Anti-tumour, toxicological and pharmacokinetic properties of a novel taurine-based nitrosourea (TCNU).
A novel nitrosourea, 1-(2-chloroethyl)-3-[2-(dimethylaminosulfonyl) ethyl]-1-nitrosourea (TCNU) tauromustine, has been investigated in a broad anti-tumour screen and, in depth toxicology and initial pharmacokinetics carried out. TCNU and its two metabolites were found to exhibit equal or better oral efficacy than that of BCNU, CCNU, MeCCNU or chorozotocin against L1210 leukemia, Walker mammary carcinoma, Lewis Lung, Harding Passey melanoma and colon carcinoma C26. The toxicological profile of TCNU after acute and 3 months treatment was similar in mice and rats to that of CCNU, with the exception that, TCNU did not cause the chronic liver disturbances found for CCNU. In dogs treated for 6 weeks with TCNU leucopenia and thrombocytopenia were the major side effects. Parent TCNU was found in all dogs. The absorption was fast, the maximum level being reach after 25 mins and the mean absorption time was 22 mins. The mean half life was 16.1 mins after intravenous and 17.4 after oral administration. The combination of these factors make TCNU an interesting clinical candidate.
Hartley-Asp
B
B
AB Leo, Helsingborg, Sweden.
Christensson
P I
PI
Gunnarsson
K
K
Gunnarsson
P O
PO
Jensen
G
G
Polacek
J
J
Stamvik
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001711:Biotransformation; D001772:Blood Cell Count; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D008297:Male; D051379:Mice; D009607:Nitrosourea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013654:Taurine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D013654:Taurine; C052991:1-(2-chloroethyl)-3-(2-(dimethylaminosulfonyl)ethyl)-1-nitrosourea