Formation of DNA adducts and tumor growth delay following intratumoral administration of DTI-015.
Intratumoral (IT) administration of DTI-015 (BCNU in 100% ethanol) utilizes solvent facilitated perfusion for the treatment of tumors. RIF-1 tumors were treated by IT injection of either ethanol alone or 0.05-1.0 mg of DTI-015 or by i.v. injection of 0.5 mg of BCNU. Treatment with ethanol alone or i.v. injection of 0.5 mg of BCNU did not produce a significant growth delay. In contrast, IT administration of DTI-015 produced a significant growth delay at each of the treatment doses (p < 0.05 to p < 0.001). We have quantified the levels of N7-(2-hydroxyethyl) guanine (N7-HOEtG) in RIF-1 tumors 24h following either IT treatment with 0.5 mg DTI-015 or i.p. administration of 0.5 mg BCNU. Levels of N7-HOEtG (micromol/mol DNA) were < or = 0.08 for both untreated controls and following i.p. treatment with BCNU and 13.1 +/- 5.6 following IT administration of DTI-015. The levels of N7-HOEtG detected in RIF-1 tumors following IT administration of DTI-015 were 164-fold higher than the level(s) of N7-HOEtG in the i.p. BCNU treated tumor samples. These studies demonstrate that IT administration of DTI-015 produces high levels of DNA adducts in the tumor which correspond to a significant increase in tumor growth delay compared to the same dose of BCNU administered systemically.
Bodell
William J
WJ
Laboratory of Molecular Therapeutics, Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, CA 94143-0555, USA. bodell@itsa.ucsf.edu
Giannini
Donald D
DD
Singh
Saira
S
Pietronigro
Dennis
D
Levin
Victor A
VA
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D002330:Carmustine / Q000008:administration & dosage*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D005260:Female; D005910:Glioma / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000032:analysis; D015552:Injections, Intralesional; D007275:Injections, Intravenous; D051379:Mice; D008809:Mice, Inbred C3H; D012878:Skin Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D013056:Spectrophotometry, Ultraviolet; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D004273:DNA, Neoplasm; C035018:N(7)-hydroxyethylguanine; D006147:Guanine; D002330:Carmustine