PHARMACOLOGY DIVISION

5.PHARMACOLOGY DIVISION

    The research program in the Pharmacology Division focuses on the discovery of new approaches for cancer treatments that can be applied clinically. The basis of this research is a fundamental investigation of the anti-tumor mechanisms of target based drugs, as well as determination of the cellular and molecular determinants of tumor cell recognition, drug sensitivity and drug resistance. The more translational research projects include development of the most appropriate schedules for different types of drugs in combination chemotherapy.
Anti-Tumor Immunity of NK-Like T Cells

    The murine NK-like tMK-2 T cell line was established by subcutaneous xenografting of surgical specimens from a patient with inflammatory breast cancer. Immunization of these tMK-2U cells enabled us to establish a U5A2-13 monoclonal antibody (mAb), which recognizes NK-like T cells. a-galactosylceramide-stimulated U5A2-13-positive T cells produced abundant IL-4 as well as extremely high levels of IFNg, but this was not observed with U5A2-13-negative T cells. Based on the present results, the U5A2-13 mAb appears to be a valuable tool for the study of NK-like T cells.⁽⁸⁸⁾ An anti-human CD57 IgG1 monoclonal antibody was established. This antibody is expected to be a useful tool for the biochemical characterization of CD57 antigen.⁽⁸⁹⁾
Detection of Thioredoxin (TRX) in Patients with Gastric Cancer

    Results of histochemical analysis of surgical specimens, as well as cytochemical and Northern blot analyses of gastric cancer cell lines, indicated that TRX is predominantly expressed in undifferentiated rather than differentiated type gastric cancer. Teleconferences between the Gustave-Roussy Institute (Villejuif, France) and the National Cancer Center (Tokyo, Japan), as a new bilateral cooperative activity, were reported.⁽⁹⁰⁾
Biological and Biochemical Pharmacology

    Antitumor activities of target-based drugs were evaluated by in vitro and in vivo studies. Target-based drugs do not always produce tumor shrinkage. Therefore, appropriate biological markers are essential for evaluating the clinical effects of these drugs.⁽⁹¹⁾ Biological markers for target-based drugs such as UCN-01, YTA0040, and E7070 were investigated. Cell cycle regulatory molecules including p16^INK4 , p27^KIP1 , IRF-1, p53, and cyclins were found to be determinants of the activities of these drugs using clinical materials and cell lines.^(92-⁹⁶⁾ Increased expression levels of p53 and p27^KIP1 correlated with a good response to cisplatin-based chemotherapy in non-small cell lung cancer patients.^(97,⁹⁸⁾ Autophosphorylation of EGFR is a possible biological marker for a tyrosine kinase inhibitor of EGFR (ZD-1839). The potential combined effects of cytotoxic and non-cytotoxic agents were examined. The new platinums exerted supraadditive effects, when combined with irinotecan, by modulating topoisomerase I activity.
Drug Resistance

    Drug-transport, intracellular de-toxification, and DNA repair are major determinants of tumor sensitivity to DNA-damaging agents. A human ATP-binding cassette transporter SMRP and its mouse homologue were isolated, and the SMRP transcript was found to be a splicing variant of the MRP5 gene designated MRP5a⁽⁹⁹⁾ and the previously identified SMRP mRNA as MRP5b. Both MRP5b and MRP5a were expressed in normal human tissues. Increased expression of the MRP5 gene was associated with exposure to platinum drugs in lung cancer cells and clinical materials.⁽¹⁰⁰⁾ A benzothiazepine analogue, K201, reversed cisplatin-resistance in human lung cancer cells in vitro and in vivo by increasing intracellular accumulation of the drugs.




5.PHARMACOLOGY DIVISION



	The research program in the Pharmacology Division focuses on the discovery of new approaches for cancer treatments that can be applied clinically. The basis of this research is a fundamental investigation of the anti-tumor mechanisms of target based drugs, as well as determination of the cellular and molecular determinants of tumor cell recognition, drug sensitivity and drug resistance. The more translational research projects include development of the most appropriate schedules for different types of drugs in combination chemotherapy. Anti-Tumor Immunity of NK-Like T Cells The murine NK-like tMK-2 T cell line was established by subcutaneous xenografting of surgical specimens from a patient with inflammatory breast cancer. Immunization of these tMK-2U cells enabled us to establish a U5A2-13 monoclonal antibody (mAb), which recognizes NK-like T cells. a-galactosylceramide-stimulated U5A2-13-positive T cells produced abundant IL-4 as well as extremely high levels of IFNg, but this was not observed with U5A2-13-negative T cells. Based on the present results, the U5A2-13 mAb appears to be a valuable tool for the study of NK-like T cells.⁽⁸⁸⁾ An anti-human CD57 IgG1 monoclonal antibody was established. This antibody is expected to be a useful tool for the biochemical characterization of CD57 antigen.⁽⁸⁹⁾ Detection of Thioredoxin (TRX) in Patients with Gastric Cancer Results of histochemical analysis of surgical specimens, as well as cytochemical and Northern blot analyses of gastric cancer cell lines, indicated that TRX is predominantly expressed in undifferentiated rather than differentiated type gastric cancer. Teleconferences between the Gustave-Roussy Institute (Villejuif, France) and the National Cancer Center (Tokyo, Japan), as a new bilateral cooperative activity, were reported.⁽⁹⁰⁾ Biological and Biochemical Pharmacology Antitumor activities of target-based drugs were evaluated by in vitro and in vivo studies. Target-based drugs do not always produce tumor shrinkage. Therefore, appropriate biological markers are essential for evaluating the clinical effects of these drugs.⁽⁹¹⁾ Biological markers for target-based drugs such as UCN-01, YTA0040, and E7070 were investigated. Cell cycle regulatory molecules including p16^INK4 , p27^KIP1 , IRF-1, p53, and cyclins were found to be determinants of the activities of these drugs using clinical materials and cell lines.^(92-⁹⁶⁾ Increased expression levels of p53 and p27^KIP1 correlated with a good response to cisplatin-based chemotherapy in non-small cell lung cancer patients.^(97,⁹⁸⁾ Autophosphorylation of EGFR is a possible biological marker for a tyrosine kinase inhibitor of EGFR (ZD-1839). The potential combined effects of cytotoxic and non-cytotoxic agents were examined. The new platinums exerted supraadditive effects, when combined with irinotecan, by modulating topoisomerase I activity. Drug Resistance Drug-transport, intracellular de-toxification, and DNA repair are major determinants of tumor sensitivity to DNA-damaging agents. A human ATP-binding cassette transporter SMRP and its mouse homologue were isolated, and the SMRP transcript was found to be a splicing variant of the MRP5 gene designated MRP5a⁽⁹⁹⁾ and the previously identified SMRP mRNA as MRP5b. Both MRP5b and MRP5a were expressed in normal human tissues. Increased expression of the MRP5 gene was associated with exposure to platinum drugs in lung cancer cells and clinical materials.⁽¹⁰⁰⁾ A benzothiazepine analogue, K201, reversed cisplatin-resistance in human lung cancer cells in vitro and in vivo by increasing intracellular accumulation of the drugs.