Correction of congenital bone marrow disorders by allogeneic bone marrow transplantation following preparation with anti-human thymocyte serum and total body irradiation.
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Biomedical subjects
Publications and source records attributed to J A Belli.
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We have studied the effects of actinomycin-D (AMD) and Adriamycin (ADRM) on the repair of radiation damage in Chinese hamster cells (V79) in plateau phase growth. Suppression of potentially lethal damage repair (PLDR) was observed in the presence of non-toxic levels of AMD and minimally toxic levels of ADRM. The suppression of PLDR by AMD persisted as long as the drug was present. Removal of AMD was followed by prompt repair of potentially lethal injury suggesting that suppression of PLDR by AMD was not accompanied by fixation of injury to a non-repairable state. On the other hand, irradiated cells exposed to ADRM eventually repair potentially lethal injury in the presence of drug after an initial delay. AMD, but not ADRM, inhibited repair of sublethal radiation damage.
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Interaction between radiation and Adriamycin damage reduced the width of the shoulder of the X-ray survival curve. This effect was found to persist for at least 24 hr after Adriamycin treatment. Adriamycin did not affect radiation damage when cells were treated either before two-dose fractionation or with the drug present between X-ray exposures. Adriamycin is unique in that its major effect on radiation response is to reduce the survival curve shoulder without affecting two-dose recovery. It is suggested that Adriamycin and radiation produce independent classes of damage that are expressed mutually for killing, with regard to the registration of sublethal radiation damage, but that repair of the latter is unaffected by Adriamycin.
Plateau-phase V79 Chinese hamster cells maintained at 37 degrees following X-irradiation demonstrated both sublethal damage repair and potentially lethal damage repair. When cells were kept at 41 degrees for 1 hr following irradiation, no sublethal damage repair was seen. In contrast, irradiated cells maintained at 41 degrees for 1 hr and then returned to 37 degrees were capable of repairing both sublethal and potentially lethal radiation damage; hyperthermic (41 degrees) inhibition of radiation damage repair was reversible. Repair was similar for cells heated before or after irradiation. The extent of sublethal damage repair (as measured by recovery ratios and quasi-threshold doses) and potentially lethal damage repair (as measured by recovery ratios and dose-modifying factors) was similar following combined heat and X-ray treatment and following X-ray treatment alone.
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The effect of actinomycin-D (AMD) on radiation damage repair was studied in plateau phase V79 Chinese hamster cells. Sublethal radiation damage repair, as demonstrated by survival fluctuations following two x-ray exposures separted by time, was observed in our plateau phase cells. Plateau phase cells exposed to 0.01-0.04 mug/ml AMD (a nontoxic regimen to 8 hours) between x-ray exposures were less able to repair sublethal damage. If plateau phase cells were plated at low dilutions into fresh medium (conditions for resuming exponential growth) immediately after the first x-ray dose, and exposed to 0.01--0.04 mug/ml AMD until the second dose, inhibition of sublethal damage repair and additional cell killing were observed particularly at 0.04 mug/ml AMD. It is suggested that radiation-drug damage interactions should be studied in plateau phase cells and in cells resuming exponential growth after plateau phase (possibly analogous to "recruitment"), as well as in exponential phase cultures.
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Hyperthermia (41 degrees C for 1 hr.) completely inhibited both sublethal and potentially lethal radiation damage repair by plateau phase cells taken from V79 Chinese hamsters. This suggests that there may be disadvantages in combining x-ray and heat therapies for the treatment of tumors.
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Mammalian cell DNA that exhibited anomalous sedimentation in alkaline sucrose gradients was examined directly by electron microscopy. Its appearance was that of duplex DNA. In addition, some duplex DNA was observed under conditions in which the sedimentation anomaly was no longer apparent. Persistence of double-stranded DNA under denaturing conditions suggests caution in the interpretation of changes in the molecular weight or conformation of DNA based solely on analysis of sedimentation profiles.
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