Incubation of Ehrlich ascites tumor cells with misonidazole under aerobic conditions causes a stimulation of glucose consumption which is probably related to stimulation of hexose monophosphate shunt activity. Incubation of Ehrlich cells with 5 mM misonidazole under hypoxic conditions results in a time-dependent inhibition of glycolysis, seen when treated cells are washed and resuspended in fresh buffered saline or media. This inhibition does not appear to be related to breakdown and loss of pyridine nucleotides from the cells during misonidazole treatment, nor is it a consequence of cell death. Post-incubation in buffer containing cysteine or cysteamine restores cellular glycolytic activity to near control levels. Partial inhibition of glucose consumption after incubation with misonidazole also occurs with V79-379A, V79-171B, EMT6 and A549 cell lines. The extent of inhibition varies among the lines, but is accompanied by approximately a 50% reduction in intracellular non-protein thiol levels in all cases. Ehrlich cells incubated anaerobically with misonidazole lose their response to the uncoupler 2,4-dinitrophenol, which normally increases glucose consumption, and exhibit less ability to metabolize pyruvate. Cells incubated under anaerobic conditions but in the absence of misonidazole do not show these effects.

Aerobiosis↗

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Non-protein thiols and cellular response to drugs and radiation.

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Animals↗

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A biochemical basis for the radiosensitizing and cytotoxic effects of chlorpromazine hydrochloride in vitro and in vivo.

There have been many investigations on the radiosensitizing and cytotoxic effects of chlorpromazine, both in vitro and in vivo. We have extended the studies to include the chemotherapeutic effect of chlorpromazine on lymphosarcoma and on a mammary adenocarcinoma arising spontaneously in breeding female CBA mice. Chlorpromazine was ineffective in the former tumor but enhanced the longevity of tumor-bearing mice in the latter case. The drug was also observed to potentiate the hyperthermic killing of L5178Y cells and inhibit cellular oxygen utilization by cultured mammalian cells. The possible mechanisms involved are discussed.

Animals↗

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Enhanced cytotoxicity of melphalan by prolonged exposure to nitroimidazoles: the role of endogenous thiols.

It was first demonstrated that prolonged exposure of hypoxic V-79 cells to misonidazole prior to irradiation produced an increased radiosensitization in 1977; it was postulated that the reduction of misonidazole resulted in intermediates capable of depleting cells of endogenous thiols, substances known to play a role in the hydrogen repair of target radicals produced by ionizing radiation. The present study shows that a prolonged exposure of V-79 cells to a variety of nitroimidazoles (misonidazole, Ro-05-9963, SR-2508, and MTR1-80) results in an enhanced cytotoxicity when these cells are subsequently exposed to melphalan. This process of enhanced melphalan toxicity occurred only when cells were pretreated with misonidazole under hypoxic conditions, suggesting that nitroreduction is necessary for chemosensitization as it is for increased radiosensitization. Different nitroimidazoles tested vary in the extent to which they sensitize cells to the subsequent action of melphalan. Repair from a misonidazole pretreatment is essentially complete by six hours. This study demonstrated that cysteamine could reduce the cytotoxicity of misonidazole and the enhancement of melphalan toxicity. This was an effect reversible with time and one implying similar mechanisms for the preincubation effect observed in vitro for radiation and chemotherapy agents.

Animals↗

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The oxidation of ascorbate by electron affinic drugs and carcinogens.

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Animals↗

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Physiological mechanisms of radiation sensitization by pentoxifylline.

The aim of this study was to investigate whether multiple injections (daily for 5 days) of the hemorheological agent pentoxifylline (PTX) affected tumor physiological parameters (i.e., tumor pO2, tumor pH, and tumor interstitial fluid pressure) during the tumor growth of FSaII murine fibrosarcoma in C3H mice. The radiation sensitization by multiple injections of PTX (daily for 5 days) was also studied. Following multiple administrations of PTX, PTX significantly improved tumor oxygenation in all sizes of tumors tested. Our results showed that the elevated tumor interstitial fluid pressure (TIFP) in solid tumors could be reduced by PTX. Based on our results with the improvement in tumor pathophysiology, PTX may be of use during tumor therapies in which the outcome may be detrimentally affected by the presence of hypoxia. As anticipated, multiple injections of PTX with fractionated x-irradiation prolonged the radiation-induced growth delay in FSaII tumors, producing an enhancement ratio of 1.8 of the growth delay at 15 days. However, we did not observe any alteration in cellular oxygen consumption (QO2) after the treatment with PTX. Therefore, we concluded that PTX-induced radiosensitization was due to an increase in tumor pO2, not a reduction in QO2.

Animals↗