SMS 201-995 enhances S-phase block induced by 5-fluorouracil in a human colorectal cancer cell line.
The action of the somatostatin analog SMS-201.995 (SMS) was tested in monotherapy and in combined therapy with the cytotoxic agent 5-fluorouracil (5-FU) on cell cycle kinetics of the human colon cancer cell line WiDr, expressing a mutant p53 (mp53). The data, obtained by flow cytometric DNA analysis, showed that SMS at 0.2 microg/ml increased apoptosis, augmenting the proportion of cells with subdiploid DNA content by 65 and 48% after 3 and 6 h, respectively. In cultures lasting 24 and 36 h, it also decreased the percentages of cells in G0/G1 phase by 22.9 and 14.3%; whereas at a dose of 0.1 microg/ml, SMS decreased the percentage of cells in G2/M by 14.3%. In contrast to SMS, 5-FU (0.1 microg/ml) augmented the apoptosis at 12 h, and markedly increased the fraction of cells in S phase, increasing its value from 24 and 72 h by 108 and 234%, respectively, in comparison to the control. The most evident finding after the combination of SMS (0.2 microg/ml) and 5-FU (0.1 microg/ml) was a potentiation of 5-FU-induced S-phase block by a further 7.9, 12.9 and 42.1% at 24, 36 and 72 h, respectively. Treatment with 5-FU also upregulated HLA class I expression of the cancer cells. In this sense, SMS was less effective and when given in combination with 5-FU did not change the effects induced by 5-FU. The data emphasize that SMS exhibits pro-apoptotic and anti-proliferative effects, which in proper dose combinations might enhance the effects of 5-FU on human colorectal cancer cells expressing mp53.
Massari
Drazen
D
Department of Physiology and Immunology, Medical School, University of Rijeka, Rijeka, Croatia.
Trobonjac
Zlatko
Z
Rukavina
Daniel
D
Radosević-Stasić
Biserka
B
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D015282:Octreotide / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects*; D013997:Time Factors
D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D015282:Octreotide; D005472:Fluorouracil