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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kelly, R. Li, W. Hochhauser, D. Bertino, J. R. Almasan, A. Banerjee, D. Fan, J. Zielinski, Z. Wahl, G. M. Yin, Y. |
| Description | Author Affiliation: Li W ( Program for Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.); |
| Abstract | Growth inhibition assays indicated that the IC50 values for methotrexate (MTX) and 5-fluorodeoxyuridine (FdUrd) in HS-18, a liposarcoma cell line lacking retinoblastoma protein (pRB), and SaOS-2, an osteosarcoma cell line with a truncated and nonfunctional pRB, were 10- to 12-fold and 4- to 11-fold higher, respectively, than for the HT-1080 (fibrosarcoma) cell line, which has wild-type pRB. These Rb-/- cell lines exhibited a 2- to 4-fold increase in both dihydrofolate reductase (DHFR) and thymidylate synthase (TS) enzyme activities as well as a 3- to 4-fold increase in mRNA levels for these enzymes compared to the HT-1080 (Rb+/+) cells. This increase in expression was not due to amplification of the DHFR and TS genes. Growth inhibition by MTX and FdUrd was increased and DHFR and TS activities and expression were correspondingly decreased in Rb transfectants of SaOS-2 cells. In contrast, there was no significant difference in growth inhibition among these cell lines for the nonantimetabolites VP-16, cisplatin, and doxorubicin. A gel mobility-shift assay showed that parental SaOS-2 cells had increased levels of free E2F compared to the Rb-reconstituted SaOS-2 cells. These results indicate that pRB defective cells may have decreased sensitivity to growth inhibition by target enzymes encoded by genes whose transcription is enhanced by E2F proteins and suggest mechanisms of interaction between cytotoxic agents and genes involved in cell cycle progression. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 22 |
| Volume Number | 92 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 1995-11-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antimetabolites, Antineoplastic Toxicity Antineoplastic Agents Drug Resistance, Neoplasm Physiology Floxuridine Methotrexate Retinoblastoma Protein Deficiency Bone Neoplasms Cell Division Drug Effects Cell Line Cisplatin Doxorubicin Etoposide Fibrosarcoma Liposarcoma Molecular Sequence Data Oligonucleotide Probes Osteosarcoma Recombinant Proteins Biosynthesis Metabolism Tetrahydrofolate Dehydrogenase Thymidylate Synthase Transfection Tumor Cells, Cultured Comparative Study Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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