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O(6)-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts.

Abstract
Tumour resistance to methylating agents is linked to expression of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (ATase). There is considerable interest in improving the efficacy of O(6)-alkylating chemotherapy by prior depletion of ATase. We have tested the ability of a modified guanine base, O(6)-(4-bromothenyl)guanine (4BTG), to inactivate ATase and to enhance the anti-tumour effect of temozolomide in an animal model system. A375M human melanoma xenografts were established in the flanks of nude mice. ATase depletion after a single dose of 4BTG or O(6)-BG (20 mg/kg i.p.) was determined over a 24 hr period. Subsequently, we tested the effect of 4BTG (20 mg/kg i.p. daily) and/or temozolomide (80-175 mg/kg i.p. daily) over a 5-day schedule on tumour growth. 4BTG was an effective inactivator of ATase in tumour, producing complete depletion within 2 hr of dosing. Furthermore, it enhanced the tumour growth delay achieved with temozolomide, increasing the tumour quintupling time by 8.7 days (95% confidence interval 6.1-11.3 days, p < 0.0001). Whilst the delay in tumour growth was indistinguishable from that observed with O(6)-benzylguanine (O(6)-BG) and temozolomide, the 4BTG combination resulted in considerably less toxicity (0/9 vs. 2/9 deaths; 6.84% weight loss vs. 9.48%, p = 0.019). 4BTG is a potent inactivator of ATase and enhances the therapeutic ratio of temozolomide in this model system to a greater extent than O(6)-BG.
AuthorsM R Middleton, J Kelly, N Thatcher, D J Donnelly, R S McElhinney, T B McMurry, J E McCormick, G P Margison
JournalInternational journal of cancer (Int J Cancer) Vol. 85 Issue 2 Pg. 248-52 (Jan 15 2000) ISSN: 0020-7136 [Print] United States
PMID10629085 (Publication Type: Journal Article)
CopyrightCopyright 2000 Wiley-Liss, Inc.
Chemical References
  • Antineoplastic Agents, Alkylating
  • Enzyme Inhibitors
  • O(6)-(4-bromothenyl)guanine
  • O(6)-benzylguanine
  • Guanine
  • Dacarbazine
  • Adenosine Triphosphatases
  • Temozolomide
Topics
  • Adenosine Triphosphatases (antagonists & inhibitors, metabolism)
  • Animals
  • Antineoplastic Agents, Alkylating (therapeutic use)
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Dacarbazine (analogs & derivatives, therapeutic use)
  • Drug Synergism
  • Enzyme Inhibitors (therapeutic use)
  • Guanine (analogs & derivatives, therapeutic use)
  • Male
  • Melanoma (drug therapy, enzymology)
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Temozolomide
  • Transplantation, Heterologous

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