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Biomedical subjects

J Moreb

Publications and source records attributed to J Moreb.

At least 19 recordsLinked to original sources
PubMed2002

Treatment of refractory acute leukemia with timed sequential chemotherapy using topotecan followed by etoposide + mitoxantrone (T-EM) and correlation with topoisomerase II levels.

A phase I/II clinical study evaluated 17 patients with refractory/recurrent acute leukemia treated with 1.5 mg/m2/day topotecan on days 1-3 followed by etoposide (100 mg/m2/day)+mitoxantrone (10 mg/m2/day) on days 4, 5 and 9, 10. Timed sequential chemotherapy using the topoisomerase I-inhibitor topotecan before the topoisomerase II-inhibitors, etoposide+mitoxantrone (T-EM) treatment is proposed to induce topoisomerase II protein levels and potentiate the cytotoxic activity of the topoisomerase II-directed drugs. Fourteen patients had refractory and three had recurrent acute leukemia. The majority of patients were heavily pre-treated with greater than three re-induction chemotherapy regimens. Ten patients responded to T-EM treatment (59%). Four of seventeen (24%) had a complete remission and one had a partial remission. Four additional patients (24%) who scored complete leukemia clearance had no evidence of disease with complete white and red blood cell recovery but with platelet counts less than 100,000. The lack of platelet recovery in one patient having a partial response was scored as a partial leukemia clearance. The toxicity profile included major non-hematological toxicity including grade 3 mucositis (29%) and neutropenic fever (65%). Paired measurements of intracellular levels of topoisomerase II isoforms alpha and beta in leukemia blast cells (bone marrow) collected before (day 0) and after topotecan treatment (day 4) showed that a relative increase of topoisomerase IIalpha (Topo IIalpha) > or = 40% strongly correlated with response after T-EM treatment. Increased Topo IIalpha levels also corresponded to increased DNA fragmentation. Two patients who had an increase of Topo IIalpha of 20-25% had either a PR or PLC while patients with a < 10% increase showed no response to T-EM treatment. We conclude that timed sequential chemotherapy using topotecan followed by etoposide+mitoxantrone is an effective regimen for patients with refractory acute leukemia, and demonstrate Topo IIalpha protein level increases after topotecan treatment.

Acute Disease↗
PubMed1999

Morbidity and mortality following bone marrow transplantation: predictive utility of pre-BMT affective functioning, compliance, and social support stability.

This study investigated the utility of 3 pretransplant psychological variables (affective functioning, compliance, social support stability) in predicting subsequent bone marrow transplantation (BMT) health outcomes. The pre-BMT psychological evaluations of 92 BMT recipients were coded along the specified psychological dimensions and used to predict post-BMT survival status and health-related quality of life. Data analyses showed that, in addition to medical risk status (low) and quality of the marrow graft (histocompatible), higher levels of pre-BMT affective functioning and social support stability significantly predicted survival status (i.e., alive) and higher levels of quality of life. These findings have important implications for the role of psychological assessment prior to BMT and the need for interventions designed to enhance psychological functioning and subsequent health outcomes following BMT.

Journal Article↗
PubMed1998

Durable remission of locally advanced breast cancer with multimodality management.

We treated 20 women with locally advanced breast cancer between January 1991 and September 1996. The treatment regimen included 4 cycles of intensive doxorubicin (30 mg/m2/d on 3 consecutive days every 2 weeks with G-CSF support), followed by appropriate surgery, followed by high dose therapy with cyclophosphamide, carboplatin and thiotepa (STAMP V, CTCb). Of the 20 patients, seven presented with inflammatory breast cancer, three with Stage IIIB, seven with stage IIIA, one with multifocal Stage IIB and two with Stage IV M1 (ipsilateral supraclavicular lymph node involvement) (including one who had an inflammatory primary) disease. Six patients had not undergone mastectomy at the time of entering the protocol. These six received the doxorubicin in a neoadjuvant fashion and were thus evaluable for tumor response. The remaining 14 received doxorubicin as adjuvant therapy prior to intensification and transplantation. All patients underwent local-regional radiation therapy and were placed on oral tamoxifen. Doxorubicin was well tolerated in this schedule with all but three patients receiving all their cycles on schedule. Both BM and PBPC were easily collected after this regimen and, when reinfused, resulted in the prompt recovery of granulocytes (median 11 days to 500 absolute granulocyte count) and platelets (median 13 days to 20,000 platelets). The six patients who received doxorubicin prior to mastectomy all had major clinical responses, but were found to have microscopic focii of breast cancer in the mastectomy specimens. The overall treatment was well tolerated with the exception of one treatment-related death (5%). The overall and relapse free survival are 70% and 58% respectively with a median follow-up of 40 months (range 12-74 months). When the Stage IV patients are censored, the relapse-free survival rate is 69%. In the bone marrow transplant phase of treatment, the major non-hematologic toxicities were stomatitis (70%) and anorexia requiring parental nutrition (75%).

Adult↗
PubMed1998

Failure of intravenous ribavirin in the treatment of invasive adenovirus infection following allogeneic bone marrow transplantation: a case report.

We report a case of fatal adenovirus infection in a 37-year-old female who underwent allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML). Post BMT she developed acute grade II graft-vs.-host disease (aGVHD) requiring high-dose steroids and anti-thymocyte globulin. Additionally, her clinical course was complicated with adenovirus-associated haemorrhagic cystitis and viraemia. Intravenous ribavirin was obtained and administered for 5 days without success; the patient's mental status deteriorated rapidly and she died on day 69 post-transplant. Radiological imaging revealed diffuse cortical necrosis. At autopsy adenovirus was identified in her bladder, kidneys and lungs.

Adenovirus Infections, Human↗
PubMed1995

Improved survival of patients with chronic myelogenous leukemia undergoing allogeneic bone marrow transplantation.

A total of 28 patients with chronic myelogenous leukemia (CML) in chronic phase (CP) received bone marrow allografts from HLA-matched siblings at the University of Florida between August 1984-July 1992. The present study compares the disease-free survival (DFS) for those patients who were transplanted before or after August 1988 using the same conditioning regimen. The analysis shows significant difference in 3-year DFS for those patients transplanted post- vs. pre-August 1988 (69.6% vs. 20%, respectively; P = 0.006). A decrease in pneumonitis due to different etiologies from pre-August 1988 (6/13, 46%) to post-August 1988 (1/15, 7%) was statistically significant (P = 0.029). A decrease, although statistically insignificant, in the overall incidence and severity of acute and chronic graft vs. host disease (GVHD) after August 1988 was also noticed. This study indicates significantly improved outcome for patients with CML in CP who have been treated in the University of Florida after August 1988. Better supportive care and prophylaxis for GVHD most likely contributed to such improvement.

Adult↗
PubMed1995

Multiorgan failure associated with lomustine overdose.

OBJECTIVE: To report a lomustine overdose in a patient with anaplastic astrocytoma. CASE SUMMARY: A 28-year-old woman with anaplastic astrocytoma was treated with partial resection and radiation therapy followed by a lomustine-containing regimen. The patient took lomustine 1400 mg po over a week, her regular dose being 200 mg on day 1 of the regimen. Pancytopenia developed within a week after the last dose of lomustine and the patient was admitted to the bone marrow transplant unit for supportive care. About 3 weeks later, the patient gradually developed a multiorgan dysfunction, including liver, brain, and lungs without evidence of infection or tumor progression, and died on day 45 of hospitalization. DISCUSSION: This is the third reported case of lomustine overdose that resulted from supplying the patient with more tablets than needed for 1 dose. Although late hematopoietic recovery may be possible after such a high dose of lomustine, other organ toxicities might be detrimental. CONCLUSIONS: Physicians and pharmacists should avoid supplying more tablets than needed for 1 lomustine dose. High doses of lomustine may cause irreversible multiorgan toxicities.

Adult↗
PubMed1994

Role of manganese superoxide dismutase in radioprotection using gene transfer studies.

Overexpression of manganese superoxide dismutase (MnSOD) has been postulated as one possible mechanism of radioprotection for hematopoietic cells. In this study retroviral constructs having the human MnSOD gene in both the sense and antisense orientations and the Neo-R gene as a selectable marker were transfected into the human erythroleukemic cell line K562 and the human melanoma cell line A375 by electroporation. Stably transfected K562 and A375 cells selected in G418 for 3 weeks were subjected to various doses of irradiation, and cell viability was assayed using a colony assay system in semisolid medium. Results demonstrated that K562 cells transfected with MnSOD in the antisense orientation displayed increased sensitivity to irradiation compared to parental or vector-transfected K562 cells. In contrast, A375 cells transfected with the sense MnSOD gene demonstrated increased resistance to irradiation compared to parental or vector-transfected A375 cells. The expression of the MnSOD gene in these transfected cell lines correlates with the up- or down-modulation of radiosensitivity. Thus, increased MnSOD protein was seen in the A375 cells containing the sense MnSOD, whereas decreased MnSOD protein was seen in the K562 cells containing the antisense MnSOD. These data provide evidence for the direct role of MnSOD in radioprotection using antisense gene transfer/inhibition studies.

Base Sequence↗
PubMed1994

Radioprotection of hematopoietic stem cells by interleukin-1.

Radioprotective agents such as interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha), when given prior to irradiation, protect animals from radiation damage. However, in vivo administration of these cytokines does not allow one to determine whether the protective effects act directly on the hematopoietic system. In the present study, we subjected male bone marrow cells to in vitro treatment with IL-1 prior to irradiation and bone marrow transplantation. We found that male bone marrow cells pretreated with IL-1 prior to irradiation increased the survival of irradiated female recipient mice when compared with nontreated irradiated marrow cells. In addition, irradiated female recipients that received IL-1-pretreated male donor bone marrow cells displayed an increased presence of male donor cells in their bone marrow, spleen, and thymus for up to 3 months posttransplant. Furthermore, serial transplantation studies revealed that male cells could only be detected in tertiary female recipients who received bone marrow from mice transplanted with IL-1-treated cells. These results indicate that IL-1 pretreatment protects both short-term and long-term repopulating stem cells from an irradiation insult and that these cells are capable of reconstituting the myeloid and lymphoid organs of recipient mice.

Animals↗
PubMed1993

A role for manganese superoxide dismutase in radioprotection of hematopoietic stem cells by interleukin-1.

Pretreatment with interleukin-1 (IL-1) has been shown to protect mice from the myelotoxicity associated with irradiation via a mechanism potentially mediated through the induction of the antioxidant enzyme manganese superoxide dismutase (MnSOD). In this study, we have compared the ability of IL-1 to induce MnSOD mRNA in murine bone marrow cells and human cell lines with its ability to protect these cells against the damaging effects of ionizing radiation. Bone marrow cells obtained from mice 6 hours after a single injection of IL-1 demonstrate a dose-dependent increase in the expression of MnSOD RNA. In this same study, IL-1 was also shown to be radioprotective when given to mice 20 hours before lethal irradiation. Similarly, in vitro treatment with IL-1 of bone marrow cells isolated from 5-fluorouracil-treated mice results in elevated levels of MnSOD RNA. Pretreatment with IL-1 also protected bone marrow long-term culture-initiating cells capable of reconstituting irradiated stromal cultures from an irradiation insult. Furthermore, IL-1-treated human bone marrow cells display both elevated MnSOD RNA and protein levels when compared with media controls. The human A375 melanoma, A549 adenocarcinoma, and factor-dependent TF-1 leukemic cell lines demonstrate low basal MnSOD RNA levels that increase following treatment with IL-1. For the A375 cells, this correlates with increased MnSOD protein expression and radioprotection by IL-1 using a colony assay. In contrast, the chronic myelogenous leukemic cell line, K562, displays a high basal MnSOD RNA level, and this RNA expression is not further increased by IL-1 treatment. In addition, these cells are comparatively radioresistant and are not further protected by IL-1 treatment. Finally, the Mo-7 cell line displays a low basal level of MnSOD RNA that correlates with a high sensitivity to irradiation and IL-1 pretreatment has no effect on MnSOD RNA levels. Our results indicate that increased radioprotection by IL-1 correlates with the induction of the antioxidant enzyme MnSOD and this induction may be an important factor in IL-1 radioprotection.

Adult↗
PubMed1992

Role of aldehyde dehydrogenase in the protection of hematopoietic progenitor cells from 4-hydroperoxycyclophosphamide by interleukin 1 beta and tumor necrosis factor.

Preincubation of human bone marrow cells with interleukin 1 beta (IL-1) and tumor necrosis factor alpha (TNF-alpha) for 20 h can protect early progenitor cells from 4-hydroperoxycyclophosphamide (4-HC) toxicity. In this report, we have studied the mechanism for such protection. We examined the effect of the length of incubation time and found that preincubation for at least 20 h with IL-1 and TNF-alpha is needed for significant protection. The addition of 2 micrograms/ml cycloheximide, a protein synthesis inhibitor, during the 20-h preincubation completely abolished the protection observed for all colony-forming cells. In order to study the role of aldehyde dehydrogenase (ALDH), an enzyme which inactivates 4-HC, we used diethylaminobenzaldehyde, an inhibitor of ALDH. Diethylaminobenzaldehyde was added during the last 10 min of the 20-h preincubation with IL-1 and TNF-alpha. Diethylaminobenzaldehyde prevented the protection of colony-forming cells from 4-HC. Finally, using the same protection assay system, we showed that a 20-h preincubation with IL-1 and TNF-alpha can also protect early progenitor cells from phenylketophosphamide, an analogue of 4-HC which is resistant to inactivation by ALDH. From these studies, we conclude that preincubation with IL-1 and TNF-alpha for at lest 20 h is required for the protection of early progenitor cells from 4-HC. During that time period, protein synthesis, specifically aldehyde dehydrogenase synthesis, is critical for the protection from 4-HC. Preincubation with IL-1 and TNF-alpha also protects early progenitors from phenylketophosphamide. Because phenylketophosphamide cannot be metabolized by ALDH, the reason for this protection must be due to other, as yet unidentified, mechanisms.

Adult↗
PubMed1992

The therapeutic potential of interleukin-1 and tumor necrosis factor on hematopoietic stem cells.

Dose intensity is emerging as a crucial determinant of success in cytotoxic cancer therapy; however, myelosuppression presents as one of the major complications encountered with increased dose intensity. Therefore, investigators are looking at the use of cytokine administration in combination with cytotoxic therapy to overcome this problem. Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) have been shown to be beneficial in protecting the hematopoietic system from radiation and chemotherapy. In this report, we give an overview of studies using IL-1 and TNF-alpha as protective agents and discuss possible mechanisms involved in their protective action. Mice pretreated with IL-1 and/or TNF-alpha were shown to be protected from the lethal effects of radiation and it has been suggested that the mechanism for this protection may be through the production of the antioxidant enzyme manganese superoxide dismutase. Similarly, aldehyde dehydrogenase, an enzyme important in the metabolic pathway of cyclophosphamide compounds, has been implicated as being important in the protection of hematopoietic cells from 4-hydroperoxycyclophosphamide. While IL-1 and TNF-alpha stimulate both of these enzymes, other mechanisms are probably also operative for other forms of chemotherapy, i.e. IL-1 and TNF-alpha were shown to protect hematopoietic progenitors from phenylketophosphamide, a cyclophosphamide derivative that is not metabolized by the enzyme aldehyde dehydrogenase. Furthermore, malignant as well as normal cells may possess receptors for these cytokines; therefore, IL-1 and TNF-alpha will have to be selective in their protection. They must be capable of protecting normal hematopoietic cells while rendering malignant cells susceptible to the toxic actions of the chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Protection of cells capable of reconstituting long-term bone marrow stromal cultures from 4-hydroperoxycyclophosphamide by interleukin 1 and tumor necrosis factor.

The cytokines interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) have been implicated in protecting normal hematopoiesis from both irradiation and chemotherapy damage. The mechanism of action of these cytokines and which cells are protected is not known. In this study, we report on the ability of IL-1 and TNF-alpha to protect hematopoietic cells capable of repopulating irradiated long-term bone marrow stromal cultures from 4-hydroperoxycyclophosphamide (4-HC). Irradiated long-term bone marrow cultures recharged with hematopoietic cells pretreated with IL-1 and TNF-alpha prior to 4-HC were shown to give rise to greater numbers of colony-forming cells at 4-5 weeks of culture within both the nonadherent and adherent cell populations of the long-term cultures when compared to controls. These results suggest that IL-1 and TNF-alpha can protect human long-term culture-initiating cells, which are closely related to reconstituting stem cells.

Bone Marrow↗