Kazumi Sampi

Induction of differentiation of human acute non-lymphocytic leukemia cells in primary culture by inducers of differentiation of human myeloid leukemia cell line HL-60

Leukemia cells from patients with acute non-lymphocytic leukemia were treated with various inducers of differentiation of the human promyelocytic leukemia cell line HL-60. All cells in 14 specimens tested underwent morphological, functional and histochemical changes after treatment with some inducers of differentiation of HL-60 cells, but the most effective inducer varied for different specimens. These results suggest that treatment with some inducers should be effective for inducing most acute myeloid leukemia cells to differentiate into morphologically and functionally mature granulocytes and macrophages.

An analysis of chromosome findings in non-Hodgkin's lymphomas

Banding studies were done on tissues from tumors excised from 22 Japanese patients with non-Hodgkins lymphomas. All tumors were found to be associated with aneuploidy. The chromosome abnormalities were diverse, with each chromosome type being involved in these abnormalities. Terminal deletions, derivative chromosomes as a result of unbalanced or nonreciprocal translocations, and markers of totally or partially unknown origin accounted for the majority of the structural abnormalities. Balanced reciprocal translocations were seen only occasionally. The 14q+, 6q-, partial trisomy of 1q, 11q+, 18q+, and 19q+ abnormalities were seen in more than two patients. The incidence of a missing sex chromosome was significantly higher than that of autosomes, but no particular other karyotypic abnormality seemed to be associated with the event. All six patients whose chromosomes could be totally characterized were in complete remission. Patients with one or more markers of unknown either totally or partially origin, had a median survival of only 8 months (p less than 0.01). Five of the former six patients showed a nodular histology. Fifteen of the latter 16 patients had a diffuse histology, with 13 of the 15 having diffuse histiocytic lymphoma. The median survival of 9.5 months for the 14 with only abnormal metaphases in the lymphatic tissues (AA-group) was shorter than the 26+ months for the seven patients with both normal and abnormal metaphases (AN-group). Thus certain aspects of chromosomal changes appear to correlate with histology and/or prognosis in non-Hodgkins lymphomas.

Effects of inhibitors of protein tyrosine kinase activity and/or phosphatidylinositol turnover on differentiation of some human myelomonocytic leukemia cells

The activities of protein tyrosine kinase and phosphatidylinositol turnover have been found to be associated with cell growth and differentiation. We examined the effects of some inhibitors for these biochemical activities in human myelogenous leukemia cells. Genistein, which is known to inhibit the activities of protein tyrosine kinase, phosphatidylinositol turnover and topoisomerase II, induced nitroblue tetrazolium (NBT) reduction and lysozyme activity in ML-1, HL-60 and U937 cells. Morphological studies showed that genistein-induced differentiation of myeloblastic ML-1 cells into promyelocytes and of promyelocytic HL-60 cells into mature granulocytes. The differentiation-inducing effect of genistein was augmented by addition of 1 alpha,25-dihydroxyvitamin D3 (VD3) or retinoic acid, VD3 being more effective than retinoic acid. Methyl 2,5-dihydroxycinamate, a protein tyrosine kinase inhibitor, had only a weak effect in inducing differentiation of ML-1 cells. On the other hand, psi-tectorigenin was more effective than genistein in inducing the differentiations of ML-1 and HL-60 cells. Psi-tectorigenin is reported to inhibit phosphatidylinositol turnover without inhibiting protein tyrosine kinase. Thus modulation of phosphatidylinositol turnover might be more important than that of protein tyrosine kinase activity for differentiation of some myelogenous leukemia cells.

Possible differentiation of human acute myeloblastic leukemia cells by daily and intermittent administration of aclacinomycin-A

A rapid decrease of myeloblasts and a remarkable increase of mature neutrophils, mostly with Pelger anomaly, were observed in the peripheral blood of a 51-year-old woman with terminal acute myeloblastic leukemia during 16 days of daily i.v. administration of 20 mg aclacinomycin-A (ACM-A). When the same dose was administered later on three consecutive days each week, a similar hematore neutrophils, mostly with Pelger anomaly, were observed in the peripheral blood of a 51-year-old woman with terminal acute myeloblastic leukemia during 16 days of daily i.v. administration of 20 mg aclacinomycin-A (ACM-A). When the same dose was administered later on three consecutive days each week, a similar hematore neutrophils, mostly with Pelger anomaly, were observed in the peripheral blood of a 51-year-old woman with terminal acute myeloblastic leukemia during 16 days of daily i.v. administration of 20 mg aclacinomycin-A (ACM-A). When the same dose was administered later on three consecutive days each week, a similar hematological change occurred again. An increase of myeloblasts observed between the third and the fifth week of this intermittent schedule was accompanied by that of mature neutrophils. Thrombopenia and anemia did not improve significantly. These findings may indicate the induction of leukemic myeloblasts by ACM-A into mature neutrophils. Administration of relatively small dose anthracyclines including ACM-A may be another potential choice in the treatment of refractory acute non-lymphocytic leukemia (ANLL) or ANLL after relapse.

Induction of differentiation of human leukemia cells by inhibitors of myosin light chain kinase

Inhibitors of myosin light chain kinase, 1‐(5‐chloronaphthalene‐1‐sulfonyl)‐1H‐hexanydro‐1,4‐diazepine hydrochloride (ML‐9) and 1‐(5‐iodonaph‐thalene‐1‐sulfonyl)‐1 H‐hexahydro‐1,4‐diazepine hydrochloride (ML‐7), induced Nitroblue tetrazolium reducing activity, lysozyme activity and morphological maturation of human monoblastic U937, THP‐1 and promyelocytic HL‐60 cells, but not of erythroblastic K562 cells. However, three analogs of ML‐9, which are an inhibitor and an activator of protein kinase C, and a calmodulin antagonist, respectively, did not induce differentiation of the cells.

A suprasellar embryonal carcinoma producing alpha-fetoprotein and human chorionic gonadotropin; treated with combined chemotherapy followed by radiotherapy

A case of primary suprasellar embryonal carcinoma that produced alpha-fetoprotein and human chorionic gonadotropin in a 12-year-old girl is reported. Partial removal of the tumor and cis-platinum-based combined chemotherapy followed by local radiotherapy resulted in a definite regression of the tumor and improvement from clinical signs and symptoms. After these treatments, the concentrations of alpha-fetoprotein and human chorionic gonadotropin in both serum and cerebrospinal fluid decreased to undetectable levels. Serum basic fetoprotein, another tumor marker, can be a tool for evaluating the clinical course following postoperative chemotherapy.

Induction of differentiation of human myeloid leukemia HL-60 cells by novel pyrimidine nucleoside analogs

New pyrimidine nucleoside analogs (18 compounds) were synthesized and their growth-inhibiting and differentiation-inducing activities on human myeloid leukemia HL-60 cells were examined. Some of the analogs were found to induce nitroblue tetrazolium (NBT) reducing activity in the HL-60 cells. The inducing activities of these compounds were compared at their concentrations for 50% inhibition of cell growth. TI-79 (3-benzyl-5-methyl-3-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine- 2,4(1H,3H)-dione) was a very effective inducer of NBT-reduction and of differentiation of the cells into mature granulocytes. The induction of NBT-reducing activity by TI-79 was inhibited by high concentrations of the natural nucleoside, adenosine. Other differentiation inducers, such as retinoic acid, 1 alpha,25-dihydroxyvitamin D-3 and staurosporin markedly enhanced the induction of differentiation of HL-60 cells by TI-79. Nucleoside analogs such as TI-79 should be useful for differentiation therapy of some types of myelogenous leukemia.

Discrepancy between in-vitro and in-vivo inductions of differentiation by retinoids of human acute promyelocytic leukemia cells in relapse

In-vitro studies of leukemic cells with retinoic acid and a therapeutic clinical trial with its derivative, etretinate, in a 58 yr-old male patient with 15;17 translocation-positive acute promyelocytic leukemia (APL) in relapse are reported. Actinomycin D was used in combination. Bone marrow promyelocytes from the patient prior to etretinate and actinomycin D matured morphologically in the liquid culture with retinoic acid; 98% were matured myeloid cells after 6 days at a concentration of 10(-6) M of retinoic acid as compared with 2% in the control culture. Positive NBT reactions were seen in none of the cells in the latter but in 95% of the cells in the former. Actinomycin D, when added alone, only induced NBT positivity, but, when used in combination with retinoic acid, increased both NBT positivity and morphologically matured cells. The patient was treated daily with 2 micrograms/kg of actinomycin D (or 20 mg/m2 or 33 mg/m2 cytosine arabinoside after the 6th day) in 24-h infusions and per oral 90 mg/body of etretinate. No effectiveness was observed both morphologically and clinically. The patient expired 15 days after the initiation of etretinate. Thus, a discrepancy existed in the response of leukemic cells from this relapsed patient with APL to the in-vitro and in-vivo attempts to include differentiation by retinoids and actinomycin D.

Burkitt's lymphoma with 2 8 translocation: A aase report with special reference to the clinical features

A case of Japanese Burkitts lymphoma (BL) with a t(2; 8) (p11; q24), a variant translocation in BL, is reported. The patient was a 45-year-old woman in whom a subcutaneous right axillary tumor first occurred. Remission was not achieved despite extensive chemotherapy. Of the four nonendemic BL, two endemic BL, and one nonendemic Burkitt-type acute lymphocytic leukemia (ALL-L3) cases with a t(2; 8) reported so far, including the present case, four (two nonendemic and two endemic) were positive for Epstein-Barr virus-determined nuclear antigen (EBNA) and two revealed extremely high antibody titers against Epstein-Barr virus (EBV), the remaining one not having been tested for EBV. Thus, a possible close relationship between the t(2; 8) and EBV infection has to be considered. The t(2; 8) in nonendemic BL seems to occur more often in adults than in children.

Differentiation of blasts from patients in myeloid crisis of chronic myelogenous leukemia by in-vivo and in-vitro plicamycin treatment.

Two cases in myeloid blast phase of chronic myelogenous leukemia (CML) responded to treatment with plicamycin alone. Their total white blood cell (WBC) count and immature myeloid cells fell in one case rapidly and in the other gradually. Approximately two to three weeks after initiation of plicamycin their total WBC count began to rise again, whereas the mature myeloid cells remained constant throughout the treatment. These results suggest that plicamycin may be effective in suppressing proliferation of blasts and promoting their maturation in the myeloid blast phase of CML, but that plicamycin alone may not be effective enough to sustain duration of response.