Summary
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.
Similar content being viewed by others
References
Johnston TP, McCaleb GS, Montgomery JA: The synthesis of antineoplastic agents XXXII N-nitrosoureas I. J Med Chem 6:669–681, 1963
De Vita V, Carbone P, Owens A, Gold L, Krant M, Edmonson J: Clinical Trials with 1,3-Bis(2-choroethyl)-1-nitro-sourea NSC-409962. Cancer Res 25:1876–1881, 1965
Hansen HH, Selawry PS, Maggia FM, Walker MD: Clinical studies with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (NSC 79037). Cancer Res 31:223–227, 1971
Anderson T, McMenamin M, Schein PS: Chlorozotocin, 2-[3-(-2-chloroethyl)-3-nitrosoureido]-D-glucopyranose an antitumor agent with modified bone marrow toxicity. Cancer Res 35:761–765, 1975
Fox PA, Panasci LC, Schein PS: Biological and biochemical properties of 1-(-2-chloroethyl)-3-(B-D-glucopyranosyl)-1-nitrosourea (NSCD 254157), a nitrosourea with reduced bone marrow toxicity. Cancer Res 37:783–787, 1977
Aoshima M, Sakurai Y: Comparative studies on the antitumor activity and the bone marrow toxicity of 1-(B-D-glucopyranosyl)-3-(-2-chloroethyl)-3-nitrosourea and 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose. GANN 68:247–250, 1977
Zeller WJ, Eisenbrand G, Fiebig HH; Chemotherapeutic activity of new 2-chloroethylnitrosourea in rat L5222 leukemia: comparison of bifunctional and water-soluble derivatives with 1,3-bis(2-chloroethyl)-1-nitrosourea. J Natl Cancer Inst 60:345–348, 1978
Zeller WJ, Eisenbrand G: Examination of newly synthesized 2-chloroethyl-nitrosoureas on rat leukemia L5222. Oncology 38:39–42, 1981
Panasci LC, Green D, Nagourney R, Fox P, Schein PS: A structure-activity analysis of chemical and biological parameters of chloroethylnitrosoureas in mice. Cancer Res 37:2615–2618, 1977
Hansch C, Leo A, Schmidt C, Jow PYC: Antitumor structure-activity relationships: Nitrosoureas vs L1210 leukemia. J Med Chem 23:1095–1101, 1980
Oseika R, Glatte P, Pannenbäcker R, Schmidt CG: Therapeutic evaluation of five nitrosoureas in a human melanoma xenograft system. Cancer Chemother Pharmacol 11:147–152, 1983
Fredholm B, Gunnarsson K, Jensen G, Müntzing J: Mammary tumour inhibiti on and subacute toxicity in rats of prednimustine and its molecular components chlorambucil and prednisolone. Acta Pharmacol et Toxicol 42:159–163, 1978
Müntzing J, Jensen G, Högberg B: Pilot study on the growth inhibition by estramustine phosphate (Estracyt®) of rat mammary tumours sensitive and insensitive to estrogens. Acta Pharmacol et Toxicol 44:1–6, 1979
Hartley-Asp B, Wilkinson R, Venitt S, Harrap KR: Studies on the mechanism of action of LS 1727, a nitroscarbamate of 19-nortestostrone. Acta Pharmacol et Toxicol 48:129–138, 1981
Berger MR, Aoride J, Schreiber J, Schmähl D, Eisenbrand G: Evaluation of new estrogen-linked 2-chloroethyl-nitrosoureas. Short term anticancer efficacy in methylnitrosoureas-induced rat mammary carcinoma and hormonal activity in mice. J Cancer Clin Oncol 108:148–153, 1984
Wei LS, Katzenellenbogen BS, Robertson DW, Simpson DH, Katzenellenbogen JA: Nitrosourea and nitrosocabamate derivatives of the antiestrogen tamoxifen as potential estrogen receptor-mediated cytotoxic agents in human breast cancer cells. Breast Cancer Res Treat 7:77–90, 1986
Huxtable RJ, Sebring LA: Towards a unifying theory for the actions of taurine. TIPS Dec 1986:481–485, 1986
Ahtee L, Boulin DJ, Paasonen MK: Transport of taurine by normal human blood platelets. Br J Pharmacol 52:245, 1974
Huxtable R, Chubb J: Adrenergic stimulation of taurine transport by the heart. Science 198:409–411, 1977
Vaaden MJ, Oradeu ACI, Marshall J, Lake M: Taurine in the retina: In: Schaffer SW, Baskin SI, Kocsis JJ (eds) The Effects of Taurine on Excitable Tissues. Spectrum Publications Inc USA, 1981, pp 145–160
Christensen HN, Hess B, Riggs TR: Concentration of taurine B-alanine and Triiodothyronine by ascites carcinoma cells. Cancer Res 14:124–127, 1954
Piez KA, Eagle H: The free amino acid pool of cultured human cells. J Biol Chem 231:533–545, 1958
Ishidate M, Sakurai Y, Yoshida T, Satoh H, Imamura H: Experimental studies on chemotherapy of malignant growth employing Yoshida sarcoma animals. VI. Effect of N-bis-B-chloroethyl-aminoacids and their derivatives. GANN, 45:528–531, 1954
Pierson HF, Fisher JM, Rabinovitz M: Modulation by taurine of the toxicity of taumustine, a compound with antitumour activity. J Natl Cancer Inst 75:905–909, 1985
Tauromustine. Drugs of the Future 11:585–587, 1986
Polacek J, Gunnarsson PO, Brandin S: Determination of TCNU, a novel antitumour agent, in plasma by high-performance liquid chromatography. J Chromatog In press
Roed H, Vindeløv LL, Spang-Thomsen M, Christensen IJ, Hansen HH: In vitro evaluation of a new nitrosourea, TCNU, against human small cell lung cancer cell lines. Cancer Chemother Pharmacol 19: 315–318, 1987
Day RS, Ziolkowski CHJ, Scudiero DA, Meyer SA, Lubiniecki AS, Girardi AJ, Galloway SM, Bynum GD: Defective repair of alkylated DNA by human tumour and SV40-transformed human cell strains. Nature 288:724–727, 1980
Erickson LC, Laurent G, Sharkey NA, Kohn KW: DNA cross-linking and monoadduct repair in nitrosourea-treated human tumour cells. Nature 288:727–729, 1980
Tew KD, Dean SW, Gibson NW: The effect of a novel taurine nitrosourea, 1-(2-chloroethyl)-3-[2-(dimethyl-aminosulfonyl) ethyl]-1-nitrosourea (TCNU) on cytotoxicity, DNA cross linking and glutathione reductase in lung carcinoma cell lines. Cancer Chemother Pharmacol 19:291–295(1987)
Molineux G, Schofiled R, Testa NG: The haemopoietic effects of TCNU in mice. Cancer Treat Rep 71:837–842 (1987)
Gunnarsson PO, Vibe-Petersen J, Macpherson IS, Warrington PS, Polacek J, Ellman M, Hansen HH, Smyth JF: Pharmacokinetics of TCNU in cancer patients. Phase I studies. Cancer Chemoth Pharmacol In press
Smyth JF, Macpherson JS, Warrington PS, Kerr ME, Whelan JM, Combleat MA, Leonard RCF: Phase I study of TCNU a novel nitrosourea. Eur J Cancer Clin Oncol 23:1845–1849, 1987
Vibe-Petersen J, Bork E, Møller H, Hansen HH: A phase I clinical evaluation of 1-(2-chloroethyl)-3-/2-(dimethyl-ami-nosulfonyl) ethyl/-1-nitrosourea (TCNU). Eur J Cancer Clin Oncol 23:1837–1843, 1987
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hartley-Asp, B., Christensson, P.I., Gunnarsson, K. et al. Anti-tumour, toxicological and pharmacokinetic properties of a novel taurine-based nitrosourea (TCNU). Invest New Drugs 6, 19–30 (1988). https://doi.org/10.1007/BF00170775
Issue Date:
DOI: https://doi.org/10.1007/BF00170775