A randomized study of misonidazole and radiotherapy for grade 3 and 4 cerebral astrocytoma

Bleehen, Norman M.; Wiltshire, Chris; Plowman, P N; Watson, Janet; Gleave, J. R. W.; Holmes, Ann; Lewin, Walpole; Treip, C. S.; Hawkins, Tanya

doi:10.1038/bjc.1981.64

Cited by 70 publications

(8 citation statements)

References 23 publications

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“…The plasma MISO elimination half life value is almost exactly the same as that reported in the Cambridge glioma trial for patients who did not experience neurotoxicity (Bleehen et al, 1981). The reduction in elimination half life and AUC, and the rise in urinary excretion of MISO, together with observation that there is no change in desmethylmisonidiazole AUC and urinary excretion, suggest that dexamethasone does not cause an induction of the microsomal enzymes responsibile for 0-demethylation.…”

Section: Resultssupporting

confidence: 75%

The role of dexamethasone in the modification of misonidazole pharmacokinetics

Jones¹,

Bleehen²,

Workman³

et al. 1983

Br J Cancer

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Section: Resultssupporting

confidence: 75%

The role of dexamethasone in the modification of misonidazole pharmacokinetics

Jones¹,

Bleehen²,

Workman³

et al. 1983

Br J Cancer

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“…However, the incidence and natural history of hypoxia in human brain tumours before and during radiotherapy is poorly understood. The benefit of the use of hypoxic cell radiosensitizers with radiotherapy for gliomas was has been reported for metronidazole (Urtasun et al, 1976) but not for misonidazole (Bleehen et al, 1981;Nelson D et al, 1983;Green et al, 1984).…”

mentioning

confidence: 98%

Anomalous patterns of nitroimidazole binding adjacent to necrosis in human glioma xenografts: possible role of decreased oxygen consumption

Parliament¹,

Franko²,

Allalunis-Turner³

et al. 1997

Br J Cancer

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Summary In contrast to reports of extensive hypoxia in human gliomas in situ measured by P02 histography, non-invasive methods of assessing glioma oxygenation, including nitroimidazole binding, have yielded surprisingly contradictory results. In order to investigate the relationship of necrosis, hypoxia, nitroreductase activity and cellular respiration in human gliomas, subcutaneous models using the human glioma cell lines M059K, M006 and M01 Ob were developed in the murine SCID host. Intracranial growth of the M006 line was achieved in nude rats. The nitroreductive capacity of glioma cell lines was assessed and found to be similar to transplanted tumours previously reported in the literature. This suggests that if substantial numbers of viable hypoxic cells were present in situ in gliomas, then nitroimidazole-binding techniques should be capable of identifying them. Inter-tumour variability in the amount of necrosis was seen. M006 xenografts growing in subcutaneous and intracranial sites revealed extensive necrotic regions histologically, some of which were surrounded by cells labelled heavily for [3H]misonidazole, while other areas were lightly labelled. Similar binding patterns were seen for subcutaneous M059K tumours, while subcutaneous M01 Ob tumours display necroses of which almost all were surrounded by heavily labelled cells. The oxygen consumption rates of tumour cell lines grown in vivo, in which venous P02 concentrations are of the order of 2-5%, were two to sevenfold less than those of the same lines grown as monolayers in vitro under oxygen concentrations of 18%. We postulate that glioma cell lines behave as 'oxygen conformers', in that their rate of oxygen consumption appears to vary with the availability of oxygen. Together with the misonidazole-binding data, the results in this glioma tumour model are consistent with coordinate inhibition or down-regulation of respiration under moderate hypoxia.

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“…Nevertheless, the toxicity of the drug to the mucosa and conjunctiva demonstrates that potentially therapeutic concentrations of FUDR are achieved in the internal carotid circula-295 tion. It is also possible that other agents such as radiation enhancers might be successfully administered in this way (19). Finally, surgical ligation of the ophthalmic artery or sparing the external carotid might allow further dose escalation.…”

Section: Discussionmentioning

confidence: 99%

Phase I clinical trial of intracarotid bis-chloroethylnitrosourea (BCNU) and 2' dioxy-5-fluorouridine (FUDR) in malignant astrocytomas

Mughal

et al. 1986

J Neuro-Oncol

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Systemic chemotherapy has been of limited benefit in the treatment of intracranial neoplasms, due, in part, to the inability to deliver effective drug doses to the neoplasm without systemic toxicity. We have completed a clinical trial of intracarotid BCNU and FUDR using an implantable pump in patients with unilateral malignant astrocytomas (Grade III and IV) in the hope of obtaining better tumor control with less systemic toxicity. Six patients had in-dwelling catheters placed in the internal carotid artery attached to a percutaneous refillable pump (Infusaid 400). The treatment program consisted of bolus BCNU 400 mg every 6 weeks and FUDR by continuous infusion at dosages ranging from 0.5 mg/24 h to 2.5 mg/24 h. The maximum tolerable dose of FUDR was 1 mg/24 h with ipsilateral mucositis and conjunctivitis being dose limiting factors. Flow studies demonstrated significant perfusion of the ipsilateral eye and surrounding face secondary to ophthalmic artery collaterals. No patient had systemic toxicity and the lowest WBC encountered was 2 400 with normal differential and platelets.

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A randomized study of misonidazole and radiotherapy for grade 3 and 4 cerebral astrocytoma

Cited by 70 publications

References 23 publications

The role of dexamethasone in the modification of misonidazole pharmacokinetics

The role of dexamethasone in the modification of misonidazole pharmacokinetics

Anomalous patterns of nitroimidazole binding adjacent to necrosis in human glioma xenografts: possible role of decreased oxygen consumption

Phase I clinical trial of intracarotid bis-chloroethylnitrosourea (BCNU) and 2' dioxy-5-fluorouridine (FUDR) in malignant astrocytomas

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