Intestinal microflora as potential modifiers of sensitizer activity in vivo.

Treatment of mice (some bearing Lewis Lung tumors), with penicillin (PEN) at 500 mg/l drinking water for one week prior to treatment with misonidazole (MIS), resulted in: the elimination of their anaerobic cecal flora; a decrease in MIS-induced neurotoxicity; an increase in pharmacological exposure to MIS; a decrease in MIS chemopotentiation; a probable increase in MIS radiosensitization; an increase in MIS induced hypothermia. Assuming no chemical interaction between PEN and MIS, these observations indicate that the intestinal microflora can influence the activity of MIS in vivo. Therefore their influence should be considered in all sensitizer-related studies in vivo. The observed reduction in the neurotoxic but not the radiosensitizing potential of MIS following PEN treatment indicates a therapeutic benefit.

The effect of phenytoin, phenobarbitone, dexamethasone and flurbiprofen on misonidazole neurotoxicity in mice.

Using a quantitative cytochemical technique for measuring beta-glucuronidase activity in the peripheral nerves of mice, we have investigated the effectiveness of four potential adjuncts for reducing the dose limiting neurotoxicity of misonidazole (MISO) in the clinic. Under the conditions used, the most effective adjunct was the steroid anti-inflammatory agent dexamethasone. When given over the week previous to MISO treatment, this agent almost completely eliminated the MISO neurotoxicity as determined at week 4 after commencement of MISO dosing. The second most effective adjunct was phenytoin, the third flurbiprofen and the last adjunct, phenobarbitone, was ineffective. Dexamethasone, phenytoin and phenobarbitone all reduced the clearance half-life of MISO and hence the drug exposure dose calculated as the area under the curve of MISO tissue concentration against time. However, no correlation was evident with these parameters and MISO neurotoxicity in the mouse. Dexamethasone, whilst affording protection against MISO toxicity, did not alter the radiosensitivity of the anaplastic MT tumour.

Quantitative cytochemical assessment of the neurotoxicity of misonidazole in the mouse.

A quantitative, cytochemical assay for measuring lysosomal enzymes in the peripheral nerves of mice has been developed. That the time course of lysosomal enzyme changes after misonidazole (MISO) treatment reflects the degree of neurotoxicity of this agent in the mouse, has been confirmed by the use of two known neurotoxic compounds: methyl mercury and acrylamide. This effect is specific to the peripheral nerves and was not found in liver, kidney, heart or cerebral cortex. Enzyme activities varied with mouse strain and sex, as did the response to MISO treatment. Of the mice studied, female C57 gave the greatest increase in beta-glucuronidase activity. With the MISO dose of 0.6 mg/g/dose the increased enzyme activity was independent of the route of administration and appeared to approach a plateau after 5 daily doses.

Neurotoxicity of radiation sensitizers in the mouse.

The neurotoxicity of a homologous series of 1-substituted, 2-nitroimidazole compounds, synthesized in this laboratory, has been studied in mice. This involves measurement of the enzyme beta-glucuronidase in the distal sciatic, tibial and common peroneal nerves. The amount of compound required to give a known neurotoxic response, in terms of elevated beta-glucuronidase (arbitrarily set at 60% increase) has been determined. A correlation between increased number of methylene groups (N) in the side chain and neurotoxicity has been shown. A correlation between increased neurotoxicity and effective octanol; water coefficient, at pH 7.4, was also established. A more soluble version of the n = 4 member of the homologous series, that is the compound RSU 1047 (NSC 328897), and misonidazole also fit this correlation of partition coefficient and dose.

Therapeutic irradiation of the central nervous system using intrathecal 90Y--DTA.

The erdication of established neuroleukaemia is often difficult, and with subsequent relapses even harder. The use of an intrathecally-injected beta emitting isotope has the advantage of preserving the bone-marrow of the vertebral column and cranium whislt irradiating the meninges. The value of intrathecal 90Y-DTPA(diethylene-triamine penta-acetic acid) has been investigated in nine patients with neuroleukaemia or CNS involvement in malignant lymphoma. Measurements of retention of the isotope in the whole body, spinal, and intracranial subarachnoid spaces have been made, together with blood levels, and are reported. The clinical results are presented. In three out of five evaluable patients 90Y-DTPA failed to maintain a chemotherapy-induced CNS remission and in two out of two evaluable patients malignant cells were not dispersed from the CNS with a single intrathecal injection of 90Y-DTA. It is concluded, therefore, that with this agent and the doses used no useful clinical result is gained.

Serum-mediated inhibition of graft-vs.-host reaction.

Rats recovering from a systemic graft-vs.-host reaction (GVHR) possess factors in the serum which can inhibit the production of a local GVHR. After incubation in vitro for 1 h at 37 degrees C these factors reduce the GVH-producing potential of parental spleen or lymph node cells to 24% of control cells treated with normal serum. These factors appear within 1 wk after initiation of a systemic GVHR and some residual activity persists for up to 8 mo. The serum activity was present in the globulin fraction and was completely removed by absorption with spleen, lymph node, or kidney homogenates from either parental strain rats. These studies indicate that during the course of a systemic GVHR, serum factors directed against the host appear in the circulation and tend to inhibit the production of further GVHR by a second challenge of either parental strain cells.