© 2007 Foundation for Promotion of Cancer Research
Genes Regulating the Sensitivity of Solid Tumor Cell Lines to Cytotoxic Agents: A Literature Review
1 Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
2 Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center at Dallas, Texas, USA
3 Department of Genome Biology, Kinki University School of Medicine, Ohno-Higashi Osaka-Sayama, Osaka, Japan
4 Division of Internal Medicine, National Cancer Center Hospital East, Kashiwanoha, Kashiwa, Chiba, Japan
For reprints and all correspondence: Ikuo Sekine, Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. E-mail: isekine{at}ncc.go.jp
Received October 26, 2006; accepted December 17, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONMETHODSRESULTSDISCUSSIONConflict of interest statementTable referencesReferences |
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In order to review gene alterations associated with drug responses in vitro to identify candidate genes for predictive chemosensitivity testing, we selected from literature genes fulfilling at least one of the following criteria for the definition of ‘in vitro chemosensitivity associated gene’: (i) alterations of the gene can be identified in human solid tumor cell lines exhibiting drug-induced resistance; (ii) transfection of the gene induces drug resistance; (iii) down-regulation of the gene increases the drug sensitivity. We then performed Medline searches for papers on the association between gene alterations of the selected genes and chemosensitivity of cancer cell lines, using the name of the gene as a keyword. A total of 80 genes were identified, which were categorized according to the protein encoded by them as follows: transporters (n = 15), drug targets (n = 8), target-associated proteins (n = 7), intracellular detoxifiers (n = 7), DNA repair proteins (n = 10), DNA damage recognition proteins (n = 2), cell cycle regulators (n = 6), mitogenic and survival signal regulators (n = 7), transcription factors (n = 4), cell adhesion-mediated drug resistance protein (n = 1), and apoptosis regulators (n = 13). The association between the gene alterations and chemosensitivity of cancer cell lines was evaluated in 50 studies for 35 genes. The genes for which the association above was shown in two or more studies were those encoding the major vault protein, thymidylate synthetase, glutathione S-transferase pi, metallothionein, tumor suppressor p53, and bcl-2. We conclude that a total of 80 in vitro chemosensitivity associated genes identified in the literature are potential candidates for clinical predictive chemosensitivity testing.
Key Words: chemotherapy • sensitivity • drug resistance • solid tumor
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INTRODUCTION |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONConflict of interest statementTable referencesReferences |
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Malignant neoplastic diseases remain one of the leading causes of death around the world despite extensive basic research and clinical trials. Advanced solid tumors, which account for most malignant tumors, still remain essentially incurable. For example, 80% of patients with non-small cell lung cancer have distant metastases either at the time of the initial diagnosis itself or at the time of recurrence after surgery for the primary tumor. Systemic chemotherapy against malignant tumors remains of limited efficacy in spite of the development in the recent past of several new chemotherapeutic agents; therefore, patients with distant metastases rarely live for long (1).
Tumor response to chemotherapy varies from patient to patient, and clinical objective response rates to standard chemotherapeutic regimens have been reported to be in the range of 20–40% for most common solid tumors. Thus, it would be of great benefit it became possible to predict chemosensitivity of various tumors even prior to therapy. DNA, RNA and protein-based chemosensitivity tests have been performed in an attempt to predict the clinical drug response, but the precise gene alterations that might be predictive of the chemosensitivity of the tumors are still unknown. Here we aimed to review the gene alterations that may be associated with the drug response in vitro (in vitro chemosensitivity associated genes) in order to identify candidate genes for predictive chemosensitivity testing in the clinical setting. The association between these gene alterations and clinical chemosensitivity in lung cancer patients has been reported elsewhere (2).
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METHODS |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONConflict of interest statementTable referencesReferences |
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In vitro chemosensitivity associated genes were identified from the medical literature as described previously (2). Briefly, we conducted a Medline search for papers on tumor drug resistance published between 2001 and 2003. This search yielded 112 papers, including several review articles. Manual search of these papers led to identification of 134 genes or gene families that were potentially involved in drug resistance based on their function. We conducted a second Medline search for in vitro studies of the 134 genes or gene families using the name of the gene as a keyword. Genes that fulfilled at least one of the following criteria for the definition of in vitro chemosensitivity associated gene were selected from the 134 genes: (i) alterations of the gene can be identified in a human solid tumor cell lines exhibiting drug-induced resistance; (ii) transfection of the gene induces drug resistance; (iii) down-regulation of the gene or of the protein encoded by it increases the drug sensitivity. For this last category, we included studies in which the gene expression or function was suppressed by antisense RNA, hammerhead ribozyme, or antibody against the gene product. Finally, a Medline search for papers on the association between gene alterations and chemosensitivity of solid tumor cell lines was performed using the name of the gene as a keyword. Papers in which the association was evaluated in 20 or more cell lines were included in this study. The name of each gene was standardized according to the Human Gene Nomenclature Database of National Center for Biotechnology Information (NCBI).
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RESULTS |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONConflict of interest statementTable referencesReferences |
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Of the 134 genes or gene families, gene alterations were found in cells exhibiting drug-induced resistance, transfection of the gene increased or decreased the drug resistance, and down-regulation of the gene altered the drug sensitivity for 45, 57 and 32 genes, respectively, and a total of 80 genes fulfilled the criteria for the definition of an ‘in vitro chemosensitivity associated gene’. The genes were categorized according to the protein encoded by them as follows: transporters (n = 15, Table 1), drug targets (n = 8, Table 2), target-associated proteins (n = 7, Table 2), intracellular detoxifiers (n = 7, Table 3), DNA repair proteins (n = 10, Table 4), DNA damage recognition proteins (n = 2, Table 4), cell cycle regulators (n = 6, Table 5), mitogenic and survival signal regulators (n = 7, Table 6), transcription factors (n = 4, Table 6), cell adhesion-mediated drug resistance protein (n = 1, Table 6), and apoptosis regulators (n = 13, Table 7).
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The association between the gene alterations and in vitro chemosensitivity was evaluated in one study for 25 genes, in two studies for seven genes, in three studies for two genes, and in five studies for one gene, and in a total of 50 studies for 35 genes (Table 8). Significant association was found between chemosensitivity and alterations of genes encoding transporters, drug targets and intracellular detoxifiers (Table 8). Genes for which such association was shown in two or more studies were those encoding the major vault protein/lung resistance-related protein (MVP) (Table 1), thymidylate synthetase (TYMS) (Table 2), glutathione S-transferase pi (GSTP1), metallothionein (MT) (Table 3), tumor suppressor protein p53 (TP53), and B-cell CLL/lymphoma 2 (BCL2) (Table 7).
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DISCUSSION |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONConflict of interest statementTable referencesReferences |
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We identified a total of 80 in vitro chemosensitivity associated genes. These genes have been the subject of considerable research, and of numerous scientific publications. In addition, we may also have to expect the existence of many other genes associated with chemosensitivity but not selected in the current study, because they have never caught the scientific eye for some reasons. Thus, the results of this study may be significantly influenced by publication bias. Nonetheless, we do believe that these genes have been selected reasonably carefully, and that they may be helpful for establishing a clinical predictive chemosensitivity test.
While the association between alterations of the 80 genes and the chemosensitivity of various cell lines was evaluated in 50 studies, significant association was observed in only 22 (44%) (Table 8). The cellular functions of a gene vary among cell types and experimental conditions. The evaluation of the gene functions, however, was conducted under only limited cellular contexts in these studies, as expected. Thus, for example, the conditions of a gene transfection experiment may differ from those of an experiment to evaluate the chemosensitivity for many cell lines. The gene functions may not necessarily be examined under all possible conditions, but the evaluation must be conducted under conditions similar to those in the clinical setting in order to develop clinical chemosensitivity testing using these genes.
The other possibility for the poor correlation to in vitro chemosensitivity may be that more than one gene alterations are involved in the chemosensitivity of tumors. This may be discussed from the standpoint of the signal transduction pathway and from the cellular standpoint. From the standpoint of the signal transduction pathway, more than one gene may be involved in the reaction to a cytotoxic agent. One of the best examples is cooperation of TP53 with another member of the p53 family, p73 (TP73), in the response to both DNA damage and chemosensitivity (3,4). From the cellular standpoint, several pathways may work additively, antagonistically, or complementally in determining the chemosensitivity of the cell. This can be understood well from the context of induction and inhibition of apoptosis being controlled by pro-apoptotic and anti-apoptotic pathways. Thus, it would be important to study several pathways at the same time, or to evaluate the net effect of the involvement of various pathways.
Complex factors influencing the cellular chemosensitivity may be operative on a tumor in vivo, in such a way that the tumor may exhibit highly heterogeneous gene alterations; that the tumor cells may interact with various host cells, including immune cells, fibroblasts and vascular endothelial cells; and that the differences in the distance between each tumor cell and blood vessels may affect the exposure level of tumor cells to a drug. No systematic approach has been developed to include this complex interplay of factors in the study of cellular chemosensitivity, although studies on cell adhesion-mediated drug resistance may be partly helpful.
Among the six genes for which the association was shown in two or more in vitro studies, four encode classical drug resistance proteins which are known to inhibit the drug–target interaction. These proteins are relatively specific for the drug as well as the cell type; e.g. TYMS is critical for 5-fluorouracil sensitivity. Thus, TYMS is a good candidate for chemosensitivity testing in patients with colorectal cancer who are treated with 5-fluorouracil (Table 2). MVP is involved in the transport of doxorubicin, therefore, it would be of interest to examine the association between the expression of MVP and the drug response in patients with breast cancer; the association of MVP with chemosensitivity has been evaluated only for brain tumor and lung cancer cell lines, to date (Table 1). However, the remaining two of the six genes, TP53 and BCL2, are associated with apoptosis, and therefore may be relatively cell-type specific. Since all the three in vitro studies using breast cancer cell lines failed to show any associations between alterations of these genes and the chemosensitivity, the association should be evaluated in other tumor types in the clinical setting (Table 7).
The recently developed cDNA microarray technique allows analysis of the mRNA expression of more than 20 000 genes at once, and as many as 100–400 genes have been statistically shown as potentail chemosensitivity-related genes in various studies (5–7). The 80 genes in the current study were selected theoretically based on their known functions, and their contribution to in vitro chemosensitivity was shown in the experiments. Thus, it would be of interest to evaluate the expression profiles of these genes by cDNA microarray analysis, even if the difference in expression between sensitive and resistant cell lines does not reach statistical significance.
In conclusion, 80 in vitro chemosensitivity associated genes were identified from a review of the literature, which may be considered to be future candidates for clinical predictive chemosensitivity testing.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONConflict of interest statementTable referencesReferences |
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None declared.
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Table references |
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Acknowledgments |
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This study was supported in part by the Lung Cancer SPORE Grant P50CA70907 and Grants-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan. We thank Yuko Yabe and Mika Nagai for their invaluable assistance in the collection and arrangement of the large number of papers.
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References |
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