Differential responses of Chinese hamster mutagen sensitive cell lines to low and high concentrations of calicheamicin and neocarzinostatin.
To shed light on the mechanism underlying the cellular response to the radiomimetic agents calicheamicin Y(1)(1) (CAL) and neocarzinostatin (NCS), several hamster cell mutants defective in different DNA repair pathways were used. Two X-ray sensitive Chinese hamster V79 mutant cell lines, XR-V9B and V-E5 were studied for their response to the induction of cell killing, micronuclei, and G2-chromosomal aberrations relative to that of parental wild-type cells. In addition, effects of CAL and NCS on bleomycin sensitive BL-V40 cells and on UV sensitive V-H1 cells were analyzed. In general, the radiosensitive cell lines showed the highest sensitivities to CAL and NCS, but also the other mutants demonstrated differences in their responses compared to wild-type cells. With respect to cell killing, expressed as D(10)-value, enhanced sensitivities of mutants with factors up to 4.4 were recorded. For the induction of micronuclei (MN) and chromosomal aberrations (CA) all cell lines, including the parental cells, show a steep increase in the frequencies at the lowest tested doses and a leveling off at higher concentrations. Probably toxic effects at the higher exposure levels are responsible for these biphasic dose effect curves. Enhanced sensitivities of the various mutants were primarily observed at the higher exposure levels. With respect to the induction of MN increased sensitivities up to a factor of 18.1 were observed for the radiosensitive mutants, whereas for CA the mutant cell lines showed a variation from resistance (0.3) of VH-1 cells up to a 3.8-fold higher sensitivity to the radiomimetic agents. However, at the lowest tested concentrations for both MN and CA, the differences between the sensitive mutants and wild-type clearly diminished, suggesting the existence of residual and/or alternative DNA repair pathways in these mutants.
van Duijn-Goedhart
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A
MGC, LUMC--Department of Radiation Genetics and Chemical Mutagenesis, Sylvius Laboratory, Leiden University, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.
Zdzienicka
M Z
MZ
Sankaranarayanan
K
K
van Buul
P P
PP
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000633:toxicity*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D053281:Enediynes; D016195:G2 Phase / Q000187:drug effects; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D015162:Micronucleus Tests; D009153:Mutagens / Q000008:administration & dosage / Q000633:toxicity*; D011836:Radiation Tolerance; D009353:Zinostatin / Q000008:administration & dosage / Q000633:toxicity*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D009153:Mutagens; C055955:calicheamicin gamma(1)I; D009353:Zinostatin