PT  - JOURNAL ARTICLE
AU  - Stevens, Malcolm F. G.
AU  - Hickman, John A.
AU  - Langdon, Simon P.
AU  - Chubb, David
AU  - Vickers, Lisa
AU  - Stone, Robert
AU  - Baig, Ghousia
AU  - Goddard, Colin
AU  - Gibson, Neil W.
AU  - Slack, John A.
AU  - Newton, Christopher
AU  - Lunt, Edward
AU  - Fizames, Christian
AU  - Lavelle, François
TI  - Antitumor Activity and Pharmacokinetics in Mice of 8-Carbamoyl-3-methyl-imidazo[5,1-<em>d</em>]-1,2,3,5-tetrazin-4(3<em>H</em>)-one (CCRG 81045; M & B 39831), a Novel Drug with Potential as an Alternative to Dacarbazine
DP  - 1987 Nov 15
TA  - Cancer Research
PG  - 5846--5852
VI  - 47
IP  - 22
4099  - http://cancerres.aacrjournals.org/content/47/22/5846.short
4100  - http://cancerres.aacrjournals.org/content/47/22/5846.full
SO  - Cancer Res1987 Nov 15; 47
AB  - A number of 3-alkyl analogues of the experimental antitumor drug mitozolomide [8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one] have been screened against murine tumors in vivo. Only the compounds with a 3-methyl- or 3-bromoethyl group possessed significant antitumor activity against the TLX5 lymphoma. The 3-methyl analogue, 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045), was investigated further and found to possess good activity, when administered i.p., against the L1210 and P388 leukemias, the M5076 reticulum cell sarcoma, B16 melanoma, and ADJ/PC6A plasmacytoma. The drug was also active when administered p.o. to mice bearing the L1210 leukemia. A daily for 5 days schedule of 100 mg/kg CCRG 81045 produced increases of survival time of treated animals compared to controls of 176 and >235% against the P388 and L1210 leukemias, respectively. In the female C57BL × DBA/2 F1 mouse the 10% lethal dose was 125 mg/kg daily for 5 days. CCRG 81045 was found to undergo mild alkaline hydrolysis and ring fission to form the linear triazene 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide, which is the putative metabolite formed upon metabolic activation of the antitumor drug dacarbazine [5-(3,3-dimethyltriazen-1-yl)imidazole-4-carboxamide]. The half-life of CCRG 81045 at 37°C in 0.2 m phosphate buffer (pH 7.4) was 1.24 h, whereas that of 5-(3-methyltriazen-1-yl)imidazole-4-carbox-amide at 25°C was reported to be 8 min (F. H. Shealy and C. A. Krauth, J. Med. Chem., 9: 34–37, 1966). The half-life of CCRG 81045 in human plasma in vitro at 37°C was 0.42 h. Pharmacokinetic experiments conducted in BALB/c mice produced plasma profiles of CCRG 81045, administered i.p. or p.o., which showed a rapid absorption phase, elimination half-lives of 1.13 h (i.p.) and 1.29 h (p.o.), and a bioavailability of 0.98. ©1987 American Association for Cancer Research.