Abstract
We report a functional link between expression of the metastasis suppressor gene nm23 and cancer cell sensitivity to the alkylating agent cisplatin. Cisplatin was 2-15-fold more inhibitory to the growth in vitro of nm23 transfectants of the K-1735 TK murine melanoma, MDA-MB-435 human breast carcinoma, and OVCAR-3 human ovarian carcinoma cell lines as compared to matched control transfectants. Administration of a single dose of cisplatin i.v. after injection of control- or nm23-1-transfected K-1735 TK melanoma cells resulted in a more pronounced inhibition of pulmonary metastatic colonization by the nm23-1 transfectants. The mechanism of nm23-dependent sensitivity to cisplatin is unknown, but was correlated with increased formation of interstrand DNA cross-links in nm23-H1 transfected breast carcinoma cells. These data suggest that elevation of tumor cell nm23 expression may be considered as a potential therapeutic strategy in combination with cisplatin treatment.
MeSH terms
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Animals
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Antineoplastic Agents, Alkylating / pharmacology*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Cell Division / drug effects
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Cisplatin / pharmacology*
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Cross-Linking Reagents / pharmacology
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DNA Damage
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DNA, Neoplasm / drug effects
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DNA, Neoplasm / metabolism
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Drug Screening Assays, Antitumor
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Female
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Humans
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Melanoma / drug therapy
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Melanoma / genetics
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Mice
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Monomeric GTP-Binding Proteins*
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NM23 Nucleoside Diphosphate Kinases
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplasms / drug therapy*
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Neoplasms / genetics*
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Nucleoside-Diphosphate Kinase*
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / genetics
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transfection
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Tumor Cells, Cultured / drug effects
Substances
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Antineoplastic Agents, Alkylating
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Cross-Linking Reagents
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DNA, Neoplasm
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NM23 Nucleoside Diphosphate Kinases
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Neoplasm Proteins
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Transcription Factors
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NME1 protein, human
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Nme1 protein, mouse
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Nucleoside-Diphosphate Kinase
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Monomeric GTP-Binding Proteins
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Cisplatin