title: Four-hourly scheduling of temozolomide improves tumour growth delay but not therapeutic index in A375M melanoma xenografts.
abstract: OBJECTIVE
  To establish whether temozolomide is more effective against A375M human melanoma xenografts if given every 4 h rather than every 24 h, in order to exploit depletion of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase) by prior doses of the drug.
  
  
  METHODS
  ATase depletion in A375M human melanoma xenografts was determined over 24 h after a single dose of temozolomide. The effect of different drug schedules (all of total dose 500 mg/kg) in delaying the growth of the xenografts was tested, and ATase depletion and DNA methylation damage assessed in tumour and normal tissue.
  
  
  RESULTS
  Maximal depletion of ATase in tumour, to 2.52 +/- 0.23% of pretreatment levels, occurred 4-8 h after a single 100 mg/kg i.p. dose of temozolomide, with 23.0% recovery of protein levels at 24 h. Scheduling of temozolomide every 4 h increased tumour growth delay (33.6 +/- 1.39 days with temozolomide 100 mg/kg 4-hourly x versus 23.2 +/- 1.43 days with temozolomide 100 mg/kg once daily x 5; P < 0.0001) at the expense of increased toxicity (17.4 +/- 1.55% animal weight loss versus 10.6 +/- 1.27%. respectively). Temozolomide every 4 h did not increase ATase depletion compared with the 5-day schedule, but resulted in greater DNA 06-guanine methylation (29.0% more in tumour, 20.8% in liver and 56.0% in brain, comparing areas under the methylation-time curve).
  
  
  CONCLUSIONS
  The 4-hourly schedule of temozolomide delayed tumour growth significantly more than the once-daily and 12-hourly schedules, probably as a result of greater DNA damage inflicted, but also increased toxicity. It remains to be seen if this regimen confers a net benefit over the standard schedule.
authors.affiliation: Cancer Research Campaign Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK. mmiddleton@picr.man.ac.uk
authors.forename: M R
authors.initials: MR
authors.lastname: Middleton
authors.forename: J
authors.initials: J
authors.lastname: Kelly
authors.forename: S
authors.initials: S
authors.lastname: Goodger
authors.forename: N
authors.initials: N
authors.lastname: Thatcher
authors.forename: G P
authors.initials: GP
authors.lastname: Margison
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D000077204:Temozolomide; D014183:Transplantation, Heterologous
chemical_list: D018906:Antineoplastic Agents, Alkylating; D006147:Guanine; D003606:Dacarbazine; C008449:O-(6)-methylguanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide