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Biomedical subjects

T Ohnuma

Publications and source records attributed to T Ohnuma.

At least 145 records · Page 8Linked to original sources
PubMed1982

Methyl-GAG in patients with malignant neoplasms: a phase I re-evaluation.

Methyl-GAG was given to 71 patients with advanced malignancies as a weekly brief infusion (30-120 minutes) or as a biweekly 24- or 120-hour infusion. Mucositis (stomatitis, pharyngitis, esophagitis, and, rarely, inflammation of other mucous membranes) was dose-limiting in all three schedules. Generalized fatigue, malaise, myalgia, dysesthesias, nausea, and vomiting were more frequent in the brief-infusion schedule. Myelosuppression was mild and not dose-related. Fever, ventricular arrhythmias, skin rash, tender swelling of the palms, neuropathy, and paralytic ileus were rare. Toxicity was increased in patients with renal insufficiency or "third-space" fluid but was not increased by hepatic dysfunction. Cumulative and overlapping toxicity was evident only in the weekly schedule. Higher doses of methyl-GAG were tolerated when the duration of infusion was increased. The recommended doses for phase II trials are 700 mg/m2 weekly as a 1-2 hour infusion, 850 mg/m2/24 hours biweekly, and 1500 mg/m2/120 hours biweekly. Therapeutic effects were seen in all schedules and included objective responses in colon carcinoma (one of 13 patients), renal cell carcinoma (one of nine), and Hodgkin's lymphoma (one of two) and objective improvements in esophageal carcinoma (one of three), endometrial carcinoma (two of two), and leiomyosarcoma (one of three).

Adult↗
PubMed1982

Phase I study of indicine N-oxide in patients with advanced cancer.

Indicine N-oxide is a pyrrolizidine alkaloid isolated from Heliotropium indicum, one of the widely used herbs in Ayurvedic medicine. Thirty-seven patients with solid tumors received the drug: 15 men and 22 women (mean age, 53 years). All had had prior chemotherapy, and 25 had had prior radiotherapy. Eighty-four percent had a performance status of 0-3 (Cancer and Leukemia Group B criteria). The drug was given as a short infusion over 15 minutes and repeated with a median interval of 4 weeks. Doses were escalated from 1 to 9 g/m2. A total of 55 courses were evaluable. Dose-limiting toxic effects were leukopenia and thrombocytopenia, and the toxicity was cumulative with repeated doses. Other toxic effects included nausea and vomiting, anemia, and hepatic dysfunction. The hematologic toxicity tended to be more pronounced in patients with hepatic dysfunction, poor marrow reserve, and heavy prior chemotherapy and radiotherapy. There were no complete or partial responses. One patient with skin melanoma and another with ovarian carcinoma had improvement lasting 2 months. The maximally tolerated dose is 9 g/m2 in our population. A recommended dose for therapeutic study is 7 g/m2. High-risk patients should be started at a dose of 5 g/m2. The treatment may be repeated at 4-week intervals with close monitoring of wbc and platelet counts. Dose reductions may be necessary for repeated courses.

Adult↗
PubMed1981

Marker profiles of human leukemia and lymphoma cell lines.

By means of the multiple marker analysis, a total of 55 human leukemia-lymphoma cell lines which included 15 T-cell, 30 B-cell, four myelomonocytic-cell, and six non-T, non-B cell lines was characterized for their marker profiles. The multiple markers used included a number of cell surface markers as detected by either rosette or immunofluorescence tests, enzyme assays, cytogenetic analysis, and certain functional assay. Based on the criteria previously defined it was found that all the cell lines were proved to represent original leukemia-lymphoma of ALL, AML, CLL, CML in blastic phase or variety of lymphomas. The monoclonality, a "frozen" state at a specific state of differentiation-maturation, and cytogenetic marker in each leukemia-lymphoma cell line were remarkable common properties and were stable for years of cultivation. Similar, if not identical, general characteristics were observed in the study on 344 cases of uncultured fresh leukemia-lymphomas by the multiple marker analysis. While no single marker specific to any type of tumor was found, the study offers not only a basis for better understanding of the biology of leukemia-lymphoma but also an insight into normal hematopoietic cell differentiation in man.

Antigens, Neoplasm↗
PubMed1981

Sequential combination of pyrazofurin and 5-azacytidine in patients with acute myelocytic leukemia and carcinoma.

The combination of pyrazofurin (PF) and 5-azacytidine (5-aza-CR) was evaluated in 12 patients with neoplastic diseases who had failed conventional therapies. They included 6 patients with acute myelocytic leukemia (AML) and 6 with various carcinomas. PF was given by i.v. bolus at doses ranging from 25 to 200 mg/m2 followed by 5-aza-CR given by continuous 24-hour infusion at doses ranging from 30 to 120 mg/m2/24 h during 40-ic diseases who had failed conventional therapies. They included 6 patients with acute myelocytic leukemia (AML) and 6 with various carcinomas. PF was given by i.v. bolus at doses ranging from 25 to 200 mg/m2 followed by 5-aza-CR given by continuous 24-hour infusion at doses ranging from 30 to 120 mg/m2/24 h during 40-ic diseases who had failed conventional therapies. They included 6 patients with acute myelocytic leukemia (AML) and 6 with various carcinomas. PF was given by i.v. bolus at doses ranging from 25 to 200 mg/m2 followed by 5-aza-CR given by continuous 24-hour infusion at doses ranging from 30 to 120 mg/m2/24 h during 40--120 h. Dose-limiting toxicity was mucocutaneous, which appeared in 11/17 courses. Skin rash was similar to that produced by PF alone, but was present after much lower doses of PF when followed by 5-aza-CR. Moderate and reversible thrombocytopenia and leukopenia occurred in 3/6 patients with carcinoma. No objective response was seen in patients with carcinoma, and no marrow remission occurred in patients with AML. 24-Hour urinary excretion of orotidine and oroticacid were measured during 11 courses in 8 patients, and were not much different than those obtained previously with PF alone. The occurrence of mucocutaneous toxicity precluded the use of higher doses of PF and 5-aza-CR, which might have been therapeutically more active.

Adenocarcinoma↗
PubMed1981

Inhibitory effects of human leukocyte and fibroblast interferons on normal and chronic myelogenous leukemic granulocytic progenitor cells.

Inhibitory effects of two human interferon preparations, leukocyte interferon (Le-IF) and fibroblast interferon (F-IF), on granulocytic progenitor cells (CFU-C) from hematologically normal cancer patients and from patients with chronic myelogenous leukemia were evaluated. There was a wide variation in sensitivity of CFU-C to both Le-IF and F-IF. F-IF was mor inhibitory against CFU-C than le-If. Normal CFU-C and chronic myelogenous leukemia CFU-C were equally inhibited by both interferons. Effects of both interferons were neutralized by corresponding specific antisera but not by the other antisera. These observations confirmed that differences in immunogenicity of the interferons may attend their different origins.

Cells, Cultured↗
PubMed1981

Asparaginase and amino acids in cancer therapeutics. Cancer and Leukemia Group B Investigators.

Asparaginase was found ineffective in improving induction frequency of acute lymphocytic leukemia of children from vincristine and prednisone, but prolonged remission duration. Prolongation of remission duration was accomplished more effectively and at lower toxic cost by administration of asparaginase after the vincristine and prednisone treatment had been completed. Asparaginase is markedly more effective against human leukemia T-cells in vitro than against several types of B-lymphocytes. This is consistent with in vivo experience. Leukemic T-cells resistant to asparaginase have been induced in vitro. Deficiency of other amino acids causes absolute cessation of RNA biosynthesis, constituting evidence for other amino acid targets critical to leukemic cell survival.

Adolescent↗
PubMed1980

Clinical and laboratory reevalution of dichloromethotrexate.

Clinical and pharmacologic effects of dichloromethotrexate (DCM) were reevaluated by an intermittent intravenous large dose schedule in patients with advanced malignancies. DCM was tolerated without Leucovorin (calcium folinate) in man, even when the initial immunoassayable DCM level approached 10(-3) M. Hepatic dysfunction occurred more frequently at high doses. Hematologic toxicity was not dose-limiting. Plasma decay of DCM was comparable to that of methotrexate (MTX). Of 50 patients treated, five including two with hepatic metastasis from colon carcinoma, responded with more than 50% regression of tumor. In vitro comparison of DCM and MTX in Molt 3 cells revealed that DCM was slightly more inhibitory than MTX on an equimolar basis. In the presence of 2.5 g/dl of human serum albumin (HA), however, inhibitory effects of DCM decreased markedly. The decreased biologic effects of DCM compared to those of MTX are due to much higher binding to HA by DCM. This phenomenon appears to explain all of the clinical and pharmacologic characteristics of DCM.

Adult↗
PubMed1980

Differences in chemotherapeutic susceptibility of human T-, B-, and non-T-/non-B-lymphocytes in culture.

Eleven human lymphoid cell lines, two T-cell lines, six B-cell lines and three non-T-/non-B-cell lines were evaluated for their asparagine dependence and for their chemotherapeutic susceptibility to asparaginase, cytosine arabinoside (ara-C), and 5-fluorouracil (FU). Two T-cell lines were asparagine dependent, whereas all B-cell and non-T-/non-B-cell lines were asparagine independent. These differences in nutritional requirements were consistent with as much as 5,000-fold differences in asparaginase sensitivity. B cells were found to be as much as 200-fold less sensitive to ara-C than T cells, irrespective of the benign or malignant nature of the cells or the presence or absence of EB virus infection. One non-T-/non-B-cell line with cell markers similar to the B-cell group behaved like a B-cell line. Two other non-T-/non-B-cells showed unique ara-C dose-response curves. FU sensitivity study revealed heterogeneity among B-cell groups. Non-T-/non-B-cell lines were uniformly FU insensitive. These differences in chemotherapeutic susceptibility were discussed in terms of usefulness as an in vitro model.

Asparaginase↗
PubMed1980

Interaction of human serum albumin with anticancer agents in vitro.

The influence of human serum albumin (HA) on the biological effects of 13 chemotherapeutic agents was studied in vitro in the human leukaemia cell line MOLT-3. On the basis of changes in biological activity influenced by HA, these drugs may be divided into three types. Type I agents include cis-diamminedichloroplatinum (II), 4'-(9-acridinylamino)methanesulphon-m-anisidide, neocarzinostatin, nitrogen mustard, adriamycin, daunorubicin and mitomycin C--drugs whose biological activities are reduced in the presence of HA. The biological activities of Type II drugs (cytosine arabinoside, fluorouracil and actinomycin D) are not influenced by HA. The biological activities of Type III drugs (bleomycin, vincristine and vinblastine) are increased in the presence of HA. These results indicate that serum HA interferes in vitro with certain anticancer agents in terms of biological activity and, probably, clinical effectiveness. HA-drug interaction may be a major factor governing the pharmacology of Type I anticancer agents in man.

Animals↗
PubMed1980

Phase I study of m-AMSA in patients with solid tumors and leukemias.

m-AMSA is a synthetic aminoacridine DNA intercalator found to have experimental murine antitumor activity. A phase I investigation was undertaken in 71 patients with solid tumors and acute leukemia. Using an intermittent every 3-week schedule in solid tumors, toxicity encountered was primarily hematologic, predominantly leukopenia with relative platelet sparing. The recommended dose for phase II evaluation in patients with solid tumors is 90 mg/m2 every 3 weeks; patients with minimal prior therapy could be treated at 120 mg/m2 and patients with hepatic dysfunction or marginal bone marrow reserve should have an initial dose reduction to 70 mg/m2. Therapeutic activity was seen in Hodgkin's disease, hepatoma, and epidermoid carcinoma of the esophagus. Various dose schedules were studied in leukemia. The recommended dose for phase II evaluation is 120 mg/m2 daily for 5 days as a daily 30-minute infusion. At this dose, nausea, vomiting, mucositis, alopecia, and hepatic toxicity were noted. Therapeutic activity was seen in AML, blastic CML, and CLL. Further clinical trials with this agent are warranted.

Acute Disease↗
PubMed1980

Initial clinical study with vindesine: tolerance to weekly iv bolus and 24-hour infusion.

Forty-six patients with inoperable cancer and leukemia in relapse were given vindesine (VDS) either by iv bolus weekly at doses ranging from 2.0 to 5.5 mg/m2 or by 24-hour continuous infusion weekly at doses ranging from 1.0 to 7.0 mg/m2 of estimated body surface area. VDS was well-tolerated by patients with normal liver function who had previously been minimally treated with myelosuppressive agents at a dose of less than or equal to 4 mg/m2 either by iv bolus or by 24-hour infusion weekly. The dose-limiting toxic effects of VDS were leukopenia and neurotoxicity. Leukopenia was cumulative but easily reversible by interruption of weekly dose. Neurotoxicity was insidious and hardly reversible. Patients with liver dysfunction appeared to develop more neurotoxicity. Other toxic effects included a decrease in hemoglobin level, transient hepatic dysfunction, cellulitis or phlebitis at the iv site, stomatitis, nausea, and vomiting. Degrees and parameters of toxic effects observed after iv bolus and 24-hour infusion of the same doses were indistinguishable except for an increased incidence of local cellulitis in the infusion group.

Adolescent↗
PubMed1980

Clinical pharmacologic effects of thymidine plus 5-FU.

Ten patients with advanced cancer were given 24 courses of thymidine (TdR) plus 5-FU. In the initial part of the study, TdR was given by continuous infusion at a dose of 8 g/m2/24 hrs x 5 days, and 5-FU was given as an iv bolus daily x 5. During the continuous TdR infusion, TdR serum levels ranged from 10(-6) to 10(-5) M, and thymine serum levels ranged from 10(-5) to 10(-4) M. 5-FU serum decay on Day 1 was rapid, and serum decay on Day 5 was slightly prolonged in two of three patients studied. The optimal dose of 5-FU with continuous infusion of TdR seemed to be between 200 and 400 mg/m2 daily x 5 in heavily pretreated patients. In the second part of the study, rapid infusion of TdR at a dose of 8 g/m2/2 1/2 hrs followed by 5-FU resulted in markedly prolonged 5-FU serum decay (initial serum half-life, approximately 240 mins) and definite increase in clinical toxicity. The dose-limiting toxic effect of both schedules was myelosuppression. Administration of TdR in one tenth of the initial infusion time resulted in a nearly 100-fold increase in peak TdR levels. Thymine was the major metabolite of TdR. 5-FU did not influence TdR blood levels. The protracted 5-FU serum decay appears to account at least in part for the increased toxicity of 5-FU when administered following TdR.

Adult↗
PubMed1979

Management of asparaginase induced hemorrhagic pancreatitis complicated by pseudocyst.

Asparaginase induced hemorrhagic pancreatitis is a rare but serious development occurring in less than 0.5% of patients treated with this drug. Severe pancreatitis with progressive abdominal distention, toxemia, hypotension and respiratory insufficiency occurred in an 18-year-old patient with acute lymphoblastic leukemia following treatment with asparaginase. There was a dramatic response to high flow peritoneal lavage with rapid recovery within 24 hours from a moribund state. The subsequent development of a pseudocyst, with progressive increase in size and development of obstructive symptoms, required surgical decompression. Transgastric cystogastrostomy was successfully carried out.

Adolescent↗
PubMed1979

High dose methotrexate followed by citrovorum factor reversal in patients with advanced cancer.

High dose methotrexate followed by citrovorum factor reversal has been utilized in twenty-six patients with advanced cancer. Four of 10 patients with head and neck cancer had an objective response. One of 7 patients with metastatic osteosarcoma to the lungs had stabilization with twenty treatments over 23 months. One patient with acute lymphocytic leukemia developed marrow aplasia but did not attain remission. The regimen was well tolerated when meticulous attention was paid to hydration, urine alkalinization, renal function and third space fluid accumulation. Life-threatening or lethal toxicity was encountered when these phenomena were not scrupulously observed.

Adolescent↗