Myeloma therapy.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
L G Israels
Publications and source records attributed to L G Israels.
Factors influencing the inhibition of repair of irradiation-induced DNA damage by 2'-deoxycoformycin and deoxyadenosine.
Permeabilized L5178Y cells were used to investigate the mechanism underlying inhibition of the repair of irradiation-induced DNA strand breaks by 2'-deoxycoformycin combined with deoxyadenosine. Permeabilized cells repaired DNA strand breaks as effectively as did intact cells, and at deoxyadenosine concentrations that produced similar levels of deoxyadenosine triphosphate (dATP), repair of DNA strand breaks was inhibited by 2'-deoxycoformycin plus deoxyadenosine to a comparable extent in both types of cells. Accompanying the increase in intracellular dATP produced by 2'-deoxycoformycin combined with deoxyadenosine was a fall in levels of deoxythymidine triphosphate (dTTP), deoxyguanosine triphosphate (dGTP), and deoxycytidine triphosphate (dCTP). The addition of dTTP, dGTP, and dCTP reversed the inhibition of DNA repair by 2'-deoxycoformycin plus deoxyadenosine, although the level of dATP was not affected. Reducing the phosphorylation of deoxy-adenosine to dATP by the addition of adenosine prevented the decrease in levels of dTTP, dGTP, and dCTP and the inhibition of DNA repair by 2'-deoxycoformycin and deoxyadenosine. In contrast, increasing the intracellular levels of dATP by the addition of 2'-deoxycoformycin together with dATP, deoxyadenosine diphosphate (dADP), or deoxyadenosine monophosphate (dAMP) had no effect on the levels of the other deoxynucleotide triphosphates and did not inhibit DNA repair. Moreover, DNA repair was not inhibited by the breakdown products of deoxyadenosine, adenine, or deoxyribose. These results suggest that inhibition of the repair of irradiation-induced DNA strand breaks by 2'-deoxycoformycin combined with deoxyadenosine requires the phosphorylation of deoxyadenosine and involves alterations in the levels of deoxynucleotide triphosphates.
Adenosine↗
Induction of apoptosis in CD4+ prolymphocytic leukemia by deoxyadenosine and 2'-deoxycoformycin.
The leukemic cells of a patient with CD4+ prolymphocytic leukemia were treated in vitro with 5 microM deoxyadenosine and 60 microM 2'-deoxycoformycin (dCF), an inhibitor of adenosine deaminase (ADA). Following treatment, the leukemic cell dATP level increased to 378 pmol/10(6) cells on day 3, after which the level plateaued. Apoptosis was apparent following 4 h of incubation, and by day 8 34% of the chromatin was fragmented. Apoptosis also occurred in control cells, but to a lesser extent than in drug-treated cells. When the patient was treated with dCF, 4 mg/M2 i.v. the leukemic cell ADA activity was inhibited 24 h following treatment, and the lymphocyte dATP content increased to 303 pmol/10(6) cells by day 6. The lymphocyte count fell 60% in 1 week, but during this time there was no evidence of apoptosis in these cells. Thus, if dCF induces apoptosis in vivo, the effete cells may be rapidly cleared from the circulation and thus elude detection.
Adenosine Deaminase Inhibitors↗
Role of glutathione and glutathione S-transferase in chlorambucil resistance.
A chlorambucil (CLB)-resistant cell line, N50-4, was developed from the established mouse fibroblast cell line NIH 3T3, by multistep drug selection. The mutant cells exhibited greater than 10-fold resistance to CLB. Alterations in GSH and glutathione S-transferase (GST) were found in CLB-resistant variants. A 7-10-fold increase in cellular GSH content and a 3-fold increase in GST activity were detected in N50-4 cells, compared with parental cells, as determined by enzymatic assays. An increase in steady state levels of the GST-alpha isozyme mRNA was found in the CLB-resistant cells, as analyzed by Northern blotting. No GST gene amplification or rearrangement was shown by Southern blot analysis. To test the relative roles of GSH and GST in CLB resistance, a number of GSH- and GST-blocking agents were used. The CLB toxicity was significantly enhanced in N50-4 cells by administration of either the GSH-depleting agent buthionine sulfoximine or the GST inhibitors ethacrynic acid or indomethacin. The resistance to CLB cytotoxicity in N50-4 cells, however, was still significantly higher than that of parental cells. The resistance of N50-4 cells to CLB was almost completely abolished by combination pretreatment yielding both GSH depletion and GST inhibition. The results indicate that both increased cellular GSH content and increased GST activity play major roles in CLB resistance in N50-4 mutant cells.
3T3 Cells↗
Mechanisms of resistance to chlorambucil in chronic lymphocytic leukemia.
The postulated biochemical mechanisms responsible for clinical resistance to chlorambucil (CLB) in chronic lymphocytic leukemia (CLL) have been examined. The total sulfhydryl, non-protein-bound sulfhydryl, protein-bound sulfhydryl (PSH) and glutathione (GSH) levels, in addition to glutathione S-transferase (GST) activities, were measured in the leukemic cells of 18 CLL patients. In addition, the formation and repair of DNA cross-links were measured following incubation of the cells with 100 microM chlorambucil in vitro. These parameters were then correlated with the subsequent clinical responses of the patients, as measured by the percent fall in lymphocyte count 3 weeks following 0.9 mg/kg chlorambucil. No correlations were observed between any of the individual parameters and clinical response, although a slight positive correlation was observed between the PSH:GSH ratio and clinical response. These findings suggest that multiple mechanisms may contribute to CLB-resistance in CLL.
Aged↗
Glutathione S-transferase activity, sulfhydryl group and glutathione levels, and DNA cross-linking activity with chlorambucil in chronic lymphocytic leukemia.
Glutathione (GSH) levels and glutathione S-transferase (GST) activities were measured in the leukemia cells of 12 patients with chronic lymphocytic leukemia. Both were correlated with prior clinical exposure to alkylating agents and with DNA cross-link formation by chlorambucil in these cells in vitro. No correlation was observed between prior exposure to alkylating agents and GSH level or GST activity. An inverse correlation was observed between GST activity and cross-linking by chlorambucil, which was enhanced if both GST activity and GSH level were related to cross-linking. These findings suggest that the combination of GST and GSH protects the DNA of leukemia cells from chlorambucil, but the role of this combination in clinical resistance remains to be determined.
Adult↗
Peripheral blood and bone marrow changes following 2'-deoxycoformycin therapy in hairy cell leukemia. Results of 200 weeks' follow-up.
Peripheral blood (PB) and bone marrow (BM) changes during 200 weeks' follow-up of 15 patients with hairy cell leukemia (HCL) undergoing low-dose 2'-deoxycoformycin (dCF) therapy are reported. Thirteen patients rapidly achieved complete remissions (CR) (median, 16 weeks). Previous splenectomy (two patients), or chemotherapy (two patients) had no effect on dCF response. Twelve patients have remained in CR. Patients with marked BM infiltration (hairy cell index [HCI] greater than 0.5; n = 5) had more pronounced pancytopenia and showed a slower hematologic recovery than those with a lesser degrees of infiltration. Additionally, patients with cytologic type II HCL (n = 5) had more pronounced pancytopenia with a greater tumor load in the BM, and exhibited slower hematologic recovery than those with type I (n = 5) HCL. There was a gradual decline in BM cellularity from 65% to 25% during year 1, a level which remained stable thereafter. Reticulin in the BM regressed in all nine patients in whom it was increased before dCF therapy. The authors have not seen any dysplastic changes in the hematopoietic cells during the period of follow-up.
Adult↗
HTLV-1 T cell lymphoma in a cyclosporine-treated renal transplant patient.
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Adult↗
Erythremic [corrected] myelosis in chronic lymphocytic leukemia.
Two patients who had both B-cell chronic lymphocytic leukemia (CLL) and dyserythropoiesis are described. One patient (Case 2) had both CLL and dyserythropoiesis. Erythrodysplasia developed in the other patient (Case 1) after treatment for CLL with alkylating agents and 2'-deoxycoformycin. The management of these patients and the possible mechanisms responsible for the development of dyserythropoiesis in CLL are discussed.
Blood Cell Count↗
Enhanced cytotoxicity and inhibition of DNA damage repair in irradiated murine L5178Y lymphoblasts and human chronic lymphocytic leukemia cells treated with 2'-deoxycoformycin and deoxyadenosine in vitro.
The effects of irradiation were evaluated in L5178Y lymphoblasts treated with the adenosine deaminase inhibitor, 2'-deoxycoformycin, and deoxyadenosine. A synergistic antitumor effect was observed in resting cells between irradiation and 2'-deoxycoformycin/deoxyadenosine, with the dose required to reduce the surviving cell fraction to 0.1 being 25% lower than predicted for an additive effect. Synergy was enhanced with increasing deoxyadenosine concentration or with increasing radiation dose. When cells were treated with 2'-deoxycoformycin/deoxyadenosine for 1 h prior to irradiation, synergy was increased by prolonging postirradiation drug treatment. With 4-h postirradiation exposure to drug, varying the preirradiation incubation time did not affect synergy. In contrast, only a small enhancement of antitumor activity was observed in irradiated proliferating cells treated with 2'-deoxycoformycin/deoxyadenosine. Incubation of resting cells with 2'-deoxycoformycin/deoxyadenosine resulted in inhibition of the rate and extent of repair of radiation-induced DNA single strand breaks and an increase in dATP, but had no effect on NAD or ATP. With removal of drug, the dATP level fell rapidly and DNA repair resumed. Repair of DNA single strand breaks was more rapid in proliferating cells than in resting cells and was minimally affected by 2'-deoxycoformycin/deoxyadenosine, although the accumulation of dATP in these cells was 2-fold greater than in resting cells. The repair of DNA single strand breaks in chronic lymphocytic leukemia cells was as rapid as for proliferating L5178Y cells, but repair was significantly inhibited by 2'-deoxycoformycin/deoxyadenosine. These results suggest that 2'-deoxycoformycin/deoxyadenosine can function as a radiosensitizer, and this effect is associated with the cellular accumulation of dATP and inhibition of repair of DNA single strand breaks.
Adenosine Deaminase Inhibitors↗
Induction of DNA strand breaks in chronic lymphocytic leukemia following treatment with 2'-deoxycoformycin in vivo and in vitro.
Four patients with refractory chronic lymphocytic leukemia were treated with the adenosine deaminase inhibitor, 2'-deoxycoformycin, and initially received 4 mg/m2 i.v. weekly. Clinical responses to therapy varied: Patient A had a minimal response; whereas Patient D showed an 85% decrease in lymphocyte count at 2 wk; and Patients B and C had intermediate responses. The pretreatment mononuclear cell adenosine deaminase activities, which ranged from 1.6 to 44.6 nmol adenosine/h/10(6) cells, decreased to approximately 1 nmol adenosine /h/10(6) cells 24 h following 2'-deoxycoformycin, and increased to 15 to 50% of the pretreatment activity prior to the second drug treatment. The clinical response to 2'-deoxycoformycin was unrelated to the pre- or posttreatment adenosine deaminase activities or to the rate of return of enzyme activities following treatment. The plasma deoxyadenosine levels and the leukemic cell dATP concentrations rose slightly with therapy, but there was no correlation between the magnitude of increase and clinical response. No significant levels of DNA strand breaks were observed in the leukemic cells following treatment, although the NAD levels decreased slightly in two patients. When peripheral mononuclear cells from the patients and two controls were incubated in vitro for 24 h with 2'-deoxycoformycin and increasing concentrations of deoxyadenosine, a concentration-dependent increase in dATP and decrease in NAD were observed in both the patients and normals. The normal cells, and cells from two patients, developed a significant number of DNA strand breaks. However, there was no relationship between the formation of DNA breaks and the degree of accumulation of dATP or depletion of NAD, or between any of these changes and subsequent clinical responses to 2'-deoxycoformycin. Based on this study, it appears that the antitumor activity of 2'-deoxycoformycin in chronic lymphocytic leukemia is unrelated to the induction of DNA strand breaks or to changes in the levels of dATP or NAD in the leukemic cells.
Adenosine Deaminase Inhibitors↗
Severe acute thrombocytopenia following infusion of plasma containing anti P1A1.
An 18-year-old girl with a preoperative platelet count of 216,000/cmm received 3 units of stored plasma at the time of surgery. Within 6 hours her platelet count had fallen to 5,000/mm3 and hemorrhagic manifestations appeared. One of the plasma donors was found to be P1A1 negative with an anti P1A1 antibody. The recipient, who was P1A1 positive, recovered normal platelet counts by day 8 post plasma infusion.
Adolescent↗
Vitamin K1 amplification of benzo(a)pyrene metabolism in chick embryos.
Seventeen-day-old chick embryos were used as a test system to assess the effect of vitamin K1(K1) on benzo(a)pyrene (BP) metabolism as measured by the induction of arylhydrocarbon hydroxylase (AHH) and cytochrome P-450 and the levels of glutathione (GSH) and glutathione S-transferase (GST) in liver. Twenty-four hours after injection of BP into the air sac there was a sharp rise in AHH and P-450 and a drop in GSH. When K1 was injected 24 hr prior to BP there was a decrease in GST activity as compared with the control plus an augmented increase in AHH induction. This augmentation in BP metabolism (Phase I) together with a concomitant decrease in at least one mechanism of Phase II conjugation is in keeping with other evidence that K1 can play an adjuvant role in BP induced mutagenicity and carcinogenicity. Ubiquinone has a much lesser effect on BP metabolism than does K1 in equimolar concentration.
Animals↗
Weekly low-dose cyclophosphamide and alternate-day prednisone: an effective low toxicity regimen for advanced myeloma.
10 of 20 patients with advanced myeloma treated with a simple regimen consisting of weekly low-dose cyclophosphamide (C; 150-300 mg/m2; maximum weekly dose = 500 mg) given intravenously or orally, and alternate-day oral prednisone (P; 50-100 mg) responded clinically and with a fall in serum M protein greater than 50% or urine M protein greater than 90%. 3 of these responders were previous primary treatment failures, all having received cyclophosphamide in combination with other drugs given at 3- to 4-wk intervals. 2 patients treated with this regimen as primary therapy also responded. Although the median survival for the 10 responders was reached at 24.5 months, 3 patients remain alive and well 50+ months from the start of CP therapy. An additional 5 patients had disease stabilization or major improvement in bone pain and/or pancytopenia for over 12 months despite failure to meet strict criteria for response. The data suggest that disease control may be achieved by the more frequent scheduling of known active drugs such as cyclophosphamide (although it alone or in combination with other drugs may be ineffective when given at standard 3- to 4-wk intervals) in combination with prednisone or a more continuous basis. This is an effective yet simple therapeutic approach to myeloma with the distinct advantage of less toxicity than the multiple drug regimens in current use. It may have particular applicability to patients who are elderly or debilitated or in patients in whom cytopenia is present initially or develops on standard melphalan/prednisone regimens.
Administration, Oral↗
Vitamin K1 increases sister chromatid exchange in vitro in human leukocytes and in vivo in fetal sheep cells: a possible role for "vitamin K deficiency" in the fetus.
The levels of the vitamin K-dependent clotting factors are markedly lower in the human fetus and newborn than in older infants and adults. Direct measurement of vitamin K1 in cord plasma records low or undetectable levels. This phenomenon, although the norm, is referred to as vitamin K deficiency and is a significant risk factor for hemorrhage in the fetus and newborn. Sister chromatid exchange (SCE), which may be used as an index of mutagenic activity, was assayed in cultured leukocytes of placental and adult blood following phytohemagglutinin stimulation. The mean number of SCEs per metaphase in human placental blood was 3.32 +/- SE 0.219 as compared with levels of 5.13 +/- SE 0.273 in young adults (p less than 0.01), and in the presence of added vitamin K1 at a concentration of 1 X 10(-6) M the SCE increased significantly in both adult and placental cells. In vitro SCE dose response curves to K1 in the blood of fetal and maternal sheep were obtained. When five fetal sheep were given 1 mg of K1 by catheter into the femoral vein the SCE increased from 3.94 +/- SE 0.15 preinjection to 5.38 +/- SE 0.23 at 24 h postinjection (p less than 0.01). In the pretreatment fetal sheep, serum vitamin K1 was below detectable levels in all seven animals in which it was assayed and reached levels as high as 0.3 X 10(-6) M 1 h post-K1 injection. The low level of K1 in the fetus may in fact confer some biological advantage by reducing the risk of mutagenic events during a period of rapid cell proliferation.
Adult↗
Menadione inhibition of benzo(a)pyrene metabolism in whole cells, microsomes and reconstituted systems.
Menadione is known to decrease the mixed function oxidase mediated metabolism of a number of substrates in microsomal systems. The present study examines the effect of menadione on benzo(a)pyrene metabolism in whole cells, microsomes and a semi-purified reconstituted mixed function oxidase system. Menadione has a high affinity for the NADPH dependent cytochrome P-450 reductase and acts as a competitive inhibitor of cytochrome P-450 reductase in the metabolism of benzo(a)pyrene. This is the mechanism of inhibition of aryl hydrocarbon hydroxylase by menadione in reconstituted systems. In a whole cell system and at low concentrations of menadione, depletion of reduced pyridine nucleotides is the initial inhibitory event.
Animals↗
The double gammopathies. Clinical and immunological studies.
A retrospective review of 1135 patients with paraproteinemias recorded 28 (2.5%) as having two M components. This group included 11 patients with myeloma, 6 with lymphoproliferative disease, 5 with a nonlymphoproliferative malignancy, and 6 with a double gammopathy of undetermined significance. In 13 cases in which the M components were measured over a period of time, three distinct patterns were observed, which may reflect the cellular and subcellular origin of the two proteins: 1) In 2 cases the minor component remained relatively stable while the dominant protein changed with time and treatment, suggesting the origin to be two cell lines--the minor arising from a quiescent clone of the monoclonal gammopathy of undetermined significance, and the major M component arising from a more rapidly proliferating plasma cell line; 2) a discordant pattern was seen in 4 patients, suggesting that the two M components arose from two separate plasma cell clones; 3) seven cases in which the proteins behaved in a concordant manner probably arose from a single plasma cell clone with incomplete class switching, producing two M components with different heavy chains.
Aged↗
The treatment of hairy-cell leukaemia with 2'-deoxycoformycin.
Eight patients with hairy-cell leukaemia (HCL) complicated by pancytopenia were treated with low dose regimens of the adenosine deaminase (ADA) inhibitor 2'-deoxycoformycin (DCF). All patients had significant haematological and clinical improvement. One patient who had been splenectomized and five patients with mild to moderate splenomegaly achieved normal blood counts within 2 months, which have been maintained for up to 18 months. Complete remissions occurred in two patients and four patients had 50-95% marrow clearance of hairy cells. The initial DCF treatments produced a 1-3 g/dl fall in the haemoglobin levels and one patient had a temporary reduction in granulocyte and platelet counts. Five patients had nausea/vomiting, and/or lethargy following DCF, but there was no correlation between the plasma levels of deoxyadenosine and adenosine and the incidence or severity of these side effects. An increased incidence of infection and drug hypersensitivity may reflect the effects of DCF on the immune system. Low dose DCF is a highly effective agent in HCL.
Adult↗