Effects of topoisomerase II inhibitors on gastric cancer cells characterized by different genetic lesions.
Gastric cancer is poorly-responsive to widely used antitumour drugs, the efficacy of which is thought to be related to the capacity of triggering apoptosis. This process requires a series of gene products including a functional p53 protein. We tested the effects of two DNA topoisomerase II poisons, etoposide and doxorubicin, on gastric cancer cell lines with different genetic lesions. We characterised MKN74 and MKN28 cells for p53 gene status and for the expression of p53 and p21 proteins, as well as of topoisomerase II alpha and beta isoforms. After drug treatments, the cells were analysed for drug cytotoxicity, colony forming ability, cell cycle distribution and presence of apoptotic features. Our findings demonstrated that both etoposide and doxorubicin have a potent anti-proliferative effect on gastric cancer cells. Cell death kinetics was different in the two cell lines, MKN74 cells being more sensitive than MKN28 to the drugs. MKN74 cells, although harboring a wt p53 gene, were unable to undergo a massive apoptosis following etoposide treatment. The response of this cell line might be related to the topoisomerase II beta isozyme, the expression of which proved to be undetectable.
Scovassi
A L
AL
Istituto di Genetica Biochimica ed Evoluzionistica CNR, Pavia, Italy.
Pellegata
N S
NS
Di Stefano
L
L
Padovan
L
L
Negri
C
C
Prosperi
E
E
Riva
F
F
Ciomei
M
M
Ranzani
G N
GN
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D016133:Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059005:Topoisomerase II Inhibitors; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II