A 78-year-old man had underwent right upper lobectomy for lung adenocarcinoma in July 1998(pT1N0M0, pStage Ia). In January2003, computed tomography showed a tumor in right lower lobe of lung, which grew slowly. He was treated with UFT. In April 2004, computed tomographyshowed multiple nodules in both lung, which was considered of metastasis of lung cancer. The increase of the nodules were observed, and treatment with gefitinib was started. Insertion mutation at EGFR in exon 20 was seen from the primarylung cancer. Since tumor growth occurred despite gefitinib administration, we converted gefitinib into S-1 using 80 mg/day for 28 days, followed by 14 days rest. Chest computed tomographyshowed a partial response. No side effect was observed, and continued internal use of S-1 until January 2007 when it was impossible to continue, and meanwhile, the increase of the tumor was not seen.

The prognosis of advanced colorectal cancer has been improved by introduction of molecular targeting agents, such as bevacizumab and cetuximab. Several clinical trials revealed a median survival time of more than 2 years. However, the main purpose of chemotherapy for advanced colorectal cancer has not been cure but prolongation of life to date. One explanation of the difficulty of cure is the inherent and/or acquired resistance to chemotherapeutic agents and molecular targeting agents. A better understanding of the mechanisms of inherent resistance will make it possible to identify predictive markers of responder or non-responder to select the optimal patients for a certain drug. Additionally, knowledge of the acquired mechanism will provide for the rational development of therapies that circumvent or overcome resistance. Although the mechanisms of the resistance of molecular targeting agents for colorectal cancer are still unclear, the inherent resistance to cetuximab or panitumumab by why of expression of KRAS mutation is the first breakthrough in this field. Further basic research and biomarker analysis of large clinical study are necessary to clarify the resistance to molecular targeting agents.

Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitor(TKI)as molecular targeted agents has given us an innovative strategy for treatment of patients with advanced non-small cell lung cancer(NSCLC). Patients with activating mutations of the EGFR generally respond to EGFR-TKI very well. HER3 has an essential role to enhance the EGFR signaling pathway, including the downstream pathway of PI3K/Akt pathway. The acquired resistance to EGFRTKI was clinically developed in patients with activating EGFR mutations. Recently, various mechanisms of acquired resistance have been developed, such as T790M, MET amplification, HGF increasing as a ligand of MET. We have to treat patients with NSCLC in the manor of individual medicine strategy today.

In the emergence of resistance to imatinib, ABL-kinase inhibitor has become a significant problem despite the remarkable clinical results achieved with this drug in the treatment of chronic myeloid leukemia. The most common cause of imatinib resistance is the selection of leukemic clones with point mutation in the ABL-kinase domain. Persistent disease is another therapeutic challenge and may in part, be due to the inability of imatinib to eradicate primitive stem cell progenitors. A multitude of novel agents have been developed and shown efficacy in overcoming imatinib resistance.

Over the last two decades since discovery of human papillomavirus (HPV) type 16 and 18 DNAs in cervical cancers by Dr. Harald zur Hausen, HPVs have been well characterized as causative agents for cervical cancer. Viral DNA from a specific group of HPVs can be detected in at least 90% of all cervical cancers and two viral genes, E6 and E7, are invariably expressed in HPV-positive cervical cancer cells. Their gene products are known to inactivate the major tumor suppressors, p53 and pRB, respectively. In addition, one function of E6 is to activate telomerase, and E6 and E7 cooperate to effectively immortalize human primary epithelial cells. Though expression of E6 and E7 is itself not sufficient for cancer development, it seems to be either directly or indirectly involved in every stage of multi-step carcinogenesis. Indeed, it has been shown that only one or two genetic alterations in addition to expression of E6 and E7 are experimentally sufficient to confer tumorigenicity to normal human cervical keratinocytes. Epidemiological and biological studies suggest the potential efficacy of prophylactic vaccines to prevent genital HPV infection as an anti-cancer strategy. However, given the widespread nature of HPV infection and unresolved issues about the duration and type specificity of the currently available HPV vaccines, it is crucial that molecular details of the natural history of HPV infection as well as the biological activities of the viral oncoproteins be elucidated in order to provide the basis for development of new therapeutic strategies against HPV-associated malignancies. This review highlights the novel functions of E6 and E7 as well as the molecular mechanisms of HPV-induced carcinogenesis.

Among cases of therapy-related acute myeloid leukemia (t-AML) due to DNA topoisomerase II inhibitors, 11q23 abnormality is often detected. The usefulness of paclitaxel as a key drug in chemotherapy for breast cancer has been demonstrated. Few studies have reported t-AML due to paclitaxel. In this study, we report a patient who developed t-AML with 11q23 abnormality and bone marrow metastasis after breast cancer treatment with paclitaxel. The patient was a 61-year-old female who developed breast cancer at the age of 54 years. Four years after resection, lung and bone metastases were detected. Weekly therapy with paclitaxel at 80 mg/m2 was administered for 10 weeks (total dose: 1,200 mg), and radiotherapy was performed; thereafter, the extent of bone metastasis increased. Pancytopenia was noted 3 years after paclitaxel therapy. Bone marrow aspiration suggested AML (M4) with (11;19)(q23;p13) chromosome abnormalities. Histopathologically, bone marrow metastasis from breast cancer was detected in the same bone marrow specimen. This patient had not received any other anticancer drugs. Based on the clinical course, t-AML may have developed after paclitaxel therapy.

A number of molecular targets have been identified in leukemia, based on the understanding of signaling pathways controlling cell differentiation, proliferation, apoptosis, and malignant transformation. Growth factors and integrins interact with their receptors and activate signaling cascades with intimate interconnections. The specific niches within the bone marrow microenvironment may provide a sanctuary for subpopulations of leukemic cells to escape chemotherapy-induced death and acquire drug resistance. Investigations into bone marrow stroma-leukemia crosstalk may result in the development of strategies against the acquisition of a chemo-resistant phenotype and enhance the efficacy of therapies in leukemia. In recent studies, we proposed novel therapeutic interventions targeting the microenvironment/leukemia interaction focusing on SDF1/CXCR4, ILK/PI3K/Akt, TGF-beta, and Notch signaling. Gene transcriptional activity is regulated by chromatin modification and DNA methylation. Nuclear receptors such as RAR, RXR, and PPARgamma exert histone acetyl transferase activity (HAT). The transcription of target genes is initiated following the ligation of these receptors, recruitment of co-activators, and replacement of repressors. We demonstrated that histone acetylation by the PPARgamma agonist CDDO, RAR/RXR agonist ATRA, and/or histone deacetylase inhibitors (HDACIs) reversed the silenced RARbeta and MDR1 genes in acute promyelocytic leukemia, and that HDACI induced apoptosis with phagocytosis through the induction of Annexin A1 in AML1/ETO-positive acute myelocytic leukemia (AML) cells. The translation of research findings into effective clinical laboratory tests is an important approach. The flow cytometric technique is a powerful tool in the field of clinical laboratory medicine, with its accurate and rapid analysis. We carried out phospho-specific flow cytometry to investigate protein phosphorylation in AML cells and detect ZAP-70 in chronic lymphocytic leukemia cells, including the evaluation of antibodies, staining epitopes, fixing and permeabilizing methods, and analyzing systems. Finally, we emphasize the potential applications of research findings and methods in the fields of clinical medicine, molecular diagnosis, and targeting therapy.

To compare mRNA levels in cancer cells and protein levels in cancerous tissue in terms of the expression of thymidine phosphorylase(TP).