THE PRIMARY IN-VITRO ANTITUMOR SCREENING OF HALF-MUSTARD TYPE PHENOTHIAZINES

The antitumor effects of ''half-mustard type'' phenothiazines were stu died on 57 different tumor cell lines, including leukemias, non-small lung cancer, colon, central nervous system, ovarian, renal, breast, an d prostate cancer; as well as melanoma cell cultures. Alkyl-urea deriv atives of phenothiazines displayed in vitro antitumor activity. The ph enothiazine phthalimido derivatives (1-6) were not active on the major ity of cancer cell cultures. In contrast, propylureas (9, 11) were act ive against some leukemia cell types. Only two compounds-with the buty lene [(CH2)(4)] linker (10, 12) were active against non-small lung can cer cells. Compounds containing the propylene linker were less effecti ve On colon cancer lines, tumor cells fi om the central nervous system and on melanoma cells the same compounds were effective, however, hav ing substituents at the 2-position of phenothiazine seems to be import ant. Surprisingly, the majority of ovarian cancer cell lines (except o ne type, IGROVI) and five of eight renal cancer. lines were not sensit ive to these phenothiazine derivatives. The two butylene linked phenot hiazine ureas (10, 12) had moderate antiproliferative action on two re nal cancer cell lines. The prostate cancer and some br east cancer cel l lines were not sensitive. Nevertheless some breast cancer cell lines were apparently sensitive to CF3-substituted phenothiazine alkylureas . On the basis of these experiments one may postulate that in the case of insensitive cells an mdr-gene encoded multidrug resistance efflux pump is responsible for the resistance. The selectivity or organ cell specificity of the effective phenothiazines will be targeted for impro vement in further studies, in order to avoid the general cytotoxic eff ects of ''half mustard type'' phenothiazines.