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We sequentially analyzed the immunoglobulin heavy chain variable (IgH V) region gene of leukemia cells obtained from a chronic myeloid leukemia (CML) patient who had three episodes of B-lymphoid crisis after bone marrow transplantation. Southern blot analysis using the JH probe showed different rearranged bands at each crisis, although the same rearranged bands of the BCR gene were observed. We amplified and sequenced the IgH V region gene of the leukemia cells by reverse transcriptase polymerase chain reaction (RT-PCR) using the primers corresponding to the consensus 5'VH and mu constant regions. The dominant leukemia clone at each crisis had a unique VH-D-JH rearrangement; VH4A (V79)-DLR2-J5 (clone-1), VH4B (DP70)-DK4-J6 (clone-2) and VH4A (V79)-DN4-J6 (clone-3) at the first, second and third crises, respectively. Further analysis by PCR amplification using the consensus 5'VH and clone-specific primers revealed that clone-1 underwent VH4--VH3 replacement at the second crisis, and that clone-3 was already in existence at the first crisis. Moreover, the DN4-J6 joining clone, in which the sequence was the same as that of clone-3, was identified at the first and third crises by PCR amplification using primers corresponding to the region upstream of the DN4 segment and DN4-J6 boundary of clone-3. These observations suggest that multiple clones were generated from the progenitor cells of blast crisis, which were transformed at a very early stage of B-lymphocyte ontogeny, by continuing rearrangement mechanisms of the IgH genes, and that the dominant clone at each crisis was undergoing change.

We treated 70 acute promyelocytic leukemia (APL) patients with daily oral 45 mg/m2 all-trans-retinoic acid (ATRA) in two multi-institutional prospective studies. Of 64 evaluable patients, 21 were refractory to initial induction chemotherapy; 10 were refractory to salvage chemotherapy; 17, five, and four were in the first, second and, third relapse, respectively; and seven were previously untreated due to old age. In the first study with ATRA from China, 18 out of 22 (82%) evaluable patients achieved complete remission (CR). Initial peripheral leukemia cell counts were significantly less in the CR cases (p0.01);100/microliters in 17 out of 18 CR cases, andor = 200/microliters in all failure cases. In the second study with ATRA from Hoffmann-La Roche, if initial leukemia cell counts were more than 200/microliters, chemotherapy was first given and then ATRA was started. Of 42 evaluable patients, 36 (86%) achieved CR. Morphological evidence of differentiation was noted in all CR cases. Patients achieving CR received standard consolidation and maintenance chemotherapies, and the 20-month predicted disease-free survival rate is 76% for cases achieving their first CR with ATRA. Toxicities attributable to ATRA were minimal and included cheilitis, xerosis, dermatitis, gastrointestinal disorders, bone pain, liver damage, and high serum triglyceridemia.

Thirty-three patients with advanced Hodgkin's disease were treated with a combination chemotherapy consisting of vincristine 1 mg/m2 iv on day 1, 8, cyclophosphamide 500 mg/m2 iv on day 1, procarbazine 100 mg/m2 p.o. day 1-7, and prednisolone 40 mg/m2 p.o. day 1-7. Twenty patients received this regimen every 4 weeks (VCPP II regimen). Furthermore, we conducted higher dose intensive VCPP II-2 regimen which was repeated every two weeks for thirteen patients. Complete response rate of both regimens was 63% (VCPP II 45%, VCPP II-2 85%). The median duration of CR was 37 + months. Leukopenia, neurotoxicity and gastrointestinal toxicity were commonly observed but were clinically manageable. These results indicate that high dose intensive chemotherapy is effective for achieving high CR rate for advanced Hodgkin's disease.

Twenty patients with advanced non-small cell lung cancer were treated with a combination chemotherapy consisting of ifosfamide (IFX), cisplatin (CDDP) and vindesine (VDS). The treatment schedule was IFX 1.3 g/m2 i.v., on days 1-5, CDDP 20 mg/m2 i.v., on days 1-5, and VDS 3 mg/m2 i.v., on days 18, and, in principle, the regimen was repeated every 4 weeks. Of 19 evaluable patients, there were 1 CR, 7 PR, 10 NC and 1 PD, with an overall response rate of 42.1%. The median duration of responses was 7.45 months, and the median survival time of all patients was 13.2 months. The major toxicities occurring were hematologic toxicity, alopecia, gastrointestinal toxicity and peripheral neuropathy. Hematologic toxicity was severe and was judged to be dose limiting, but clinically manageable. These results indicate that this combination chemotherapy is active against non-small cell lung cancer and deserves further studies.

One hundred and six patients with advanced breast cancer were treated with chemoendocrine therapy consisting of adriamycin (40 mg/m2) i.v. on day 1 and cyclophosphamide (130 mg/m2) i.v. daily for 5 days every 3 weeks, ftorafur (500 mg/m2) and tamoxifen (40 mg) orally daily. Of 82 evaluable patients, 16 showed complete response (20%), 32 partial response (39%), 32 no change (39%), and two progressive disease (2%). The overall response rate was 59%, and the median duration of response was 16.3 (3.5-67+) months with a median survival time from the start of chemoendocrine therapy of 25.5 (3.5-67+) months. The median survival time of responders (32.5 months) was significantly longer than that of non-responders (15.3 months). The major toxicities were hair loss, G1 symptoms, and hematological toxicity, but these were clinically well tolerated. No serious cardiac, renal or liver damage was seen. These results indicated that the addition of tamoxifen to the ACF regimen increased the number of complete responses and prolonged the survival time of responders.

Eight patients with acute non-lymphocytic leukemia in adults refractory to Daunomycin (DM)-based conventional regimens were treated with AMSA-based regimens. Complete remission (CR) was obtained in 4 (50%) and partial remission (PR) in 2 (25%). The median time to CR was 26.5 days and 3 cases achieved CR in the first cycle. The median duration of CR was 8.3 months. Hematologic toxicity was severe and the nadir (median) of leukocytes and platelets was 0.15 x 10(3)/microliters and 15.5 x 10(3)/microliters, respectively. Other adverse effects were mucositis, nausea.vomiting and hepatotoxicity which occurred over 50%, while cardiac toxicity was not observed. This study indicates that AMSA is clinically non-cross-resistant to DM and considered to be an active drug for salvage therapy.

Clinical studies of combination therapy with chemotherapeutic agents and interferon (IFN) were performed. Seventeen patients with non-Hodgkin's lymphoma (NHL) and 2 patients with Hodgkin's disease (HD) were treated by combination chemotherapy (COPP or CHOP), and then received 300 X 10(4) U of alpha-IFN daily for 14 days. Complete remission was seen in 11 of 15 evaluable patients with NHL and both of 2 patients with HD. Myelosuppression such as leukopenia and thrombocytopenia was observed in half of the patients. Other side effects were fever, liver dysfunction, alopecia, and peripheral neuropathy. However, all these side effects were mild and well tolerated even in elderly patients.

Twenty-eight patients with a metastatic breast cancer who have achieved a complete remission from a combination chemotherapy that included doxorubicin have been analyzed to ascertain the factors which affect the duration of the response and the survival time. The median duration of a complete remission was 26 months. Relapses occurred in 17 patients (61%), of which the median duration of the response was 18 months and 71% of the relapses occurred at the sites of the prior dominant disease. Most of the patients suffered a relapse while they were receiving maintenance chemotherapy. The number of metastasized organs were one or two in 89% of the patients. The dominant sites of the disease were mainly the visceral (61%) and soft tissue (29%), and the duration of survival was found to be longer in patients with a visceral metastasis. In the group of patients who experienced a recurrence 2 years or more after their operation showed a statistically longer remission and survival time than those who experienced a recurrence within 2 years. The duration of survival from the start of chemotherapy was 45.5 months for complete responders and 21 months for partial responders. This difference was statistically significant (p less than 0.001), though no difference was found between partial responders and "no-change" patients (18.5 months). The tendency towards a relapse at the site of the initial involvement and while receiving maintenance therapy suggests that the majority of patients with a metastatic breast cancer who achieved a complete remission with this combination chemotherapy still have a substantial subclinical residual tumor. Maintenance treatment should be investigated to ascertain the procedures and duration of therapy. Thus, these results have indicated that it is necessary to achieve a complete remission in order to obtain a long term survival.

Drug resistant phenomenon to antitumor agents remains a major problem in cancer chemotherapy. In this study, we attempted to overcome drug resistance using high-dose chemotherapy with autologous bone marrow transplantation (ABMT). The main regimen consisted of Cyclophosphamide 60 mg/kg/day and thio-TEPA 6 mg/kg/day which were infused for 3 consecutive days. Three patients with malignant lymphoma, four with breast cancer, two with gastric cancer and one with ovarian cancer. All of whom were refractory to conventional chemotherapies were treated. The overall response rate was 70%. Severe bone marrow suppression, mucositis and diarrhea were observed in all patients, but these were not life-threatening and clinically manageable. Furthermore, the administration of granulocyte colony stimulating factor (G-CSF) has significantly (p less than 0.05) shortened the duration of leukopenia, and has been judged to be useful for reducing severe infections and for shortening the period stayed in clean room. Our results indicates that high-dose chemotherapy with ABMT is an effective method for overcoming drug resistance.