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Cytostatic action of two nitrosoureas derived from cysteamine
Author(s) -
Bourut Charlotte,
Chenu Evelyne,
Godenèche Denise,
Madelmont JeanClaude,
Marla René,
Mathé Georges,
Meyniel Gaston
Publication year - 1986
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1986.tb11154.x
Subject(s) - nitrosourea , chemistry , cysteamine , lewis lung carcinoma , glioma , procarbazine , melanoma , carcinoma , fibrosarcoma , pharmacology , stereochemistry , cancer research , biochemistry , cyclophosphamide , cancer , medicine , pathology , chemotherapy , biology , vincristine , metastasis
1 2‐Chloroethyl nitrosocarbamoylcystamine or ICIG‐1325 (CNCC) is a lipid‐soluble isomeric mixture of nitrosoureas. 2 Its dose‐effect relationship on L1210 leukaemia is characterized by a large maximally efficient dose‐range (MEDR), greater than that of other nitrosoureas. CNCC also demonstrated significant therapeutic activity on intracerebrally (i.c.) transplanted L1210 leukaemia and on six transplanted solid tumours, TM2 mammary carcinoma, M555 ovarian carcinoma, B16 melanoma, glioma 26, 3LL, Lewis lung carcinoma and colon 26 carcinoma. It was inactive on fibrosarcoma ICIG‐Ci4. Its antitumour activity spectrum is wider than that of the related compounds 2‐[3‐(2‐chloroethyl) 3‐nitrosoureido]D‐glucopyranose (CZT), (chloro‐2‐ethyl)‐1 (ribofuranosyl‐isopropylidene‐2′‐3′paranitrobenzoate‐5′)‐3 nitrosourea (RFCNU), and (chloro‐2‐ethyl)‐1 (ribopyranosyl triacetate‐2′‐3′‐4′)‐3 nitrosourea (RPCNU). 3 A study of its metabolic disposition in animals has shown that CNCC undergoes extensive first‐pass metabolism leading to the formation of four main plasma metabolites. 4 These metabolites are water‐soluble nitrosoureas that arose from the bioreduction of the disulphide bridge followed by the methylation and the oxidation of the thiol groups. 5 Experimental screening was performed with these chemically synthesized metabolites. Both N'‐(2‐chloroethyl)‐N‐[2‐(methylsulphinyl)ethyl]‐N'‐nitrosourea (CMSOEN 2 ) and N'‐(2‐chloroethyl)‐N‐[2‐(methylsulphonyl)ethyl]‐N'‐nitrosourea (CMSO 2 EN 2 ) are very active on L1210 leukaemia grafted intraperitoneally (i.p.) and i.c., L40 leukaemia, B16 melanoma, glioma 26 and Lewis lung carcinoma. Their effectiveness is better than that of the parent compound CNCC. In addition, the percentage of mice cured after CMSOEN 2 or CMSO 2 EN 2 treatment is increased especially on B16 melanoma and glioma 26. 6 Haematological toxicity of both active metabolites is lower than that of CNCC, particularly on platelets which is the main toxicity location due to nitrosoureas.