surface Ig capping and absolute differences in extent were found for anti-Ig-induced B cell motility. These strain differences were not restricted to the B cell surface Ig molecules, however, since capping by Con A of its receptor sites on B and T cells and random T cell motility were also affected. A genetic analysis of A and CBA mice revealed that each of the traits studied is probably affected by two gene differences between the two strains analyzed. The possible roles of microtubules and cyclic nucleotides in these genetic differences were also explored. Colchicine, which depolymerizes microtubules, raised the low capping and motile responses of CBA spleen cells to the high responses characteristic of A strain cells. This implies an excess of microtubular function in CBA cells. Raising the level of cyclic AMP also raised the low CBA capping response to the high A level, but did not differentially effect the motile responses of cells of the two strains. The possible significance and locus of action of these effects is discussed.
Animals↗