| Budget Amount *help |
¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 1996: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1995: ¥4,000,000 (Direct Cost: ¥4,000,000)
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| Research Abstract |
The MAGE-1, -2, -3, -4, -6, and -12genes are frequently expressed in many different cancers, but are not expressed in normal cells or normal tissues other than testis and placenta. MAGE-1 and -3 peptides are currently used as vaccines for cancer patients, and three of 12 HLA-A1 patients with metastatic melanoma responded to MAGE-3 peptide. Therefore, MAGE protein could be a potential vaccine for HLA-A1 cancer patients. However, CTL were not detected in the peripheral blood of the responding patients, and there was no available monitoring methods to know the efficacy of MAGE vaccine. Further, biological roles of proteins of MAGE family remain to be investigated. We investigated serum level of MAGE-4 protein, one of the family of MAGE proteins, in various cancer patients. MAGE-4 protein was detected as a non-degraded form in both the supernatant of MAGE-4^+ tumor cell line and serum of cancer patients with different types of histology (lung cancer, head and neck cancer, and hepatocellula
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r carcinomas. For example, serum level of the MAGE-4 protein of lung cancer patients (n=100, mean=1.17ng/ml) was significantly (p=0.0013) higher than that of either patients with benign pulmonary diseases (n=80, mean=0.33ng/ml) or HD (n=68, mean=0.32ng/ml) (Shichijo et al., JJCR,in press, 1977). The serum level of MAGE-4 was higher than the cutoff level (1.15ng/ml) in 34 of 100 cancer patients, but no one in the other groups reached the cutoff level. The similar results were obtained in sera of the other cancer patients. In addition, it is of note that surgical removal of tumor mass resulted in decrease of serum level of MAGE-4 protein and recurrence was associated with it's reincrease (Iwamoto et al., Int. J.Cancer, in press, 1997). Furthermore, serum MAGE-4 was significantly higher in patients with both hepatocellular carcinoma and hepatitis C virus positive liver cirrhosis, a high risk group of hepatocellular carcinoma. These information could be important for better understanding of biological roles of MAGE proteins, and measurement of serum levels of MAGE-4 protein could be useful for detection of MAGE-4^+ cancers with different types of histology.
HLA class I-restricted and tumor-specific CTLs have been observed in T cells of peripheral blood mononuclear cells (PBMC) stimulated with autologous tumor cells or IL-2-activated tumor infiltrating lymphocytes (TILs) of patients with melanomas. Genes encoding peptide antigens recognized by CTLs have been cloned from melanomas using these CTLs. However, either the presence of these CTLs or peptide antigens have been rarely reported in either adenocarcinoma of squamous cell carcinoma, two major human cancers needed for development of new treatment modalities. We have investigated HLA-A locus-restriction and tumor-specificity of IL-2 activated TILs from esohageal cancers, gastric cancers, colon cancers and lung cancers. The results showed the presence of HLA class lredtricted and tumor specific CTLs in TILs of esophageal cancers (Toh et al., Cell lmmunol. in press, 1997), gastric cancers (Hoshino et al., Int. J.Cancer in press, 1997), colon cancers (Gouhara et al., JJCR,in press, 1997) and non-small lung cancers (Seki et al., Cell lmmunolo. in press, 1997). These CTLs could be a tool for identification of genes encoding tumor-rejection antigens for development of cancer vaccines. Less
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