ENHANCEMENT BY O-6-BENZYL-N2-ACETYLGUANOSINE OF OETHYL]-N[2-(METHYLSULPHONYL)ETHYL]-N'-NITROSOUREA THERAPEUTIC INDEX ON NUDE-MICE BEARING RESISTANT HUMAN-MELANOMA

The exposure of cells to O-6-benzyl-N2-acetylguanosine (BNAG) and seve ral guanine derivatives is known to reduce the activity of O-6-alkylgu anine-DNA alkyltransferase (MGMT) and to enhance the sensitivity of Me r(+) (methyl enzyme repair positive) tumour cells to chloroethylnitros oureas (CENUs) in vitro and in vivo. High water solubility and the pha rmacokinetic properties of BNAG make it a candidate for simultaneous a dministration with CENUs by the i.v. route in human clinical use. In v ivo we have shown previously that BNAG significantly increases the eff iciency of oethyl]-N-[2-(methysulphonyl)ethyl]-N'-nitrosourea (cystemu stine) against M4Beu melanoma cells (Mer(+)) through its cytostatic ac tivity by the i.p. route, but also increases its toxicity. To investig ate the toxicity of BNAG and cystemustine when administered simultaneo usly in mice, we compared the maximum tolerated dose and LD50 doses of cystemustine alone or in combination with 40 mg kg(-1) BNAG by the i. p. route. The toxicity of cystemustine was enhanced by a factor of alm ost 1.44 when combined with BNAG. To compare the therapeutic index of cystemustine alone and the cystemustine/BNAG combination, pharmacologi cal tests were carried out in nude mice bearing Mer(+) M4Beu human mel anoma cells. Isotoxic doses were calculated using the 1.44 ratio. The treatments were administered three times by the i.v. route on days 1, 5 and 9 after s.c. inoculation of tumour cells. Although the toxicitie s of the treatments were equal, SNAG strongly enhanced tumour growth i nhibition. These results demonstrate the increase of the therapeutic i ndex of cystemustine by BNAG and justify the use of BNAG to enhance ni trosourea efficiency in vivo by i.v. co-injection.