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Biomedical subjects

W R Vogler

Publications and source records attributed to W R Vogler.

At least 37 records · Page 2Linked to original sources
PubMed1993

Autologous bone marrow transplantation with alkyl-lysophospholipid-purged marrow.

Autologous bone marrow transplantation (ABMT) appears to offer clinical benefit to leukemia patients, but the major reason for failure is relapse. This may be related to the presence of residual leukemic cells in the harvested marrow. To circumvent this problem, various procedures have been developed to purge ex vivo residual leukemic cells from the marrow. The alkyl-lysophospholipids are a new group of anticancer drugs that target membranes as their major site of action. They are unique in that they are relatively selectively toxic to neoplastic cells and spare normal marrow stem cells and progenitor cells. The most active compound is edelfosine. Twenty-nine patients with acute leukemia in second or subsequent remission or early relapse or in first remission, either with a history of treated extramedullary relapse, or requiring more than one induction program to achieve remission, underwent ablative therapy followed by infusion of autologous marrow which had been purged by a 4-hour exposure to edelfosine prior to cryopreservation. Thirty-one percent of the patients are alive and free of leukemia for a median of 630 days (range 185-1,613). These results in this high-risk group of patients warrant further investigation.

Acute Disease↗
PubMed1993

High-dose carboplatin in the treatment of hematologic malignancies.

Carboplatin is a second-generation platinum complex developed to be less ototoxic and nephrotoxic than cisplatin. The major toxicity was found to be myelosuppression; thus, it was tried in acute leukemia. When given by daily bolus injection for 5 days, carboplatin exhibited some activity but was associated with additional nonhematologic toxicity as well. When administered by continuous infusion, responses were higher and toxicity less. The Eastern Cooperative Oncology Group (ECOG) conducted a phase II study of carboplatin 315 mg/m2 daily given by continuous infusion for 5 days to adults with refractory and relapsed acute leukemia. A second course was given if the bone marrow on day 14 revealed persistent leukemia. Those achieving a complete remission (CR) were given an additional course as consolidation. The median age was 49 years among acute myelogenous leukemia (AML) patients and 46 years in acute lymphoblastic leukemia (ALL) patients. Of 46 eligible patients enrolled in the study (36 AML and 10 ALL), 8 (17%) achieved a CR (6 AML and 2 ALL). Remissions were observed in 2 of 10 primary refractory patients (1 AML and 1 ALL). When treated in first relapse, 5 of 14 patients (36%) achieved a CR. In 38 instances marrow specimens were examined after treatment; 10 (26%) showed no change, 16 (42%) were hypoplastic, and 12 (32%) were hypoplastic with residual leukemic cells. Of the 18 deaths that occurred on study, 14 were due to infection, 2 due to infection and bleeding, 1 due to uncontrolled gastrointestinal bleeding and 1 due to graft-versus-host disease in a patient who had relapsed after bone marrow transplantation. Marrow suppression was usually prolonged. Nonhematologic toxicity was mild. Gastrointestinal toxicity consisted of easily controlled nausea and vomiting. Three patients had grade 3 diarrhea. Grade 3 or more renal toxicity was observed in 8 patients, all of whom had received nephrotoxic antibiotics for treatment of bacterial or fungal infections. One patient died of renal failure that developed near the end of a second induction course. Ototoxicity was observed in 11 patients (24%) and was grade 2 or less in all but 3. These results indicate that carboplatin is an active agent in leukemia. Further studies are under way in combination with other agents such as etoposide, mitoxantrone, 5-azacytidine, and daunorubicin in treatment of acute leukemia and in combination with ifosfamide and etoposide in refractory lymphomas.

Adult↗
PubMed1992

Autologous bone marrow transplantation in acute leukemia with marrow purged with alkyl-lysophospholipid.

Alkyl-lysophospholipids are anticancer agents that are selectively toxic to leukemic cells and relatively sparing of normal bone marrow cells. Thus, they would be likely candidates for purging remission marrows before autologous bone marrow transplant. One of the more promising agents is edelfosine, which could be safely used for purging without prolonging marrow recovery. Assays for marrow progenitor cells were performed before and after purging and cryopreservation in 64 patients. There was no significant reduction in colony formation after purging when compared with unpurged cryopreserved marrow, but there was a significant reduction after cryopreservation. Twenty-four patients with acute leukemia in second (16 patients) or third remission (3 patients), early relapse (3 patients), or in first remission with successfully treated extramedullary relapse (2 patients) received marrow-ablative chemotherapy and total body irradiation followed by infusion of marrow purged for 4 hours with 50 to 100 micrograms/mL of edelfosine. There were 9 lymphoblastic and 15 myelogenous leukemia patients. The median time to granulocyte recovery to 500/microL was 26 and 33 days for the 50 and 75 microgram/mL doses, respectively. The patient whose marrow was purged at the dose of 100 micrograms/mL failed to engraft. The median time to platelet recovery to 25,000/microL was 45 and 37 days for the 50 and 75 micrograms/mL doses, respectively. Twenty-nine percent of the patients remain disease free from 131 to 1,291 days, with a median of 356 days. These results have established that purging with 75 micrograms/mL of edelfosine is a safe dose and is recommended for a phase II trial.

Adolescent↗
PubMed1992

Membrane interactions of mastoparan analogues related to their differential effects on protein kinase C, Na, K-ATPase and HL60 cells.

Membrane interactions of tetradecapeptide toxin mastoparan (MP) and analogues (MP-3, MP-X and polistes MP), as indicated by inhibition of various enzymatic and cellular activities, were investigated. MP-3 was found to be the least active in inhibiting protein kinase C (PKC; activated by phosphatidylserine vesicles, synaptosomal membranes or phorbol ester), synaptosomal membrane Na,K-ATPase and proliferation and viability of leukemia HL60 cells. MP-3, however, was as active as others in inhibiting PKC activated by arachidonate monomers and phorbol ester binding. The unique properties of MP-3, the [des-Ile1-Asn2]-analogue of MP, might be related to its low functional amphiphilicity compared to others and useful in further delineating biological activities associated with or regulated by membranes.

Amino Acid Sequence↗
PubMed1992

Use of the polymerase chain reaction to detect hypermethylation in the calcitonin gene. A new, sensitive approach to monitor tumor cells in acute myelogenous leukemia.

Based on the recent observations that, in a majority of patients with acute leukemia, the 5' end of the calcitonin gene was hypermethylated and abnormal DNA fragments were observed following HpaII restriction digestion, we have developed a PCR-based method to sensitively detect this abnormal methylation of the calcitonin gene in AML. Applying the concept of competitive PCR, a semi-quantitative correlation was obtained between the amount of hypermethylation and the amount of leukemic cells present. These results suggest that this method will be useful to monitor the amount of tumor cells in bone marrow from patients with AML.

Base Sequence↗
PubMed1992

Strategies in the treatment of acute myelogenous leukemia.

The current treatment of acute myelogenous leukemia is far from satisfactory despite some recent advances. This review focuses on current strategies designed to improve treatment outcome. With advances in molecular biology, the definition of a complete remission should be redefined as a molecular remission where any abnormal gene rearrangement has disappeared or a clonal remission with morphologic characteristics of a complete remission, but with detectable genetics or molecular abnormalities. Abnormal gene rearrangements permit the detection of minimal residual disease, the significance of which remains to be determined. New drug development remains an important area of research and several new drugs are active in acute myelogenous leukemia. These include etoposide, idarubicin, mitoxantrone and carboplatin. Various combinations are undergoing clinical trials. Prognostic factors which predict for outcome include phenotyping, cytogenetics, cytokinetics, drug resistance and age. Proto-oncogene expression as a predictor of response is under investigation. Post-induction therapy remains controversial and approaches have included allogeneic bone marrow transplantation, autologous bone marrow transplantation with or without purging, intensive consolidation and maintenance programs. The superiority of one approach over the other has not been firmly established. Differentiating agents such as all-trans retinoic acid, and growth factors, the latter for supportive care, or recruitment of leukemic cells into the cycle are being investigated. Understanding the mechanisms of drug resistance should lead to the development of new approaches. Thus, with knowledge generated in many areas, the future should bring increasing success in treating AML.

Antineoplastic Agents↗
PubMed1992

Large granular lymphocyte proliferation with the natural killer-cell phenotype.

Lymphoproliferated disorders involving large granular lymphocytes (LGL) can be divided into a common T-cell subset (CD3+, CD8+) and a rarer natural killer (NK)-cell subset (CD2+, CD3-). The immunophenotype, clinical pathologic features, and cytogenetic and molecular genetic analyses are reported for seven patients with NK-cell-LGL proliferation. The typical immunophenotype was CD2+, CD3-, CD4-, CD11b+, and CD16+ or CD56+. A low but variable percentage of cells were CD8+ or CD57+. Unusual phenotypes with CD2- (1 of 7), CD11b- (1 of 7), or CD16-/CD56- (1 of 7) cells were seen. Strong NK-cell activity was observed in all cases, indicating that none of the NK-cell markers (CD11b, CD16, CD56, CD57) is essential for NK-cell activity. One patient died shortly after diagnosis from coexistent refractory multiple myeloma and another patient died within 1 month from the LGL proliferation. The other patients had been followed for 12 to 70 months, with a median follow-up period of 38 months. There was no progression of their LGL proliferation. Lymphocyte counts varied from 3.3 x 10(3)/microL to 58.4 x 10(3)/microL at the time of diagnosis. Unexplained anemia and neutropenia were observed in one patient. Cytogenetic abnormalities were detected in two of four patients studied with t(6;12) in one and der(5), der(6), and der(11) in the other. The approximately T gamma and T beta genes were in the germline configuration and Epstein-Barr virus DNA was undetectable in five of five patients studied. Natural killer-cell LGL proliferations were morphologically indistinguishable from T-cell LGL proliferations. However, the two were immunophenotypically and genotypically distinct and NK-cell activity was consistently observed in the former. Most of the NK-cell proliferations also were chronic indolent disorders and the incidence of associated cytopenias seemed to be lower than T-cell LGL proliferations.

Adult↗
PubMed1992

Late intensification therapy in adult acute lymphoid leukemia. The Southeastern Cancer Study Group Experience.

One hundred ninety-two evaluable patients were treated on a multicenter protocol for adult acute lymphoid leukemia to determine in a prospective randomized fashion if late intensification chemotherapy beginning after about six months of treatment would improve remission duration and survival. The complete remission rate was 60%. The median remission duration was 13.5 versus 25.9 months (P = 0.31) for standard maintenance therapy and late intensification, respectively, and the median survival was 17.5 versus 34.7 months (P = 0.19) respectively. Although there was a suggestion that the late intensification strategy was helpful, relapse proved to be common during the early phases of treatment; thus, insufficient numbers of patients were available at the randomization point to conclusively address the possible value of late intensification. Intensive therapy earlier in remission should be evaluated.

Adolescent↗
PubMed1992

A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study.

PURPOSE: A randomized clinical trial was undertaken to compare the therapeutic effectiveness of idarubicin (IDR) to daunorubicin (DNR), and both were given in combination with cytarabine (CA) in acute myelogenous leukemic (AML) patients. PATIENTS AND METHODS: Newly diagnosed patients were given a daily infusion of CA (100 mg/m2) for 7 days and were assigned randomly to receive DNR (45 mg/m2) or IDR (12 mg/m2) daily for the first 3 days. Those patients who achieved a complete remission (CR) were given three consolidation courses that consisted of CA (100 mg/m2 intravenously [IV]) and thioguanine (TG; 100 mg/m2 orally) every 12 hours for 5 days and either DNR (50 mg/m2) or IDR (15 mg/m2) on the first day of each cycle. After consolidation, patients received late intensification, which consisted of the same drugs used for induction except that the CA was given for 5 days and the anthracycline for 2 days. Four courses were planned at 13-week intervals. RESULTS: The CR rates were 75 of 105 (71%) on the IDR arm and 65 of 113 (58%) on the DNR arm (P = .03). The median survival and median remission durations were 297 and 433 days, respectively, on the IDR arm. The median survival and median remission durations were 277 and 328 days, respectively, on the DNR arm. Six deaths occurred during late intensification, five on IDR and one on DNR; this approach was abandoned after 47 patients were entered. The median survival was significantly longer for patients who received late intensification. CONCLUSION: This trial demonstrated that IDR was more effective than DNR in remission induction in AML.

Adolescent↗
PubMed1992

Phase II clinical trial of carboplatin in relapsed and refractory leukemia.

Carboplatin is a second-generation platinum complex drug which has demonstrated activity against a variety of neoplasms including acute leukemia, particularly when given by continuous intravenous (i.v.) infusion. Adults with acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL), either refractory or in first or second relapse, were given a continuous i.v. infusion of carboplatin at a dose of 315 mg/m2 daily for 5 days. A second course was given if the bone marrow at day 14 showed persistent leukemia. If the marrow was hypoplastic, treatment was delayed until marrow recovery was documented. Those with residual leukemia were given a second course. Those achieving complete remission (CR) were given an additional course as consolidation. Of the 46 eligible patients entered (36 AML and 10 ALL) eight achieved CR (17%) of which 6 were AML and 2 ALL. Of nine primary refractory patients, two achieved CR, one AML and one ALL. Excluding the inevaluable patients (protocol violations, patient refused further therapy, early deaths prior to day 14, the CR rate was eight of 28 (29%). All except two CRs required two courses of induction. The non-hematologic toxicity was minimal except for renal and auditory toxicity. Renal toxicity greater than grade 2 was seen in 17 patients and was associated with concomitant use of nephrotoxic antibiotics. In two patients, renal failure was a major factor in the cause of death. Ototoxicity was observed in 11 patients, but was grade 3 in only three. There were 18 deaths during the study. Fourteen died of infection, two died of infection and hemorrhage, one died of hemorrhage while aplastic, and one died of other causes. This trial indicates that carboplatin is an active agent in acute leukemia and warrants further investigation.

Bone Marrow↗
PubMed1991

Bone marrow transplant retinopathy.

Five of eight patients (62%) who survived at least six months after autologous or allogeneic bone marrow transplantation for acute leukemia developed occlusive microvascular retinopathy. Treatable retinal microangiopathy included a high incidence (80%) of clinically significant macular edema and one case of proliferative retinopathy with subhyaloid hemorrhage. The bone marrow transplant protocol required high-dose cytarabine hydrochloride and 1,200 cGy of total body irradiation. The development of radiation retinopathy after such low doses of teletherapy suggests that high-dose chemotherapy may increase the susceptibility for the development of retinopathy at otherwise safe radiation doses.

Adolescent↗
PubMed1991

Comparison of selective cytotoxicity of alkyl lysophospholipids.

Alkyl lysophospholipids have been shown to be cytooxic to a number of neoplastic tissues. One, ET-18-OCH3, has been used to selectively purge leukemic cells from mixtures with normal marrow progenitor cells, in vitro and in vivo. We have measured the 50% inhibitory (IC50) effect of a series of ether lipids (EL) on leukemic cells (HL60, K562, Daudi, KG-1, KG-1a) and normal marrow progenitor cells. Cells were incubated with varying concentrations of EL for 4 hr and assayed for viability, [3H]thymidine incorporation and clonogenicity in semi-solid media. The effect on protein kinase C (PKC) activity was assayed for each compound. Compounds tested included three glycerophosphocholine analogs--ET-18-OCH3, ET-16-NHCOCH3, and BM 41.440. In addition, a lipoidal amine, CP 46665, an ethyleneglycolphospholipid, AEPL, and four single chain alkylphosphocholine analogs, HePC2, HePC3, HePC4 and HePC6 were also tested. During the period of incubation, the cells remained viable (greater than 70%) as judged by trypan blue dye exclusion. The glycerophosphocholines were the most active and showed the highest therapeutic index. The lipoidal amine was active, but toxic to normal marrow progenitor cells. The ethyleneglycolphospholipid was active against HL60, but not against the other cell lines. The single chain alkylphosphocholine analogs were less active. All of the compounds inhibited PKC activity; however, the glycerophosphocholines were the most inhibitory.

Antineoplastic Agents↗
PubMed1991

Effects of hexadecylphosphocholine on protein kinase C and TPA-induced differentiation of HL60 cells.

Several structural analogs of alkylphosphocholine (APC) were studied for their effects on protein kinase C (PKC) and 12-O-tetradecanoylphorbol-13-acetate (TPA) elicited biochemical and cellular events in HL60 cells. Hexadecylphocholine (He-PC2), the APC prototype, inhibited PKC competitively with respect to phosphatidylserine an noncompetitively with respect to CaCl2, both with an apparent Ki of about 15 microM. Inhibition of PKC by He-PC2 was selective, since cyclic AMP dependent protein kinase and Ca2+/calmodulin dependent protein kinase II were relatively unaffected. He-PC2 inhibited TPA-induced depletion of PKC and TPA-stimulated phosphorylation of cellular proteins in HL60 cells. TPA-induced differentiation of HL60 cells was also inhibited by He-PC2, and this inhibition was synergistic or additive to the effects of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), a PKC inhibitor. The present findings are consistent with the hypothesis that inhibition of PKC might be related, in part, to the antineoplastic effect of He-PC2 and ether lipid analogs such as ET-18-OCH3 (1-octadecyl-2-methyl-glycero-3-phosphocholine).

Cell Differentiation↗
PubMed1990

Inhibition of protein kinase C, (sodium plus potassium)-activated adenosine triphosphatase, and sodium pump by synthetic phospholipid analogues.

The effects and modes of action of certain antineoplastic phospholipid analogues (racemic 1-O-octadecyl-2-O-methyl glycero-3-phosphocholine, BM 41.440, JH-1, CV-3988, and HePC) on (sodium plus potassium)-activated adenosine triphosphatase (Na,K-ATPase) and sodium pump activities were investigated. Inhibition of Na,K-ATPase in purified rat brain synaptosomal membranes by these lipids, in contrast to ouabain, was subject to membrane surface dilution and unaffected by whether the reaction was started with KCl, NaCl, or ATP. Kinetic analysis indicated that the analogues, again dissimilar to ouabain, were likely to interact directly or indirectly with sodium-binding sites of Na,K-ATPase located at the intracellular surface of the plasma membrane, a conclusion also supported by studies using the inside-out vesicles of human erythrocyte membranes. The studies also showed that ouabain (but not the lipids) increased the affinity constant of Na,K-ATPase for K+, whereas the lipids (but not ouabain) increased that for Na+. The lipids also inhibited 86Rb uptake by intact human leukemia HL60 cells at potencies quite comparable to those seen for inhibition of purified protein kinase C or Na,K-ATPase. It is suggested that Na,K-ATPase (sodium pump) might represent a hitherto unrecognized site of action for the lipid analogues, and that the antineoplastic effects of the agents might be due to, in part, inhibition of both protein kinase C and Na,K-ATPase and perhaps other membrane-associated enzymes.

Biological Transport, Active↗
PubMed1990

Cross-resistance pattern of cell lines selected for resistance towards different cytotoxic drugs to membrane-toxic phospholipids in vitro.

The synthetic ether lipids ET-18-OCH3 and BM41.440 and a derivative, hexadecylphosphocholine, were tested for inhibition of [3H]-thymidine uptake into a Chinese hamster ovarian cell line (AUXBl) and its multidrug-resistant subline selected for colchicine resistance (CHRC5). The activity of all three compounds against the multidrug-resistant subline was equal to or higher than that against the parent line. The same result was found for their activity against a human leukemic lymphoblastic cell line (CEM/O) and its methotrexate-resistant subline (CEM/MTX). In contrast, two multidrug-resistant cell lines selected for resistance to Adriamycin, the mouse leukemia cell line P388/ADR and the murine sarcoma cell line S180/ADR, expressed modest cross-resistance to the lipids as measured by thymidine uptake. Experiments performed using the trypan-blue dye-exclusion assay yielded comparable results, although this system revealed a slightly different sensitivity in showing the cytotoxicity of the drugs. By this assay, modest cross-resistance for ET-18-OCH3 and BM41.440 to Adriamycin was found only after 24 h incubation and decreased after 48 h incubation, with almost equal sensitivity to both drugs being shown by the parental (P388/W) and resistant lines (P388/ADR). Furthermore, findings from a human tumor-cloning assay were in accordance with these data, although they did not indicate cross-resistance for the P388/ADR cell line. These results suggest that certain ether lipids and derivatives might represent valuable anticancer drugs warranting further study in the setting of resistant disease.

Animals↗
PubMed1990

Therapy of acute myelogenous leukemia in patients over the age of 50: a randomized Southeastern Cancer Study Group trial.

In a randomized trial, 299 evaluable patients with acute myelogenous leukemia, age greater than or equal to 51, were initially randomized to cytosine arabinoside, 100 mg/m2/day, by continuous intravenous infusion for seven days, plus either daunorubicin 45 mg/m2/day x 3 (DA), or m-AMSA 200 mg/m2/day x 3 days (MA). Complete remission (CR) rates were not significantly different, 47% for DA and 42% for MA. Toxicities were similar except that severe hepatic toxicity, serum bilirubin greater than or equal to 7 mg/dl, was more frequent in patients receiving MA (10%) than in patients receiving DA (4%), p less than 0.05. Deaths during induction were significantly more frequent in patients receiving MA (38%) than in patients receiving DA (25%), p = 0.018. Patients achieving a CR received thioguanine, cytosine arabinoside, and daunorubicin (TAD) for three cycles as consolidation. Among evaluable patients, 82/102 (80%) stayed in CR during these three cycles. Patients were then randomized to either no maintenance or to DA every 13 weeks x 4 cycles, at a dose slightly lower than used for induction. Remission duration was similar for the two maintenance programs, 10.7 months for no maintenance and 8.5 months for DA. The percentage of patients evaluable for maintenance achieving three year relapse-free survival was similar for the two maintenance programs, 28% for no maintenance and 21% for DA. However, overall survival was significantly greater (40 vs 12 months, p = 0.007) for patients receiving no maintenance therapy, due to greater survival after recurrence in these patients. At each phase of the study there were substantial numbers of non-evaluable cases, often due to incomplete evaluation of remission status. Of the 379 patients initially entered into the trial, 35% obtained a complete remission. Of all the patients who achieved a complete remission, 61% were both evaluable and in remission upon completion of the maintenance phase. Of these patients who completed the maintenance phase in remission, 15% were relapse free survivors three years following initiation of maintenance therapy. Overall, only 3.2% of patients who entered the trial (35% x 61% x 15%) were continuous relapse-free survivors three years into the maintenance phase.

Aged↗
PubMed1990

Ophthalmological and other toxicities related to cytosine arabinoside and total body irradiation as preparative regimen for bone marrow transplantation.

Cytosine arabinoside, 3 g/m2, every 12 h for 6 days, followed by fractionated total body irradiation, 200 cGy twice daily for 3 days, was administered to 39 adult patients undergoing bone marrow transplantation. Allogeneic transplant patients received cyclosporin and methotrexate for prophylaxis of graft-versus-host disease. There were 21 autologous transplants (16 with acute leukemia, four with an advanced stage of chronic myelocytic leukemia, and one with lymphoma) and 18 allogeneic transplants (14 with acute leukemia, two with an advanced stage of chronic myelocytic leukemia and two with myelodysplastic syndrome). Toxicities were compared between the two groups. There was a significantly greater degree and duration of mucositis and a greater frequency of radiation-type retinopathy developing in the allogeneic group, predominantly in those having had radiation for prophylaxis or treatment of central nervous system leukemia. Seven of 11 acute leukemic patients who received autologous transplants in remission survive. Two of seven acute leukemias who received allogeneic transplants while in remission survive. Although the increased morbidity, retinitis and mucositis, observed in the allogeneic group indicates that this regimen when combined with methotrexate and cyclosporin is too toxic, the results in autologous transplantation in acute leukemia in remission are encouraging.

Bone Marrow Transplantation↗