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B F Kimler

Publications and source records attributed to B F Kimler.

At least 91 records · Page 5Linked to original sources
PubMed1984

Lack of recovery from radiation-induced sublethal damage in human haematopoietic cells.

The effect of ionizing radiation on the growth of bone marrow cells from haematologically normal controls or from patients with acute nonlymphocytic leukaemia was studied using colony formation as an endpoint. A modified agar culture method which incorporated daily feeding with new medium was utilized to allow the growth of leukaemic cell colonies. Analysis of radiation-dose survival curves revealed that normal bone marrow cell populations exhibited a relatively steep slope, with values of D0 averaging 0.88 Gy, and essentially no shoulder to the survival curves. The leukaemic cells tested also displayed survival curves with negligible shoulders and steep slopes (average value of D0 = 0.66 Gy). The average values of D0 for normal and leukaemic cells were significantly different (P less than 0.001). The ability of hematopoietic progenitor cells to recover from the accumulation of sublethal damage was also investigated by allowing a fractionation interval between doses. As expected from the lack of significant shoulder on the survival curve, there was no evidence of recovery from sublethal damage. These results provide a rationale for the use of fractionated radiation therapy for whole-body irradiation prior to bone marrow transplant.

Bone Marrow↗
PubMed1983

Bleomycin and brain tumors. A review.

A logical inference from the recent reports indicating that malignant brain tumors are composed of a heterogeneous cell population is that combination chemotherapy will be required for effective brain tumor control. For several years we have been investigating the use of Bleomycin as an agent to be used in conjunction with radiation therapy and a nitrosourea compound. Since systemically administered Bleomycin does not cross the blood-brain-barrier and has significant toxicity when used parenterally in high doses, we have studied the use of smaller doses of Bleomycin injected directly into the brain tumor cavity. Such an intracerebral dose was more effective in prolonging survival of rats burdened with experimental 9L gliosarcomas than an intravenous dose that is 25 times as great. The combination of intracerebrally administered Bleomycin and radiation therapy was more effective than either modality alone. Furthermore, the combination of Bleomycin delivered intracerebrally and BCNU given systemically was more effective than either agent used alone. Finally, in a Phase I clinical of Bleomycin given via an Ommaya reservoir to eight patients with recurrent malignant brain tumors, we have demonstrated that individual doses of up to 7.5 units and cumulative doses of up to 255 units can be administered without significant toxicity.

Adult↗
PubMed1983

Correlation of the structure of amino-substituted anthraquinones to cytotoxicity in cultured Chinese hamster cells.

A number of substituted anthraquinones (SAQs) are currently being tested as cancer chemotherapeutic agents because of their structural similarity to Adriamycin (ADR) and other DNA-intercalating antibiotics. In this study, the effect of SAQs on the induction of cytotoxicity of asynchronous Chinese hamster cells in culture was studied and compared to those produced by ADR and dihydroxyanthraquinone (DHAQ), a SAQ previously shown to be more effective than ADR. SAQs produced cytotoxicity that was dependent upon the concentration and duration of drug exposure. A correlation was noted between the activity of a compound (the concentration required to produce a certain level of cell kill) and the presence of a particular triangular arrangement of one nitrogen atom and two oxygen atoms. There was also a correlation between chemical structure and antitumor activity in the murine P388 leukemia model system. This correlation between chemical structure and biological activity may aid in the development of new SAQs with greater potential as cancer chemotherapeutic agents.

Animals↗
PubMed1983

Effect of dihydroxyanthraquinone (DHAQ) and radiation on the survival of cultured Chinese hamster ovary cells.

Dihydroxyanthraquinone (DHAQ) is currently being tested as a cancer chemotherapeutic agent because of its structural similarity to Adriamycin (ADR) and other DNA-intercalating antibiotics. The interaction of DHAQ and ionizing radiation on the induction of cell lethality was investigated in Chinese hamster ovary cells in culture. In asynchronous populations of cells, DHAQ produced a slight enhancement of radiation-induced cell lethality as evidenced by changes in both shoulder and slope of the radiation dose-survival curves. However, DHAQ had no effect on either the extent or time course of recovery from sublethal radiation damage. In synchronous populations of cells treated at various times before or after selection in mitosis, the combination of DHAQ and radiation produced greater cell killing than that predicted based on simple additivity of effect, with a decided enhancement for cells treated during S phase. These results indicate that DHAQ is similar to other DNA-intercalating antibiotics in regard to the interaction with ionizing radiation to produce cell lethality.

Animals↗
PubMed1982

Interaction of razoxane and radiation on cultured Chinese hamster cells.

Razoxane [(+/-)-1,2-bis(3,5-dioxopiperazine-1-yl)propane] was investigated for its effects on the survival of irradiated Chinese hamster fibroblasts in vitro. Razoxane alone produced cytotoxicity that was dependent upon drug concentration and pulse exposure time, with a preferential lethality for cells treated while in the DNA-synthetic phase. Razoxane enhanced radiation-induced cell killing when used as either a pulse exposure or a continuous treatment. In asynchronous populations of cells, this was expressed as an increase in the slope and a reduction in the shoulder of the radiation dose-survival curve. In synchronous populations of cells, a modest increase in cell killing was observed for those cells treated in G1 and G2, with a greater enhancement for cells treated in the S-phase. Overall, razoxane may potentiate the radiation-induced killing of cultured mammalian cells by a number of mechanisms: 1) a blockade of cell cycle progression causing an accumulation of cells in radiosensitive phases of the cell cycle; 2) selective cytotoxicity of cells in radioresistant phases of the cell cycle; 3) inhibition of the accumulation of sublethal radiation damage; or 4) interaction of the damages induced by each agent so as to produce an enhanced effect. These mechanisms may need to be considered if razoxane and radiation therapy are to be used in combined modality therapeutic approaches.

Animals↗
PubMed1982

Modification of radiation-induced division delay by caffeine analogues and dibutyryl cyclic AMP.

The mitotic selection procedure for cell cycle analysis was utilized to investigate the concentration-dependent modification of radiation-induced division delay in Chinese hamster ovary (CHO) cells by methyl xanthines (caffeine, theophylline, and theobromine) and by dibutyryl cyclic AMP. The methyl xanthines (concentrations from 0.5 to 1000 micrograms/ml) all reduced radiation-induced division delay with the effect being linear between approximately 100 and 1000 micrograms/ml. After doses of 100-300 rad, delay was reduced by 75, 94 or 83 per cent at 1000 micrograms/ml for each drug, respectively. However, the addition of dibutyryl cyclic AMP had an opposite effect: radiation-induced delay was increased by the concentration range of 0.3 to 300 micrograms/ml. These results indicate that in mammalian cells the control of cell cycle progression and the modification of radiation-induced division delay are not simply related to intracellular levels of cyclic AMP. Rather, there appear to be at least two competing mechanisms which are differentially affected by caffeine analogues or by direct addition of dibutyryl cyclic AMP. The direct effect of caffeine and the methyl xanthines on membrane calcium permeability is considered.

Animals↗
PubMed1982

Effect of dihydroxyanthraquinone (NSC 279836) and thoracic irradiation on long-term survival of rats.

Dihydroxyanthraquinone (DHAQ; NSC 279836) is a recently synthesized compound that is structurally similar to Adriamycin and produces greater antitumor effects in murine model systems. We compared DHAQ to Adriamycin in rats, with and without irradiation of the chest at various intervals after drug treatment. A single injection of Adriamycin (1 mg/kg i.p.) had little effect on animal survival, even if combined with radiation (12 Gy 25 MV X-rays), greater than 90% being alive at 1 year. A single injection of DHAQ (3 mg/kg i.p.) was equally uneffective up to 200 days after treatment (survival, greater than 90%). However, between 200 and 370 days after treatment, all animals died, producing a median survival time of 280 days. Further, when DHAQ was combined with radiation, there was an increase in animal deaths between Days 300 and 200. For animals irradiated on Days 0, 43, and 93 after DHAQ treatment, only 50, 75, and 80%, respectively, survived to Day 200. All animals that survived past Day 200 subsequently died by 1 year, displaying the same kinetics of lethality as those animals that had received DHAQ only. A repeat experiment using DHAQ at 1 mg/kg produced similar results. Based on these findings, we conclude that DHAQ produces a long-term (greater than 200 days) toxicity in rats that is not detectable by short-duration toxicity screening. In addition, radiation enhances short-term (less than 200 days) lethality, with the degree of enhancement decreasing as the interval between drug and radiation is increased.

Animals↗
PubMed1982

Comparison of the effects of dihydroxyanthraquinone and adriamycin on the survival of cultured Chinese hamster cells.

Dihydroxyanthraquinone [1,4-dihydroxy-5,8-bis ((2-([(2-hydroxyethyl)amino)ethyl)amino))-9,10-anthracenedione (DHAQ) (NSC 279836)] is currently being tested as a cancer chemotherapeutic agent because of its structural similarity to Adriamycin (ADR) and other DNA-intercalating antibiotics. We have therefore studied the effect of DHAQ on the survival of cultured Chinese hamster cells in direct comparison to ADR. Both DHAQ and ADR produced cytotoxicity that was dependent upon the concentration and duration of drug exposure. For 1-hr pulse exposures of asynchronous populations of exponentially growing cells, a 5- to 10-fold greater concentration of ADR than of DHAQ was required to produce the same level of cell killing. There were also differences in the cell cycle age specificity demonstrated by treating at various times before or after selection of cells in mitosis. DHAQ produced the greatest cytotoxicity in cells treated while in G1 or G2; ADR was more effective on cells located in S phase or mitosis. Overall, DHAQ was found to be similar to ADR and other DNA-intercalating antibiotics with regard to the induction of cell lethality. The only differences were those of the concentration required to produce a certain level of effect and of the cell cycle phase specificities for maximum effect.

Animals↗
PubMed1981

Combination of dihydroxyanthraquinone and radiation on L1210 murine leukemia.

A new synthetic anthraquinone, dihydroxyanthraquinone (DHAQ), was tested as a single agent and in combination with whole-body x-irradiation in mice bearing L1210 leukemia in the ascites form. DHAQ alone had significant antitumor activity as evidenced by prolonged mean survival times; radiation was ineffective. The combination of the two modalities produced a therapeutic benefits greater than that produced by either agent alone: mean survival times were increased and a number of cures (animals alive at 30 days) produced. These results suggest the potential of using DHAQ and radiation in a combined modality therapeutic approach.

Animals↗
PubMed1980

Effect of dihydroxyanthraquinone and radiation on G2 progression.

The effect of dihydroxyanthraquinone (DHAQ), a potential anticancer chemotherapeutic agent, on the progression of Chinese hamster ovary cells into mitosis and on the division delay induced by ionizing radiation was studied using the mitotic selection procedure for cell cycle analysis. Following the addition of DHAQ, the number of mitotic cells selected from an asynchronous population remained unaltered for a refractory period and then decreased. This effect was concentration dependent with transition points between the S/G2 boundary at 10(-4) micrograms/ml and the G2/M boundary at greater than or equal to 10(2) micrograms/ml. The duration of the transient division delay was dependent upon the concentration of drug used and the duration of pulse exposure. When cells were treated with pulses of DHAQ in addition to X-irradiation, there was no change in the location of the radiation transition point. There was an increase in the duration of division delay compared to that produced by X-ray alone that was dependent upon the concentration and duration of drug treatment. The effect of DHAW is similar to that of other cancer chemotherapeutic agents (Adriamycin, bleomycin, and lucanthone), and the same cautions should therefore be considered when combining DHAQ and radiation for clinical use.

Animals↗
PubMed1980

The search for new hypoxic cell radiosensitizers.

A number of newly synthesized compounds whose chemical structure suggested possible or remotely possible ability to radiosensitize hypoxic mammalian cells were studied in an in-vitro system. Those compounds that were not excluded because of insolubility or extreme cytotoxicity were tested for radiosensitizing ability. The correlation between chemical structure and radiosensitizing ability will be used for the rational design of additional compounds with a high probability of being effective hypoxic cell radiosensitizers. It is hoped that this will contribute to attempts to improve the cure rate of patients with malignant tumors through the use of radiation therapy and hypoxic cell radiosensitizers.

Cell Survival↗