Cargando…

Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU.

Because the nitrosourea CCNU is given exclusively by the oral route in man, we have carried out studies in mice on the antitumour activity, acute toxicity and pharmacokinetics of oral CCNU, either alone or in combination with the chemosensitizer misonidazole. In both plasma and KHT tumour the peak c...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, F. Y., Workman, P.
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 1985
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1976817/
https://www.ncbi.nlm.nih.gov/pubmed/3966974
_version_ 1782135133570072576
author Lee, F. Y.
Workman, P.
author_facet Lee, F. Y.
Workman, P.
author_sort Lee, F. Y.
collection PubMed
description Because the nitrosourea CCNU is given exclusively by the oral route in man, we have carried out studies in mice on the antitumour activity, acute toxicity and pharmacokinetics of oral CCNU, either alone or in combination with the chemosensitizer misonidazole. In both plasma and KHT tumour the peak concentration and "early" AUC for total nitrosoureas were about 1.4-1.5 fold greater for the oral compared to the i.p. route. These differences were reflected in the roughly twofold greater antitumour activity for the oral route. In contrast, acute toxicity tests showed that oral CCNU was 1.45 times less toxic to normal tissue, although the dose-limiting organ may be different for the two routes. Misonidazole reduced the antitumour activity of oral CCNU by dose modifying factors (DMF) of 0.58-0.71. Similarly, the acute toxicity was also diminished by a DMF of 0.74. Misonidazole has a complex effect on oral CCNU pharmacokinetics. The plasma and tumour total nitrosourea peak concentrations were reduced by 1.5 and 1.7 fold respectively. Misonidazole also reduced the "early" nitrosourea AUC, with the extent of the reduction depending on the minimum effective concentration (MEC) chosen. For example, the plasma nitrosourea AUC was reduced by factors of 1.05 and 9.6 for MEC values of 1 and 2 micrograms ml-1 respectively. We propose these pharmacokinetic changes to be the underlying mechanism for the reduction of oral CCNU cytotoxicity by misonidazole. Clinical trials of such combinations should be accompanied by detailed pharmacokinetic evaluation.
format Text
id pubmed-1976817
institution National Center for Biotechnology Information
language English
publishDate 1985
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-19768172009-09-10 Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU. Lee, F. Y. Workman, P. Br J Cancer Research Article Because the nitrosourea CCNU is given exclusively by the oral route in man, we have carried out studies in mice on the antitumour activity, acute toxicity and pharmacokinetics of oral CCNU, either alone or in combination with the chemosensitizer misonidazole. In both plasma and KHT tumour the peak concentration and "early" AUC for total nitrosoureas were about 1.4-1.5 fold greater for the oral compared to the i.p. route. These differences were reflected in the roughly twofold greater antitumour activity for the oral route. In contrast, acute toxicity tests showed that oral CCNU was 1.45 times less toxic to normal tissue, although the dose-limiting organ may be different for the two routes. Misonidazole reduced the antitumour activity of oral CCNU by dose modifying factors (DMF) of 0.58-0.71. Similarly, the acute toxicity was also diminished by a DMF of 0.74. Misonidazole has a complex effect on oral CCNU pharmacokinetics. The plasma and tumour total nitrosourea peak concentrations were reduced by 1.5 and 1.7 fold respectively. Misonidazole also reduced the "early" nitrosourea AUC, with the extent of the reduction depending on the minimum effective concentration (MEC) chosen. For example, the plasma nitrosourea AUC was reduced by factors of 1.05 and 9.6 for MEC values of 1 and 2 micrograms ml-1 respectively. We propose these pharmacokinetic changes to be the underlying mechanism for the reduction of oral CCNU cytotoxicity by misonidazole. Clinical trials of such combinations should be accompanied by detailed pharmacokinetic evaluation. Nature Publishing Group 1985-01 /pmc/articles/PMC1976817/ /pubmed/3966974 Text en https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Article
Lee, F. Y.
Workman, P.
Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU.
title Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU.
title_full Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU.
title_fullStr Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU.
title_full_unstemmed Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU.
title_short Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU.
title_sort misonidazole protects mouse tumour and normal tissues from the toxicity of oral ccnu.
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1976817/
https://www.ncbi.nlm.nih.gov/pubmed/3966974
work_keys_str_mv AT leefy misonidazoleprotectsmousetumourandnormaltissuesfromthetoxicityoforalccnu
AT workmanp misonidazoleprotectsmousetumourandnormaltissuesfromthetoxicityoforalccnu