Journal Article•
Effects of Caffeine on L-Cells Exposed to Mitomycin C
01 Nov 1970-Cancer Research (American Association for Cancer Research)-Vol. 30, Iss: 11, pp 2724-2729
TL;DR: Mouse L-cells exposed to mitomycin C which passed through their first DNA-synthetic period in the absence of caffeine had no additional loss of viability when plated in it at later times, indicating that the same system shown previously to exist in L- cells for the repair or alteration of ultraviolet light damage is also functional against damage produced by mitomyin C.
Abstract: Summary Mouse L-cells were grown in suspension culture and exposed to varying concentrations, from 0.2 to 4 μg/ml, of mitomycin C for periods ranging from 0.5 to 3.5 hr. A plot of cell colony-forming ability versus concentration of mitomycin C for different times of exposure yielded a series of exponential survival curves which were related by the fact that the product of the time of exposure and the concentration of mitomycin C required to reduce survival to 10% (C10) were a constant. However, the value of C10 was dependent on the pH of the cell culture at the time of exposure to mitomycin C. If, immediately after exposure to mitomycin C, the survival of the cells was measured in medium containing 2 mM caffeine, the C10 was 0.5 times that observed in the absence of caffeine. When the treated cells were incubated in the absence of caffeine for one generation time and their survival was measured in its presence, no difference in C10 over that observed in normal medium was seen. With a synchronous population of L-cells, evidence was obtained that cells exposed to mitomycin C which passed through their first DNA-synthetic period in the absence of caffeine had no additional loss of viability when plated in it at later times. These results indicate that the same system shown previously to exist in L-cells for the repair or alteration of ultraviolet light damage is also functional against damage produced by mitomycin C.
Citations
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TL;DR: Intermittent dosage schedules are predicted to be better on the basis of pharmacokinetic and cytopathologic studies, and Tumors resistant to other alkylating agents are frequently sensitive to Mitomycin C.
423 citations
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TL;DR: The structure–activity relationships discussed in this chapter indicates that platinum complexes superior to those initially described will become available for clinical use.
Abstract: Publisher Summary This chapter reviews that DNA is the principal target molecule for neutral platinum complexes in a variety of biological systems. The most convincing mechanism for the cytotoxic action of these agents on cells in culture is that reactions with DNA impair its function as a template for further DNA replication. A variety of reactions with DNA has been described, but it is not yet known whether all or only some of these are important in inactivating the DNA template. Not only are most lesions in DNA recognized and removed by an excision–repair process, but in Chinese hamster cells all seem to be recognized by a caffeine-sensitive process that facilitates the ability of the replicating machinery to synthesize past them. Inability to synthesize past lesions is associated with mitotic-delay chromosome damage and eventually cell death. It remains to be determined whether all other cytotoxic platinum compounds act by a similar mechanism. The chapter reviews that enforces diuresis can dramatically decrease the kidney toxicity induced by these agents, one of the initial obstacles to their clinical application seems to have been overcome. On the basis of their present clinical status, these agents clearly have a permanent place in the armamentarium of the clinician. Finally, the structure–activity relationships discussed in this chapter indicates that platinum complexes superior to those initially described will become available for clinical use.
388 citations
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TL;DR: It is proposed that (ADP-ribose)n takes part in cellular repair mechanisms, either by modifying chromatin structure or by a specific participation in DNA repair, and that the biosynthesis is stimulated by DNA damage.
Abstract: Inhibitors of poly(ADP-ribose) polymerase show a synergistic potentiation of cytotoxicity with certain DNA-damaging agents. Non-toxic concentrations of 5-methylnicotinamide dramatically potentiate the cytotoxicity of N-methyl-N-nitrosourea as tested by the cloning ability of mouse leukaemia (LI210) cells. A dose-enhancement factor of about 10 is observed. This potentiation is dependent on the concentration of 5-methylnicotinamide. The methylxanthines theobromine, theophlline and caffeine also increase the cytotoxicity of methylnitrosourea. Thymidine, in the presence of sufficient deoxycytidine to overcome the perturbation of deoxynucleotide metabolism, also potentiates the cytotoxicity of methylnitrosourea. Nicotinate, which is not an inhibitor of poly-(ADP-ribose) polymerase, has no effect on methylnitrosourea toxicity.
A very small, but consistent, enhancement of the toxicity of y-radiation by the same inhibitors has been observed.
We suggest that this potentiation of cytotoxicity is mediated by inhibition of (ADP-ribose)n biosynthesis; and that the biosynthesis is stimulated by DNA damage. We therefore propose that (ADP-ribose)n takes part in cellular repair mechanisms, either by modifying chromatin structure or by a specific participation in DNA repair.
194 citations
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01 Jan 1978TL;DR: This chapter discusses some studies on the interaction of various compounds with cellular DNA and the biochemical and biological consequences of these reactions in a variety of cell systems and focuses attention on DNA as the principal target for a number of chemotherapeutically useful cytotoxic agents and for numerous known carcinogens.
Abstract: Publisher Summary This chapter discusses some studies on the interaction of various compounds with cellular DNA and the biochemical and biological consequences of these reactions in a variety of cell systems and it focuses attention on DNA as the principal target for a number of chemotherapeutically useful cytotoxic agents and for numerous known carcinogens. The chapter further discusses some observations establishing that some DNA reactions are recognized and modified by various enzyme systems. These DNA repair processes clearly protect cells from lethal effects of DNA reactions in both bacterial and mammalian cells. Decreased sensitivity of sublines of cells in culture have been shown in some instances to be related either to their increased capacity for excision repair of damage to their DNA or to their greater capacity to carry out postreplication DNA repair. However, it is by no means established, although quite likely, that clinical resistance to cytotoxic agents in cancer chemotherapy is similarly characterized by the emergence of, or conversion of a tumor cell to, a cell with altered DNA repair capacity that confers decreased sensitivity to cytotoxic agents as compared with that of the original tumor cell.
172 citations
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TL;DR: The search for evidence of SCEs at a MOLECULAR level and the enzymology of seE Formation and the relationships to DNA Replication Fork are described.
Abstract: INTRODUCTION 11 INFORMATION ABOUT CHROMOSOME ORGANIZATION PROVIDED BY SCE ANALYSIS 12 SCE INDUCTION 15 SeE Induction by Diff erent Types of DNA Damage 16 Duration of the SCE Response 22 Modulation of the seE Response 23 CORRELATES OF SCEs ........ 32 Chromosome Breaks 32 Somatic Recombination 33 Meiotic Recombination 33 Somatic Mutation 33 Effects on Integrated DNA Sequences 34 THE SEARCH FOR EVIDENCE OF SCEs AT A MOLECULAR LEVEL ........ 35 FUTURE PROSPECTS 36 Sequences that Might Mediate DNA Interchange 36 The Relationship of SCE Formation to the DNA Replication Fork 37 The Enzymology of seE Formation 38 Comporison Between Gene Copy Number Change and SCE Formation 38 BIOLOGICAL IMPORTANCE OF SeEs 40 SUMMARY 42
169 citations
References
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TL;DR: Pure virus lines were established by isolating the virus population produced in single plaques, which had the same morphological, serological, and pathogenic properties as the parent strain.
Abstract: Plaques have been produced with the three types of poliomyelitis viruses on monolayer tissue cultures of monkey kidney and monkey testis. The number of plaques was proportional to the concentration of the virus. Each plaque originates, therefore, from a single virus particle, defined as the virus unit that is unseparable by dilution. The plaques are due to the specific action of the virus since they are suppressed by type-specific antiserum. Pure virus lines were established by isolating the virus population produced in single plaques. These derived virus lines had the same morphological, serological, and pathogenic properties as the parent strain. High titer virus stocks, with titers up to 7 x 10(8) plaque-forming particles per ml., were obtained.
3,394 citations
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TL;DR: Measurements of ultraviolet-induced pyrimidine dimers in cellular DNA show that normal diploid human skin fibroblasts excise up to 70 per cent of the dimer in 24 hours, but that fibro Blasts derived from the individual with XP excise less than 20 per cent in 48 hours.
Abstract: Xeroderma pigmentosum (XP) is a recessively transmitted disorder of man characterized by increased sensitivity to ultraviolet light. Homozygous, affected individuals, upon exposure to sunlight, sustain severe damage to the skin; this damage is characteristically followed by multiple basal and squamous cell carcinomas and not uncommonly by other malignant neoplasia. A tissue culture cell line was derived from the skin of a man with XP. Our measurements of ultraviolet-induced pyrimidine dimers in cellular DNA show that normal diploid human skin fibroblasts excise up to 70 per cent of the dimers in 24 hours, but that fibroblasts derived from the individual with XP excise less than 20 per cent in 48 hours. Alkaline gradient sedimentation experiments show that during the 24 hours after irradiation of normal cells a large number of single-strand breaks appear and then disappear. Such changes are not observed in XP cells. XP cells apparently fail to start the excision process because they lack the required function of an ultraviolet-specific endonuclease. These findings, plus earlier ones of Cleaver on the lack of repair replication in XP cells, raise the possibility that unexcised pyrimidine dimers can be implicated in the oncogenicity of ultraviolet radiation.
428 citations
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TL;DR: The number of breaks in the polynucleotide chains of the DNA in murine leukaemia cells, the bacterium Micrococcus radiodurans and in Isolated DNA are approximately the same and the results suggest that the molecular weight of the mammalian DNA is very high.
Abstract: The number of breaks produced by X-rays In the polynucleotide chains of the DNA in murine leukaemia cells, the bacterium Micrococcus radiodurans and in Isolated DNA are approximately the same. The leukaemia cells have an efficient system for rejoining broken strands. The results also suggest that the molecular weight of the mammalian DNA is very high.
291 citations
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TL;DR: The survival of colony-forming ability of mouse L cells after ultraviolet light (UVL) irradiation can be changed drastically by immediately incubating the cells in growth medium to which caffeine has been added, and it is purely a postirradiation phenomenon, being dependent on the time after irradiation that caffeine is added to the cells.
Abstract: The survival of colony-forming ability of mouse L cells after ultraviolet light (UVL) irradiation can be changed drastically by immediately incubating the cells in growth medium to which caffeine has been added. The nature of this effect is similar to previous results obtained by other workers for UVL-irradiated bacteria containing a dark-reactivation system. The nature of these similarities is as follows: The effect of caffeine on L cells is concentration-dependent in the range of 0.3 to 5 mM, and it is purely a postirradiation phenomenon, being dependent on the time after irradiation that caffeine is added to the cells. Cells incubated for one generation time in the absence of caffeine show no decreased colony-forming ability when incubated in its presence. The caffeine effect is not seen if the cells are exposed to ionizing radiation instead of UVL irradiation. Substitution of some of the thymine moieties of L cell DNA with BUdR sensitizes the cell to UVL, but when such cells are plated in the presence...
212 citations