Effect of O6-(4-bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model.

2.50
Hdl Handle:
http://hdl.handle.net/10541/81239
Title:
Effect of O6-(4-bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model.
Authors:
Middleton, Mark R; Thatcher, Nick; McMurry, T Brian H; McElhinney, R Stanley; Donnelly, Dorothy J; Margison, Geoffrey P
Abstract:
The DNA repair protein O(6)-alkylguanine DNA alkyltransferase (ATase) is a major component of resistance to treatment with methylating agents and nitrosoureas. Inactivation of the protein, via the administration of pseudosubstrates, prior to chemotherapy has been shown to improve the latter's therapeutic index in animal models of human tumours. We have also shown that rational scheduling of temozolomide, so that drug is administered at the ATase nadir after the preceding dose, increases tumour growth delay in these models. We now report the results of combining these two approaches. Nude mice bearing A375M human melanoma xenografts were treated with vehicle or 100 mg/kg temozolomide ip for 5 doses spaced 4, 12 or 24 hr apart. Each dose was preceded by the injection of vehicle or 20 mg/kg 4BTG. All treatments resulted in significant delays in tumour quintupling time compared with controls: by 6.2, 5.9 and 16.8 days, respectively, for 24-, 12- and 4-hourly temozolomide alone and by 22.3, 21.3 and 22.1 days, respectively, in combination with 4BTG. Weight loss due to TMZ was unaffected by the presence of 4BTG. This was of the order of 6.2-10.6% with 24- and 12-hourly administration and 17.4-20.1% (p < 0.0001) with 4-hourly treatment. In our model, combining daily temozolomide with 4-BTG confers increased antitumour activity equivalent to that achieved by compressing the temozolomide schedule but with less toxicity. Using temozolomide schedule compression with 4-BTG does not improve on this result, suggesting that ATase inactivation with pseudosubstrates is a more promising means of enhancing the activity of temozolomide than compressed scheduling.
Affiliation:
Cancer Research UK, Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom.
Citation:
Effect of O6-(4-bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model. 2002, 100 (5):615-7 Int. J. Cancer
Journal:
International Journal of Cancer
Issue Date:
10-Aug-2002
URI:
http://hdl.handle.net/10541/81239
DOI:
10.1002/ijc.10532
PubMed ID:
12124813
Type:
Article
Language:
en
ISSN:
0020-7136
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorMiddleton, Mark R-
dc.contributor.authorThatcher, Nick-
dc.contributor.authorMcMurry, T Brian H-
dc.contributor.authorMcElhinney, R Stanley-
dc.contributor.authorDonnelly, Dorothy J-
dc.contributor.authorMargison, Geoffrey P-
dc.date.accessioned2009-09-16T10:22:16Z-
dc.date.available2009-09-16T10:22:16Z-
dc.date.issued2002-08-10-
dc.identifier.citationEffect of O6-(4-bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model. 2002, 100 (5):615-7 Int. J. Canceren
dc.identifier.issn0020-7136-
dc.identifier.pmid12124813-
dc.identifier.doi10.1002/ijc.10532-
dc.identifier.urihttp://hdl.handle.net/10541/81239-
dc.description.abstractThe DNA repair protein O(6)-alkylguanine DNA alkyltransferase (ATase) is a major component of resistance to treatment with methylating agents and nitrosoureas. Inactivation of the protein, via the administration of pseudosubstrates, prior to chemotherapy has been shown to improve the latter's therapeutic index in animal models of human tumours. We have also shown that rational scheduling of temozolomide, so that drug is administered at the ATase nadir after the preceding dose, increases tumour growth delay in these models. We now report the results of combining these two approaches. Nude mice bearing A375M human melanoma xenografts were treated with vehicle or 100 mg/kg temozolomide ip for 5 doses spaced 4, 12 or 24 hr apart. Each dose was preceded by the injection of vehicle or 20 mg/kg 4BTG. All treatments resulted in significant delays in tumour quintupling time compared with controls: by 6.2, 5.9 and 16.8 days, respectively, for 24-, 12- and 4-hourly temozolomide alone and by 22.3, 21.3 and 22.1 days, respectively, in combination with 4BTG. Weight loss due to TMZ was unaffected by the presence of 4BTG. This was of the order of 6.2-10.6% with 24- and 12-hourly administration and 17.4-20.1% (p < 0.0001) with 4-hourly treatment. In our model, combining daily temozolomide with 4-BTG confers increased antitumour activity equivalent to that achieved by compressing the temozolomide schedule but with less toxicity. Using temozolomide schedule compression with 4-BTG does not improve on this result, suggesting that ATase inactivation with pseudosubstrates is a more promising means of enhancing the activity of temozolomide than compressed scheduling.en
dc.language.isoenen
dc.subjectCancer Transplantationen
dc.subject.meshAdenosine Triphosphatases-
dc.subject.meshAnimals-
dc.subject.meshCell Division-
dc.subject.meshDacarbazine-
dc.subject.meshDisease Models, Animal-
dc.subject.meshGuanine-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMelanoma-
dc.subject.meshMice-
dc.subject.meshMice, Nude-
dc.subject.meshNeoplasm Transplantation-
dc.subject.meshTime Factors-
dc.titleEffect of O6-(4-bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK, Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom.en
dc.identifier.journalInternational Journal of Canceren

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