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Biomedical subjects

A D Ho

Publications and source records attributed to A D Ho.

At least 199 records · Page 11Linked to original sources
PubMed1988

Enzymes of purine metabolism in lymphoid neoplasms, clinical relevance for treatment with enzyme inhibitors.

A few enzymes of the purine degradative pathway have proved valuable in diagnosis and treatment of lymphomas and lymphocytic leukemia. Of particular interest are the enzymes adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP) and ecto-5'-nucleotidase (5NT). Intact activities of ADA and PNP have been shown to be vital for lymphoid cells. During development, lymphoid precursors go through remarkable changes in the concentrations of these enzymes and the neoplasms derived from them show a "frozen" biochemical profile similar to the corresponding normal cell of origin. Knowledge of the role of these enzymes has led to the pharmacological use of enzyme inhibitors for the specific treatment of lymphoid neoplasms. This review concerns the enzymatic make-up of normal and neoplastic lymphocytes and exploitation of this knowledge for the treatment of lymphomas. Special emphasis will be put on the clinical use of an ADA-inhibitor, deoxycoformycin.

5'-Nucleotidase↗
PubMed1988

Deficiency in interferon production of peripheral blood leukocytes from patients with non-Hodgkin lymphoma.

In search for a rationale for the use of interferons (IFNs) in treatment of non-Hodgkin lymphoma (NHL), we have investigated the IFN system of 13 patients with low-grade NHL, 15 patients with high-grade NHL, and 20 patients with chronic lymphocytic leukemia or leukemic immunocytoma (CLL/IC). Production of IFN induced by phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), Corynebacterium parvum, Herpes simplex virus (HSV), Newcastle disease virus (NDV), and interleukin 2 (IL-2) were studied in the peripheral leukocytes from the patients and from 21 control persons by means of a whole blood technique. All three groups of patients with NHL had significantly reduced production upon stimulation by NDV (p ranged between 0.0038 and less than 0.0001) compared to controls. Similarly, C. parvum also induced lower titers of IFN in the leukocytes of patients with non-leukemic NHL (p = 0.0015 for low-grade NHL and p = 0.0038 for high-grade NHL). When stimulated by PHA, the IFN response of all groups of patients was within normal range. With the exception in low-grade NHL, Con A also induced normal titers of IFN in the patients with NHL. The levels of IFN induced by PWM, HSV, and IL-2 were very low and no differences between controls and patients could be found. As NDV and C. parvum induce mainly IFN-alpha and the mitogens PHA and Con A mainly IFN-gamma, our results suggest that there is a deficiency in the IFN-alpha response in the patients with NHL but normal response in IFN-gamma. This deficiency may have implications for the choice of subtypes of IFN in the treatment of NHL.

Adult↗
PubMed1988

Deoxycoformycin in therapy of refractory lymphoid neoplasms.

Knowledge of the vital role of the purine degradative enzyme adenosine deaminase (ADA) in the differentiation of T and B lymphocytes has stimulated interest in the pharmacologic inhibition of ADA as specific cytotoxic therapy for lymphoproliferative diseases. 2'-Deoxycoformycin (DCF) is a tight-binding ADA-inhibitor and has shown activity in T and B cell neoplasms. In this phase-II study, the efficacy and toxicity of DCF in chronic T and B cell neoplasms is investigated. We report the preliminary results of treatment in 27 patients (8 with Sézary syndrome, 11 with B-chronic lymphocytic leukemia (CLL), and 8 with hairy cell leukemia (HCL)), who were refractory to conventional therapy. DCF was applied at a dosage of 4 mg/m2 weekly x 3, then 4 mg/m2 every other week x 3. Three of the 8 patients with Sézary syndrome and 3 of the 11 patients with B-CLL attained a partial remission. One complete and 7 partial remissions have been achieved thus far in the 8 patients with HCL refractory to interferon alpha treatment. Other than nausea in 10 patients (mainly grade 1 and 2), transient skin rash in 4 patients and Herpes infections in 4 patients (mainly grade 2), no other major toxicities were observed. Thus DCF is highly active in hairy cell leukemia that did not respond to interferon alpha, and shows moderate activity in refractory Sézary syndrome and B-CLL.

Antineoplastic Agents↗
PubMed1988

Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia--an active and well-tolerated regimen.

Both mitoxantrone and etoposide have been shown to be active in monotherapy trials of relapsed and refractory acute myelogenous leukemia (AML). This phase II study was undertaken to assess the antitumor activity and toxicity of the combination in refractory and poor-risk AML. The regimen consisted of mitoxantrone, 10 mg/m2/d intravenously (IV), and etoposide, 100 mg/m2/d as short infusion, both on days 1 to 5. Sixty-one patients are evaluable for response and toxicity. Twenty-one were primarily refractory to conventional courses of cytarabine, daunorubicin, and thioguanine; 20 patients had poor-risk first relapse (relapse within 6 months of first complete remission [CR] or relapse under continuous maintenance therapy); 11 had second or subsequent relapses; and nine developed secondary AML after myelodysplastic phase or myelofibrosis. Twenty-six patients (42.6%) attained a CR and seven (11.5%) a partial remission (PR). The median duration of continuous CR was 4.7 months, with a range of 21 days to 14 months, excluding four patients who underwent autologous bone marrow transplantation. Severe myelosuppression was observed in all patients, with a median time to CR of 49 days. Nonhematologic toxicity included stomatitis (mainly grade 1 and 2) in 41 patients, nausea (mainly grade 1 and 2) in 44, infections (mainly grade 3) in 33, and fever of unidentified origin in 11. Other than transient, mild cardiac failure in nine patients, in some of them combined with grade 1 to 2 tachyarrhythmia, no other drug-related cardiac events were observed. Two cases of early death within the first 6 weeks of treatment were registered. Thus, the combination of mitoxantrone and etoposide is a highly active and well-tolerated regimen for refractory and poor-risk AML.

Adolescent↗
PubMed1988

Decrease of natural killer cell activity and monokine production in peripheral blood of patients treated with recombinant tumor necrosis factor.

Tumor necrosis factor (TNF), a protein predominantly produced by activated macrophages/monocytes, is presently available in recombinant, purified form for clinical trials. Intensive studies in many laboratories have shown that besides the tumorcytotoxic effects, TNF acts on a large array of different cells and has potent immunomodulatory activities. In a clinical phase I study, some immunologic functional parameters of blood cells from patients who received 24-hour infusions of recombinant human TNF (rhTNF) were analyzed. Natural killer (NK) cell activity, TNF production, interleukin-1 (IL-1) production and mitogen-induced proliferation were measured either in whole blood samples or in cultures of peripheral mononuclear leukocytes of the patients directly before and after rhTNF infusion. NK cell activity, TNF and IL-1 production capacity and proliferative responses to concanavalin A (Con A) were significantly reduced after rhTNF application. We conclude from these observations that rhTNF in vivo acts directly or indirectly on NK cells and monocytes by either inactivating their functional capacity or by absorbing the relevant cells to the endothelial cell layer, thus removing them from circulation.

Adult↗
PubMed1988

Clinical response to deoxycoformycin in chronic lymphoid neoplasms and biochemical changes in circulating malignant cells in vivo.

Deoxycoformycin (DCF), an adenosine deaminase (ADA) inhibitor, has been shown to be active in lymphoid neoplasms. The mechanism of cytotoxicity might involve accumulation of deoxyadenosine triphosphate (dATP), depletion of the nicotinamide adenine dinucleotide (NAD) and ATP pool, induction of double-stranded DNA strand breaks, or inhibition of S-adenosyl homocysteine hydrolase (SAH-hydrolase). We have investigated the biochemical changes in the circulating malignant cells of patients with chronic leukemia/lymphoma who were treated with DCF (4 mg/m2 weekly). Blood samples were taken from 17 patients with 60% or more circulating leukemic cells before, 4, 24, and 48 hours and five days after the first administration of DCF. Leukemic cells were separated and studied for changes in ADA, dATP, ATP, NAD, and SAH-hydrolase levels and DNA strand breaks and the data analyzed according to clinical response. Inhibition of ADA activity was found in all except one patient at 4 to 24 hours after the first administration of DCF. dATP started to accumulate at four hours, reached a maximum level between 24 and 48 hours, and returned to base values on the fifth day. Intracellular ATP and NAD levels were transiently reduced in some of the patients. However, no correlation between these changes and a clinical response could be found. DNA strand breaks could be studied in 13 patients. A significant increase in DNA breaks at 24 to 48 hours was found in six of the seven responders but only in one of the six nonresponders. At 24 hours, SAH-hydrolase levels were reduced in all seven responders studied, but only in two of the seven nonresponders. The difference in inhibition of SAH-hydrolase was statistically significant (P = .0023). These results suggest that DNA strand breaks and inhibition of SAH-hydrolase correlate with clinical response.

Adenosine Deaminase Inhibitors↗
PubMed1987

2'-Deoxycoformycin (Pentostatin) in hairy cell leukemia: response in patients refractory to interferon alpha.

Three patients with advanced hairy cell leukemia received low-dose deoxycoformycin treatment after failure to respond to therapy with interferon alpha. Patients 1 and 2 had progressive disease after splenectomy and subsequent treatment with recombinant interferon alpha (for 7 and 3 months, respectively). DCF was administered at 4 mg/m2 weekly for 3 weeks, and then once every week for 6 weeks. Patient 1 was in complete remission after 9 weeks of treatment and patient 2 in partial remission with normalization of peripheral blood counts. The third patient, also splenectomized, developed hepatotoxicity after therapy trial with interferon for 24 days and no objective improvement was observed at this stage. She subsequently responded to DCF treatment with improvements in blood counts and bone marrow. This report demonstrates that DCF is highly effective in hairy cell leukemia and non-cross-resistant with interferon alpha.

Adult↗
PubMed1987

[Clinical relevance of glucocorticoid receptors in the treatment of lymphoid neoplasias].

A generalized view on the mechanism of steroid hormone action is presented with special emphasis on glucocorticoids and their lymphocytolytic effects. The present knowledge on the structure and function of glucocorticoid receptors is reviewed. Following hormone binding, the receptor complex is activated to a form which is able to interact with chromatin or DNA. Several types of receptor mutants have been obtained in an animal cell culture system which allows selection of cell variants. The biochemical analysis of these mutants helped to establish a domain model of receptor structure. The quantitative effect of receptor numbers and hormone activity on lymphocytolysis is described in a cell culture model system and the results are discussed in view of the rational treatment of lymphoid neoplasia with glucocorticoids. The clinical experience with glucocorticoids alone and in combination therapy with cytostatic drugs is summarized. Our special emphasis is on acute lymphoblastic leukemia and malignant lymphoma as patients with these diseases can now be treated with remarkable success rates.

Antineoplastic Agents↗
PubMed1987

Combination of low-dose cytarabine and 13-cis retinoic acid in the treatment of myelodysplastic syndromes.

Responses have been reported in patients with myelodysplastic syndromes (MDS) after low-dose cytarabine (Ara-C) or 13-cis-retinoic acid (13-CRA) therapy. Recently, combination of these two substances in vitro was shown to produce a synergistic effect on differentiation of leukemic cells. We conducted a phase II trial with low-dose Ara-C (5 mg/m2 per 12 h s.c.) and 13-CRA (60 mg/m2 per day orally) in 14 patients with MDS, six of whom had refractory anemia with excess of blasts (RAEB), seven had RAEB in transformation (RAEBt) and one chronic myelomonocytic leukemia (CMML). The drugs were administered from day 1 to 14 and the treatment courses repeated every 4 to 8 weeks. One partial response and one minor response could be achieved. Major toxicity included dry skin, mucositis and cheilitis in 11 of the 14 patients. The response rate is no better than the results reported in the literature with either drugs alone. As yet there is no satisfactory treatment for MDS.

Adult↗
PubMed1987

Biochemical mechanisms of deoxycoformycin toxicity in chronic leukemias.

The in-vitro effects of deoxycoformycin (dCF) on dATP, NAD, ATP and DNA strand breaks have been evaluated in the cells from 42 patients with various types of chronic lymphoid leukemia. These included 18 with B-cell chronic lymphoid leukemias of different types (BCL); 10 with hairy cell leukemia (HCL) and 14 with T-cell chronic lymphoid leukemias of different types (TCL). The dATP concentrations in HCL, BCL and TCL increased from means of 2.9, 1.8 and 3.0 to 100.3, 68.2 and 51.3 pmol/10(6) cells respectively after 2 h with 10(-5) M dCF and 10(-4)M deoxyadenosine. After 18-24 h, the NAD levels and total double-stranded DNA decreased to 37 and 12.5% (HCL) to 36 and 21.6% (BCL) and 40 and 20.5% (TCL) of control values respectively. Similar decreases were observed in ATP levels. The results do not suggest that these measurements in vitro would predict which patients with these disorders will respond to dCF therapy. Although HCL responds particularly well to dCF in vivo, no difference in the in-vitro effects of dCF studied here could be detected between cases of HCL and the other types of chronic leukemia.

Adenosine Triphosphate↗
PubMed1987

Mitozantrone-induced toxicity and DNA strand breaks in leukaemic cells.

By applying the fluorometric analysis of DNA unwinding (FADU) the in vitro effect of mitozantrone on DNA strand breaks was studied in seven different human leukaemic/lymphoma cell lines and in fresh leukaemic samples from seven patients with acute myeloid leukaemia refractory to conventional treatment. Pulse exposure to mitozantrone for 30 min invariably caused strand breaks. In the cell lines JM 1, KM3 and RPM I 8420 DNA strand breakage was progressive upon further incubation in drug free medium. These cell lines were killed by pulse exposure to mitozantrone. In the cell lines Molt 4, Daudi, Raji and HL-60, the DNA strand breaks induced by mitozantone were only moderate and these cell lines were also resistant to killing by mitozantrone in vitro. The leukaemic cells of one of the seven patients behaved also like the cell lines that were sensitive and a complete remission was achieved in this patient using mitozantrone as single agent therapy. The other patients with a pattern similar to the resistant cell lines proved to be clinically refractory. Thus mitozantrone induces rapidly progressive DNA strand breaks as early as 30 min in leukaemic cells that are sensitive. The measurement of DNA strand breaks by the fluorometric analysis of DNA unwinding is a rapid method which might predict response to drugs whose major effect is on the induction of strand breaks.

Cell Line↗
PubMed1987

[Primary treatment of hairy cell leukemia with low-dose human recombinant interferon-alpha-2c (Hr-IFn alpha 2c) in comparison with therapy following splenectomy. Interferon (IFn-alpha 2c) in HCL before or after splenectomy].

Within less than 14 months of recruitment 32 centers enrolled 97 patients in a multicenter trial for low-dose treatment of hairy cell leukemia (1.2 X 10(6) IU/m2 X 28 days s.c. with dose reduction according to clinically judged improvement) or ultra-low dose treatment (1.2 X 10(5) IU/m2, s.c. daily increasing to a well-tolerated dose) with Hr IFn-2c (arg). Induction therapy was limited to 84 days. Patients who reached the clinical stage Jansen I or A were then randomized to 2 arms either to receive further IFn (1.2 X 10(6) IU/m2 s.c.) twice a week or to be taken off treatment. For both arms induction therapy was reinstituted whenever a patient lost the criteria of Jansen stage A or I. The study included obligatory central diagnostic procedures and several special investigations. During the first year of the study a special problem evolved in the group of 34 patients with recurrent disease after splenectomy. Ten of them died, 9 of septicemia and 1 of bleeding complications, whereas only 1 death occurred in those patients who received IFn before splenectomy. The risk factors and the response to therapy in the two groups will be analyzed in order to define the criteria that will be needed for the proper choice of primary treatment for HCL. It appears important to us to restrict splenectomy to selected patients.

Clinical Trials as Topic↗
PubMed1987

[Phase III study of chemotherapy in low-malignancy non-Hodgkin's lymphomas: comparison of vincristine-vindesine combination chemotherapy].

In a phase-III study in non-Hodgkin's lymphoma of low malignancy we compared a combination therapy with vincristine (COP) with a vindesine combination (CEP). Remission rates, duration of remission and survival was favorable for the CEP combination without reaching the level of significance. The peripheral neurotoxicity of grade 2 and 3 according to WHO criteria was observed more frequently with vincristine. The vincristine-induced neurotoxicity in 6 patients was not impaired when a change was made to vindesine treatment.

Antineoplastic Combined Chemotherapy Protocols↗