The antitumor effects of "half-mustard type" phenothiazines were studied on 57 different tumor cell lines, including leukemias, non-small lung cancer, colon, central nervous system, ovarian, renal, breast, and prostate cancer, as well as melanoma cell cultures. Alkyl-urea derivatives of phenothiazines displayed in vitro antitumor activity. The phenothiazine phthalimido derivatives (1-6) were not active on the majority of cancer cell cultures. In contrast, propylureas (9, 11) were active against some leukemia cell types. Only two compounds with the butylene [(CH2)4] linker (10, 12) were active against non-small lung cancer cells. Compounds containing the propylene linker were less effective. On colon cancer lines, tumor cells from the central nervous system and on melanoma cells the same compounds were effective, however, having substituents at the 2-position of phenothiazine seems to be important. Surprisingly, the majority of ovarian cancer cell lines (except one type, IGROVI) and five of eight renal cancer lines were not sensitive to these phenothiazine derivatives. The two butylene linked phenothiazine ureas (10, 12) had moderate antiproliferative action on two renal cancer cell lines. The prostate cancer and some breast cancer cell 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 improvement in further studies, in order to avoid the general cytotoxic effects of "half mustard type" phenothiazines.

Antineoplastic Agents↗

PubMedDate not supplied

The in vitro antitumor assay of "half-mustard type" phenothiazines in screens of AIDS-related leukemia and lymphomas.

Twelve different "half-mustard type" phenothiazines were newly synthesized and tested on seven AIDS-related lymphoma (ARL) tumor cell lines, one leukemia CCRF-CEM cell culture and five different lymphoma lines; RL, KD-488, AS283, PA682 and SU-DHL-7 cell lines. The alkylene-urea substituted phenothiazines affected the growth and inhibited the growth rate of AIDS-related lymphoma cells. The Cl-substituent at the 2-position was more effective than the CF3 substitution. In AIDS-related leukemia also the compounds with Cl at the 2-position with propylene or butylene linkers, -(CH2)3- and -(CH2)4-, respectively, were more effective than the CF3 substituted compounds. Two of the six phenothiazine-substituted alkyl-urea derivatives, i.e., 1-(2-chloroethyl)-3-(2-chloro-10H-phenothiazin-10-yl)propyl-l-urea (9, GI50 = -5.66, TGI = -5.04) and 1-(2-chloroethyl)- 3-(2-chloro-10H-phenothiazin-10-yl)butyl-1-urea (10, GI50 = -5.61, TGI = -5.12) exhibited antitumor activity for AIDS-related leukemia and five AIDS-related lymphomas. The trifluoromethyl-substituted derivatives were not as effective on AIDS-related tumor cell lines. Apparently, the substituent at the 2-position on the phenothiazine and the alkylene number of the linker attached to the nitrogen of the phenothiazine ring have an important role in the compound's antitumor effects on AIDS-related leukemia and lymphomas.

Antineoplastic Agents↗

PubMedDate not supplied

The primary in vitro anticancer activity of "half-mustard type" phenothiazines in NCI's revised anticancer screening paradigm.

Some new phenothiazines have been synthesized on the basis of previous studies. The anticancer activity of "half-mustard type" phenothiazines was investigated on sixty different cancer cell lines in vitro. The percentage of growth (PG), 50% inhibition of growth (GI50), the tumor growth inhibition (TGI) and the concentration required for 50% lethality of cells (IC50) were examined and calculated in the presence of various (from 10(-4) to 10(-8) M) concentrations of phenothiazine alkylurea derivatives. The following cell lines were involved in the study: 6 leukemia, 9 non-small-cell lung cancer, 7 colon cancer, 6 central nervous system cancer, 8 melanoma, 6 ovarian cancer, 8 renal cancer, 2 prostate and 8 breast cancer cell lines. The antileukemic activity of four chloroethyl-substituted phenothiazine-alkylureas was shown by considerable growth inhibition, in the 10(-5) M range, of the six different leukemia cell lines. The 50% inhibition of growth was nearly the same for the four compounds on all cell lines. Tumor growth inhibition (TGI) and IC50 value to cells varied from -4.0 to -4.66. The two derivatives with the butylene bridge were more effective than propylene linked compounds against the CCRP-CEM, HL60 (TB), K-562 and MOLT-4 cell lines. However, the anti-leukemic activity of the derivatives was nearly the same for RPMT 8226 and SR cell lines. The substituent at the 2- position of phenothiazine ring and the length of the linker between the side chain nitrogen and the phenothiazine ring system are apparently important for antileukemic activity. Four of the 9 non-small-cell lung cancer cell lines were sensitive, while the other 5 cell lines were not. The compounds had a slight growth inhibitory effect on colon cell carcinoma and melanoma cells in which case the butylene linker seemed to be more effective than the propylene linker. At the same time, all of the compounds were weak or mostly inactive on cancer cells from the central nervous system. One ovarian cancer line of the 6, the IGROVI was sensitive to butylurea phenothiazines, however, the other five were not sensitive at all. The difference in the sensitivity of various renal cell carcinomas was significant: 5 lines were not sensitive, three of them (786-0, RXF-393 and TK-10) were sensitive to only butylene-substituted phenothiazine-ureas, propylene substitution resulted in ineffective compounds. The compounds were not able to inhibit the 2 prostate and 4 breast cancer cell lines, even at 10(-4) M. It was interesting that propylene-linked ureas were more effective than butylene-linked derivatives on MCF-7, but butylene-linked derivatives were more effective than propylene-linked compounds on MDA MB-231 and MDA-N. In addition, MDA MB 435 was more sensitive to the trifluoromethyl derivatives than the compounds without this substituent. Since the phthalimido-alkyl phenothiazines were not active at the first level of prescreen, these compounds were omitted from this study. The drug sensitivity of some cancer cell lines was not uniform for the different groups, therefore we postulate that the resistance can be related to some kind of (existing) drug-efflux mechanism. Apparently, the tumor specificity of phenothiazine alkylureas is more related to the leukemia specificity of alkylureas than to any CNS or lung specificity of phenothiazines.

Antineoplastic Agents↗