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

Mark A. Wuonola, Michael G. Palfreyman, Noboru Motohashi, Masami Kawase, Sabit Gabay, Radha Raman Gupta, J. Molnár

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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 anti-leukemic 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 anti-leukemic 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.

Original languageEnglish
Pages (from-to)337-348
Number of pages12
JournalAnticancer Research
Volume18
Issue number1 A
Publication statusPublished - Jan 1998

Fingerprint

Phenothiazines
Mustard Plant
Cell Line
Growth
Neoplasms
Leukemia
Non-Small Cell Lung Carcinoma
Ovarian Neoplasms
Colonic Neoplasms
Inhibitory Concentration 50
Urea
Melanoma
In Vitro Techniques
Central Nervous System
Breast Neoplasms
Kidney Neoplasms
Renal Cell Carcinoma
Pharmaceutical Preparations
phenothiazine
Prostate

Keywords

  • Anticancer activity
  • Phenothiazines

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wuonola, M. A., Palfreyman, M. G., Motohashi, N., Kawase, M., Gabay, S., Gupta, R. R., & Molnár, J. (1998). The primary in vitro anticancer activity of 'half-mustard type' phenothiazines in NCI's revised anticancer screening paradigm. Anticancer Research, 18(1 A), 337-348.

The primary in vitro anticancer activity of 'half-mustard type' phenothiazines in NCI's revised anticancer screening paradigm. / Wuonola, Mark A.; Palfreyman, Michael G.; Motohashi, Noboru; Kawase, Masami; Gabay, Sabit; Gupta, Radha Raman; Molnár, J.

In: Anticancer Research, Vol. 18, No. 1 A, 01.1998, p. 337-348.

Research output: Contribution to journalArticle

Wuonola, MA, Palfreyman, MG, Motohashi, N, Kawase, M, Gabay, S, Gupta, RR & Molnár, J 1998, 'The primary in vitro anticancer activity of 'half-mustard type' phenothiazines in NCI's revised anticancer screening paradigm', Anticancer Research, vol. 18, no. 1 A, pp. 337-348.
Wuonola MA, Palfreyman MG, Motohashi N, Kawase M, Gabay S, Gupta RR et al. The primary in vitro anticancer activity of 'half-mustard type' phenothiazines in NCI's revised anticancer screening paradigm. Anticancer Research. 1998 Jan;18(1 A):337-348.
Wuonola, Mark A. ; Palfreyman, Michael G. ; Motohashi, Noboru ; Kawase, Masami ; Gabay, Sabit ; Gupta, Radha Raman ; Molnár, J. / The primary in vitro anticancer activity of 'half-mustard type' phenothiazines in NCI's revised anticancer screening paradigm. In: Anticancer Research. 1998 ; Vol. 18, No. 1 A. pp. 337-348.
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N2 - 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 anti-leukemic 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 anti-leukemic 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.

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