Apoptosis is a form of cell death responsible for development and homeostasis of living bodies. This article summarizes the recent advent of apoptosis research in view of the induction factors molecular mechanism of the induction and relation to various diseases including cancer.

Chronic myelogenous leukemia (CML) expresses two types of bcr-abl chimeric mRNA. One is b3a2 type in which bcr exon 3 binds to abl exon 2, the other is b2a2 type that bcr exon 2 binds to abl exon 2. Either bcr-abl is normally expressed, but both types of bcr-abl mRNA can be expressed at the same time in a patient. We report here a rare case of CML expressing two types of bcr-abl mRNA and discuss the possibility that this double expression would help to monitor the clinical course of CML.

We report a case of 53-year-old man with acute myelogenous leukemia (M2) showing a karyotype of t(7;11) (p15;p15), del(10) (q11;q12), who was complicated with perforation of a duodenal ulcer during the antileukemic chemotherapy using behenoyl ara-C, daunorubicin, 6-mercaptopurine and prednisolone. As his bone marrow still showed high cell density and leukemic proliferation at the time of intestinal perforation, the therapeutic regimen was changed to a combination of behenoyl are-C and mitoxantrone, and daily rhG-CSF was concurrently administered for the purpose of early establishment of bone marrow hypoplasia. On the 8th day after the therapeutic regimen had been changed, his bone marrow became nearly aplastic, and complete remission was obtained on the 24th day. This case may indicate that the concurrent administration of cell-cycle specific antileukemic drugs and rhG-CSF is available for AML patients with emergent need of leukemic cell reduction.

A 18-year old female with acute myelogenous leukemia (AML), M2 had translocation: t(6;9) (p23; q34). The patient entered into hematological complete remission after two courses of BHAC-DMP chemotherapy with disappearance of cytogenetic abnormality. However, minimal residual disease (MRD) detected with DEK/CAN chimeric m-RNA by reverse transcription polymerase chain reaction (RT-PCR) was continuously observed, although decreased quantitatively, following several courses of consolidation and intensification chemotherapies. MRD was detected also in the harvested peripheral blood stem cells (PBSC). Leukemia relapsed with the reappearance of t(6;9) 2 months after the subsequent peripheral blood stem cell transplantation (PBSCT). Leukemia became refractory to chemotherapy, and the patient died 5 months thereafter.

A 46-year-old man with Werner's syndrome was admitted with epigastralgia and body weight loss. The peripheral blood findings showed anemia, thrombocytosis and eosinophilia. Bone marrow aspiration and biopsy revealed increases in eosinophils and megakaryocytes, myelodysplastic change with 6.6% myeloblast, and myelofibrosis. Chromosomal analysis revealed 46, XY, +der(1;7), -7, del(20). He was diagnosed as having myelodysplastic syndrome with myelofibrosis or essential thrombocythemia. Three months later, pancytopenia appeared with a relative increase of blasts positive for CD41 and negative for myeloperoxidase. He died of respiratory failure due to pneumonia. An autopsy revealed severe myelofibrosis with proliferation of megakaryocytes and blasts. A final diagnosis of acute megakaryoblastic leukemia was made. Werner's syndrome is rare, and it is even more unusual to have the complication of acute leukemia with der (1;7) seen in this case.

A 63-year-old male was admitted because of pneumonia. Peripheral blood findings showed pancytopenia with increase of blasts. A bone marrow specimen showed hypocellular marrow with increase of blasts. The blasts were positive for CD7, CD34, and HLA-DR and negative for other lymphoid antigens and myeloid antigens involving myeloperoxidase. Rearrangement of immunoglobulin heavy chain was demonstrated by Southern blotting analysis. T cell receptor beta, T cell receptor gamma and immunoglobulin light chain rearrangement were negative. A diagnosis of stem cell leukemia was made. In vitro, the blasts did not respond to recombinant human granulocyte colony-stimulating factor (rhG-CSF), cytarabine (Ara-C) and all-trans retinoic acid (ATRA). However, in the blasts of culture without cytokeins, CD33 expression was newly induced. Remission was not obtained by chemotherapies with cyclophosphamide, etoposide, prednisolone and Ara-C. Four months later, marrow specimens showed hypoplasty with myelofibrosis. One year later, the blasts showed CD33 expression with negative myeloperoxidase. The leukemia was transformed to minimally differentiated myeloid leukemia from stem cell leukemia. This condition was thought to be "smoldering leukemia" because of the slow development and refractoriness to chemotherapy. Nineteen months later the patient died due to respiratory failure by pneumonia and pulmonary bleeding despite therapy.

Recently, clinical application of gene technology in oncology and hematology has been markedly advanced. Pathogenesis of leukemic transformation has been thought that it was resulted from cumulation of activation or mutation in oncogenes or onco-suppressor genes. As a matter of fact, many specific chromosomal abnormalities in leukemias have been thought to be due to production of chimeric fusion gene by translocation and activation in some kinds of oncogenes under specific regulatory genes after translocation. In addition to those, inactivation of onco-suppressor genes, such as RB gene or p53 gene, may be also related to leukemogenesis in some leukemias. Laboratory examinations using molecular technology are being necessary for clinical diagnosis and treatment in many hematological disorders. The examinations detecting rearrangement of major BCR or minor BCR in Ph1 positive leukemias, TCR in T cell malignancy, immunoglobulin in B cell malignancy, PML-RAR alpha fusion gene in APL have become routine for diagnosis of some leukemias. Moreover, these examinations are useful for judgement of treatment effects and evaluation of minimal residual diseases. In this paper, we also discuss the usefulness and importance of these technology especially in stem cell transplantation and cytokine therapy, and the future possibility in this technology for gene therapy.

Recent results from molecular biology have shown that lung cancer is characterized by multiple, sequentially appearing molecular changes that include genetic and epigenetic alterations. Among all types of lung cancer, small cell lung cancer (SCLC) is associated with the lowest rate of 5-year survival. In this symposium, we introduce our findings regarding the c-kit oncogenes in SCLC. We found that the c-kit gene is strongly expressed in SCLC. The c-kit gene was not expressed in normal bronchial epithelial cells, which indicates that this gene is abberantly transcribed in SCLC. In addition, c-kit-positive cases of SCLC showed autophosphorylation in response to recombinant human stem cell factor. Furthermore, adding rh stem cell factor of SCLC cell lines induced a significant chemotactic response and moderate in vitro cell growth. These results strongly suggest that abnormal expression of the c-kit gene may be involved in the pathogenesis of SCLC by autocrine/paracrine stimulation via the c-kit/SCF signal pathway. To overcome drug resistance, we assessed the efficacy of a chimeric toxin targeted to c-kit receptors.

Telomeres are the functional domains positioned at the ends of chromosomes. It is essential for the stable maintenance of chromosomes. Telomerase is an enzyme that has an important role in the DNA replicator at telomeres. Its activity is specifically activated in cancer cells. We have reported a novel specific and sensitive assay (stretch RCR assay) for the detection of telomerase activity. We analyzed the telomerase activity in leukemias using this method. The results showed that telomerase is specifically activated during the progression stages of leukemia. The "telomere crisis model" has been proposed for explaining the role of the telomere dynamics in malignancies.

A 58-year-old male who had a left hemicolectomy for descending colon cancer on July 1, 1993 was admitted to our hospital. A CT scan revealed a homogeneous low-density mass in the inferior portion of the spleen. Under the diagnosis of solitary splenic metastasis, a splenectomy was performed on August 10, 1995. Histologically, splenic tumor revealed moderately differentiated adenocarcinoma consistent with the primary tumor. Flow cytometric analysis revealed DNA diploidy in the primary tumor, and DNA aneuploidy (DNA index = 1.76) in the metastatic tumor. Using fluorescence in situ hybridization with p17 H8, numerical aerrations of chromosome 17 were observed in the primary tumor.

A 48-year-old female was admitted to our hospital because of pancytopenia and pneumonia in February, 1993. The increase of abnormal promyelocytes with t (15; 17) and PML-RAR mRNA was detected in bone marrow aspirate and a diagnosis of acute promyelocytic leukemia was made. She obtained complete remission after the administration of all-trans retinoic acid (ATRA) and following chemotherapy. Then she received peripheral blood stem cell transplantation in September, 1993. However she noticed a umbilical tumor in June, 1995. Abnormal promyelocytes were demonstrated not only in bone marrow aspirate but also in the umbilical tumor. Because of the poor response to ATRA and development of fever, a side effect of ATRA, G-CSF and prednisolone were administrated together with ATRA. After the combined therapy, umbilical tumor disappeared and she obtained complete remission again. These findings suggest that combined therapy of ATRA and G-CSF is effective to the low responder to ATRA and that combined use of ATRA and prednisolone reduces the side effect of ATRA without diminishing the favorable effect on differentiation.

We have developed a highly sensitive method to detect pelvic lymph node(LN) metastasis using reverse transcriptase-polymerase chain reaction(RT-PCR) with the primers specific for prostate-specific antigen(PSA) gene in combination with the fine needle aspiration biopsy(FNAB). The specimens were obtained from pelvic LN from 15 prostate cancer patients and 15 bladder cancer patients. The aspirated samples (0.05 approximately 0.1 ml) were used for detecting the fragment of PSA mRNA by RT-PCR and Southern blot analysis, and the rest of samples were submitted to conventional cytology. Expression of PSA gene was detected in 9 cases of FNAB samples including all 5 cytologically positive and further more 2 cytologically class III cases, and 2 of 8 cytologically negative cases. RT-PCR of FNAB samples from all cases of bladder cancer were negative for the detection of PSA gene. The sensitivity of PSA gene by RT-PCR was very high and could detect 10 degrees cancer cell. In conclusion, our study suggested that RT-PCR for detection of PSA gene in FNAB samples might become a new diagnostic tool for detection of small foci of prostatic cancer metastasis in LN and combination use of RT-PCR and cytology could greatly contribute to accuracy in diagnosis.

The etiology of breast cancer involves a complex interplay of exogenous and endogenous factors, including genetic factors. The identification of oncogenes, tumor suppressor genes and human mismatch repair genes has helped to refine the characterization of breast carcinogenesis. The major types of genetic alterations in breast cancer are amplification of protooncogenes (ERBB2 and MYC) and DNA from chromosome band 11q13; mutation of p53; and loss of heterozygosity on 1p, 3p, 8p, 11p, 13q, 16q, 17p, 17q, 18q. The latter may imply inactivations of tumor suppressor genes. Recently, two distinct familial breast cancer susceptibility genes, BRCA1 and BRCA2, have been isolated. These findings enable to use these genes for genetic diagnosis in clinical oncology.

Hybrid fusion genes are specific tumor markers of several leukemic subtypes. The use of reverse transcription-polymerase chain reaction (RT-PCR) to amplify chimeric cDNAs allows sensitive detection of the leukemia clone. The clinical relevance of minimal residual disease (MRD) remains controversial. In this report, an infantile acute lymphoblastic leukemia with t(4;11) (q21; q23) was analyzed after each treatment for the presence of MRD by RT-PCR amplification of the MLL/LTG4 fusion gene which became available recently. The patient soon achieved a hematological CR, after induction therapy, and underwent autologous BMT following consolidation chemotherapy for 9 months. However, he relapsed three months after the BMT. MRD was always detectable during his clinical course. These findings suggest that the detection of MRD of the MLL/LTG4 fusion transcript is a useful tool for monitoring MRD and selecting treatment.

Here we report a case of acute myelogenous leukemia (M2, FAB classification) presenting with cytogenetic abnormalities of ins(21;8), +del(8) without t(8;21). A 8;21 chromosome translocation is frequently found in acute myelogenous leukemia, especially in the M2 subtype. The translocation results in a fusion transcript between AML1 and MTG8 (ETO), assigned on chromosomes 21 and 8, respectively. Among patients with a t(8;21) abnormality, solid leukemic tumor deposits outside the marrow or good response to chemotherapy are observed frequently. Decrease in neutrophil alkaline phosphatase score and positive rate, and eosinophilia in bone marrow or the blast cells with Auer rods expressing CD19, CD56 antigens occur at a relatively high rate. Although our case lacked these clinical, cytological and cytochemical features, expression of chimeric AML1-MTG8 mRNA was detected. AML1-MTG8 fusion transcript may play a critical role in leukemogenesis of AML M2. Studies on this case may help to reveal the oncogenic function of the AML1-MTG8 fusion gene in AML M2.

A 28 year-old woman in the 26th week of pregnancy was admitted to our hospital on February 6, 1993, because of anemia and thrombocytopenia. On admission, her hemoglobin was 8.2 g/dl, platelet count 6.3 x 10(4)/microliter, and WBC 6,300/microliter with 43% blasts. The bone marrow examination showed hyperplastic bone marrow with 38.8% blasts. She was diagnosed as having 8;21 translocation acute myelocytic leukemia (M2). In the 30th week of pregnancy, she gave birth to a 1449 g male infant by induction delivery. After DCMP therapy, complete remission was obtained. She has been in complete remission for 32 months and her child is growing healthy after overcoming an underweight condition due to premature birth, respiratory distress syndrome, circulation insufficiency and hyperbilirubinemia. This case suggests that in the event of second trimester pregnant patients with acute leukemia, we should wait for the proper time at which successful delivery can be expected, and then intensified remission induction chemotherapy should be carried out after the delivery.