Anti-tumour, toxicological and pharmacokinetic properties of a novel taurine-based nitrosourea (TCNU)

Abstract

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.

A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

“…Tauromustine (TCNU, 131 ), a CENU analog of the amino acid taurine, as well as its two probable metabolites 132 and 133 (Table ) were synthesized by two methods, as outlined in Scheme . The justification for choosing taurine as a carrier for nitrosoureas was based on the hypothesis that taurine interacts with membrane phospholipids, thereby modifying their function.…”

Increased degradation rate of nitrososureas in media containing carbonate

“…However, a limited number of nitrosoureas have been fully developed for clinical use due to their toxic side effects (Hanssen et al 1971;Hartley-Asp et al 1988). The introduction of the N-nitroso group destabilizes the bond between the nitrogen and the adjacent carbon atom at physiological pH.…”

The polarographic behavior of the antitumor agent tauromustine and assay of its tablets

“…It is active against a wide variety of experimental tumors, both in vivo and in vitro [1,2], in addition to nitrosourea-resistant tumors [31. Reviewing the literature revealed that only a highperformance liquid chromatography (HPLC) method was described for the determination of tauromustine and its metabolites in plasma and urine [4,5]. Nothing, however, was reported regarding its electrochemistry.…”

“…CH3 CHZ-CHZ-Cl Tauromustine (I) is a new nitrosourea antitumor derived from taurine, an endogenous aminoethanesulfonic acid. It is active against a wide variety of experimental tumors, both in vivo and in vitro [1,2], in addition to nitrosourea-resistant tumors [31.…”