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M Edelstein

Publications and source records attributed to M Edelstein.

At least 19 recordsLinked to original sources
PubMed2001

Design, synthesis, and biological evaluation of analogues of the antitumor agent, 2-(4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469).

2-(4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469) is among the most highly and broadly active antitumor agents to have been evaluated in our laboratories and is currently scheduled to enter clinical trials in 2001. The mechanism or mechanisms of action of XK469 remain to be elaborated. Accordingly, an effort was initiated to establish a pharmacophore hypothesis to delineate the requirements of the active site, via a comprehensive program of synthesis of analogues of XK469 and evaluation of the effects of structural modification(s) on solid tumor activity. The strategy formulated chose to dissect the two-dimensional parent structure into three regions-I, ring A of quinoxaline; II, the hydroquinone connector linkage; and III, the lactic acid moiety-to determine the resultant in vitro and in vivo effects of chemical alterations in each region. Neither the A-ring unsubstituted nor the B-ring 3-chloro-regioisomer of XK469 showed antitumor activity. The modulating antitumor effect(s) of substituents of differing electronegativities, located at the several sites comprising the A-ring of region I, were next ascertained. Thus, a halogen substituent, located at the 7-position of a 2-(4-[(2-quinoxalinyl)oxy]phenoxy)propionic acid, generated the most highly and broadly active antitumor agents. A methyl, methoxy, or an azido substituent at this site generated a much less active structure, whereas 5-, 6-, 8-chloro-, 6-, 7-nitro, and 7-amino derivatives all proved to be essentially inactive. When the connector linkage (region II) of 1 was changed from that of a hydroquinone to either a resorcinol or a catechol derivative, all antitumor activity was lost. Of the carboxylic acid derivatives of XK469 (region III), i.e., CONH2, CONHCH3, CON(CH3)2, CONHOH, CONHNH2, CN, or CN4H (tetrazole), only the monomethyl- and N,N-dimethylamides proved to be active.

Animals↗
PubMed2001

Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors.

Most traditional cytotoxic anticancer agents ablate the rapidly dividing epithelium of the hair follicle and induce alopecia (hair loss). Inhibition of cyclin-dependent kinase 2 (CDK2), a positive regulator of eukaryotic cell cycle progression, may represent a therapeutic strategy for prevention of chemotherapy-induced alopecia (CIA) by arresting the cell cycle and reducing the sensitivity of the epithelium to many cell cycle-active antitumor agents. Potent small-molecule inhibitors of CDK2 were developed using structure-based methods. Topical application of these compounds in a neonatal rat model of CIA reduced hair loss at the site of application in 33 to 50% of the animals. Thus, inhibition of CDK2 represents a potentially useful approach for the prevention of CIA in cancer patients.

Alopecia↗
PubMed2001

Acetyl-coa: alcohol acetyltransferase activity and aroma formation in ripening melon fruits.

Melon varieties (Cucumis melo L.) differ in a range of physical and chemical attributes. Sweetness and aroma are two of the most important factors in fruit quality and consumer preference. Volatile acetates are major components of the headspace of ripening cv. Arava fruits, a commercially important climacteric melon. In contrast, volatile aldehydes and alcohols are most abundant in cv. Rochet fruits, a nonclimacteric melon. The formation of volatile acetates is catalyzed by alcohol acetyltransferases (AAT), which utilize acetyl-CoA to acetylate several alcohols. Cell-free extract derived from Arava ripe melons exhibited substantial levels of AAT activity with a variety of alcohol substrates, whereas similar extracts derived from Rochet ripe melons had negligible activity. The levels of AAT activity in unripe Arava melons were also low but steadily increased during ripening. In contrast, similar extracts from Rochet fruits displayed low AAT activity during all stages of maturation. In addition, the benzyl- and 2-phenylethyl-dependent AAT activity levels seem well correlated with the total soluble solid content in Arava fruits.

Acetates↗
PubMed2001

Gamma interferon is not required for arthritis resistance in the murine Lyme disease model.

Lyme arthritis is the most common complication following infection of human individuals with Borrelia burgdorferi sensu stricto. In mice, B. burgdorferi infection leads to arthritis of the tibiotarsal joints. Arthritis severity in mice is under host genetic control, as BALB/c mice developed mild arthritis but C3H/He mice developed severe disease following B. burgdorferi infection. To study the role of gamma interferon (IFN-gamma) in arthritogenesis, targeted mutant mice lacking the IFN-gamma receptor (IFN-gammaR) were infected by inoculation with B. burgdorferi. IFN-gammaR(-/-) and parental 129/SvEv mice developed mild arthritis of similar severity, as determined both by weekly tibiotarsal joint measurements and histopathology at 2 and 5 weeks postinfection. Both strains of mice had the same spirochetal burden in the joints, suggesting that the IFN-gammaR(-/-) mice were not impaired in controlling spirochetal expansion in vivo. The wild-type mice mounted a Th1 response, with a predominance of CD4(+) IFN-gamma(+) T cells observed by flow cytometry. In contrast, the IFN-gammaR(-/-) mice mounted a Th2 response, with a predominance of CD4(+) IL-4(+) T cells. As expected given their cytokine profile, the IFN-gammaR(-/-) mice produced fewer CD8(+) IFN-gamma(+) and MAC-1(+) IL-12(+) cells and less immunoglobulin G2a (IgG2a) than their wild-type counterparts. These results strongly suggest that IFN-gamma is not required for arthritis resistance or as part of an effective immune response against B. burgdorferi.

Animals↗
PubMed2000

The potential of Lagenaria rootstock to confer resistance to the carmine spider mite, Tetranychus cinnabarinus (Acari: Tetranychidae) in Cucurbitaceae.

Antibiosis and resistance of six Cucurbita and two Lagenaria accessions to the carmine spider mite, Tetranychus cinnabarinus Boisduval, were evaluated in the laboratory. Significant differences among accessions were observed three days after the inoculation of detached leaf discs. The Lagenaria accessions, Slawi and Sus, proved to be the most resistant to mites, with average populations of mite eggs, 87 and 95%, respectively less than that of the susceptible C. pepo accession, Orangetti. The Cucurbita accessions, Tace, Brava, Tetsukabuto, Phoenix and TZ-148 had mite egg totals 4, 9, 13, 26 and 40%, respectively, less than those of accession Orangetti. The Sus accession of Lagenaria was resistant to T. cinnabarinus from the four-leaf stage until fruit set in laboratory and field tests. Grafting the susceptible Brava onto Sus rootstock increased the resistance of the scion to the same level as that of non-grafted Sus. Grafting the susceptible Cucumis melo Noy Yizre'el on resistant or susceptible rootstocks of Cucurbita and Lagenaria accessions did not affect its susceptibility to T. cinnabarinus. The results indicate that resistance to T. cinnabarinus can be transferred by grafting from Lagenaria stocks to Cucurbita scions but not in the opposite direction.

Animals↗
PubMed1999

Preclinical efficacy of thioxanthone SR271425 against transplanted solid tumors of mouse and human origin.

A highly active and broadly active thioxanthone has been identified: N-[[1-[[2-(Diethylamino)ethyl]amino]-7-methoxy-9-oxo-9H-thioxanthen++ +-4-yl] methylformamide (SR271425, BCN326862, WIN71425). In preclinical testing against a variety of subcutaneously growing solid tumors, the following %T/C and Log10 tumor cell kill (LK) values were obtained: Panc-03 T/C = 0, 5/5 cures; Colon-38 (adv. stage) T/C = 0, 3/5 cures, 4.9 LK; Mam-16/C T/C = 0, 3.5 LK; Mam-17/0 T/C = 0, 2.8 LK; Colon-26 T/C = 0, 1/5 cures, 3.2 LK; Colon-51 T/C = 0, 2.7 LK; Panc-02 T/C = 0, 3.1 LK; B16 Melanoma T/C = 13%, 4.0 LK; Squamous Lung-LC12 (adv. stage) T/C = 14%, 4.9 LK; BG-1 human ovarian T/C = 16%, 1.3 LK; WSU-Brl human breast T/C = 25%, 0.8 LK. The agent was modestly active against doxorubicin (Adr)-resistant solid tumors: Mam-17/AdrT/C =23%, 0.8 LK; and Mam-16/C/Adr T/C = 25%, 1.0 LK, but retained substantial activity against a taxol-resistant tumor: Mam-16/C/taxol T/C = 3%, 2.4 LK. SR271425 was highly active against IV implanted leukemias, L1210 6.3 LK and AML1498 5.3 LK. The agent was equally active both by the IV and oral routes of administration, although requiring approximately 30% higher dose by the oral route. Based on its preclinical antitumor profile, it may be appropriate to evaluate SR271425 in clinical trials.

Animals↗
PubMed1998

Hemorrhagic ascites due to congestive heart failure.

Ascites due to congestive heart failure (CHF) is characteristically serous in gross appearance. Although hemorrhage into ascites commonly indicates a malignant or inflammatory cause, cirrhosis of the liver is a well known cause of bloody ascites. We report a case of hemorrhagic ascites due to biventricular congestive heart failure in which workup for other causes was negative and hemorrhage cleared after 4 months. In as much as the mechanism of ascites is similar in both cirrhosis and CHF, we propose that a similar mechanism could cause bleeding into ascites in CHF.

Aged↗
PubMed1998

In vitro screening model for the detection of agents active against myelogenous leukemia.

This study was directed at defining the optimal in vitro screening methodology for the selection of new anti-myelogenous leukemia agents. Using thousands of samples of synthetic compounds from the Eastman Pharmaceutical, Inc. and Sterling Research Corporation (Eastman/Sterling) inventory, a number of sequential combinations of 8 cell lines were employed to optimize the model. The cells in these lines were of either murine (L1210 lymphocytic leukemia, C1498 myelogenous leukemia, and colony-forming unit-granulocyte macrophage [CFU-GM]) or human (HL-60, K-562, HEL, and THP-1 myelogenous leukemias, and CFU-GM) origin. The focus of the study was to find the most efficient and cost-effective manner in which to test compounds for both cytotoxicity against the tumor cells and for differential cytotoxicity against tumor as compared with normal cells.

Animals↗
PubMed1996

4-Hydroperoxycyclophosphamide purged autologous bone marrow transplantation in non-Hodgkin's lymphoma patients at high risk of bone marrow involvement.

Between June 1990 and January 1994, 19 patients with non-Hodgkin's lymphoma (NHL) at high risk for bone marrow involvement underwent 4-hydroperoxycyclophosphamide (4-HC) purged bone marrow transplantation. Eleven patients had low grade, seven intermediate grade and one high grade NHL and 7/19 patients had received three or more previous chemotherapeutic regimens. Four patients were transplanted in first partial remission (PR) and the remainder in responsive relapse. Fourteen patients had bone marrow (BM) involvement at diagnosis and/or at relapse. The median times to granulocyte and platelet recovery were 26 and 29 days, respectively. There were two toxic deaths and one complete responder developed secondary AML at 31 months post-BMT. Seventeen of 18 evaluable patients achieved a complete remission (CR) and one patient a PR. Fourteen patients (74%) are progression-free at a median follow-up of survivors of 34 months (range 29-55). The 3 year event-free (EFS) and overall survival (OS) probabilities are both 67%. No statistically significant difference was seen between EFS or OS and BM involvement or histologic grade at diagnosis. At 29 months, 4/7 patients with a morphologically involved BM harvest had relapsed or died compared to 1/12 patients with negative BM (P = 0.03). These results are encouraging and warrant further investigation of 4-HC purging in NHL.

Adult↗
PubMed1995

Citizen participation and empowerment: the case of local environmental hazards.

Local environmental hazards place millions of citizens at risk of physical, emotional, and financial harm. While the discovery of such hazards can be fundamentally disempowering for individuals and communities, few scholars have examined the dynamics of empowerment in this context. We explore the relationships among forms of empowerment, citizen participation, and local environmental hazards, and offer a model of the processes of empowerment and disempowerment appropriate to a broad range of citizen issues. On the basis of this analysis we recommend a partnership approach to community decision making that is designed both to reduce the likelihood that local environmental hazards will develop and to minimize the disempowering impact of any threats that do occur.

Community Participation↗
PubMed1995

Prenatal stress prevents the desensitization of the corticosterone response to TFMPP by desmethylimipramine, but not by phenelzine, in adult male offspring.

Gravid female rats were subjected to one hour of restraint stress twice daily or left undisturbed from days 14-21 of gestation. Adult 105-day old male non-stressed (NS) and stressed (S) offspring were treated once daily with saline, desipramine (DMI) (10 mg/kg, sc) or phenelzine (5.0 mg/kg, sc) for 14 days. Twenty-four hours after the last injection, animals were challenged with saline or 1-(m-trifluoromethylphenyl)piperazine (TFMPP) (5.0 mg/kg, sc), a serotonin1B/2C (5-HT1B/2C) agonist, and plasma prolactin and corticosterone concentrations were measured one hour later. As compared to acute saline administration, TFMPP significantly increased prolactin and corticosterone concentrations in all groups. In NS offspring, both DMI and phenelzine treatment augmented the prolactin response, but blunted the corticosterone response, to TFMPP. In S offspring, the prolactin response to TFMPP also was augmented by phenelzine or DMI treatment, whereas the corticosterone response to TFMPP was blunted during phenelzine treatment. However, DMI treatment was not able to desensitize the corticosterone response to TFMPP in the S rats. The results indicate the adaptive capacity of 5-HT systems to DMI administration was compromised in adult animals exposed to stress in utero.

Adaptation, Physiological↗
PubMed1994

Exposure to threshold doses of nicotine in utero: I. Neuroendocrine response to restraint stress in adult male offspring.

Gravid female rats were injected subcutaneously with saline or nicotine (3.0 mg/kg and 0.05 mg/kg, bid) from day 4 to day 20 of gestation or were left undisturbed. In adult 120-day old male offspring, the ACTH, corticosterone and prolactin concentrations before, during (15, 30, 45 and 60 minutes) and after (30, 60, 90 and 120 minutes) one hour of restraint stress were studied. Baseline (non-stress) concentrations of each hormone were comparable among the groups. As compared to saline controls, ACTH concentrations were significantly higher during stress at 30 and 60 minutes in the high-dose nicotine (HN) animals, with the average ACTH concentration during stress also being significantly higher in the HN rats. Neither nicotine regimen affected the corticosterone response to stress at any time-point. The prolactin response to stress was significantly reduced in the HN group at 45 and 60 minutes as compared to saline controls, with the average prolactin concentration also reduced during stress. During recovery, average ACTH concentrations were significantly higher in the HN group, and significantly lower in the LN group, with no differences found for either corticosterone or prolactin. The results indicate that exposure to a high-dose of nicotine during gestation, and to a very low-dose as well, produced functional alterations in adult male offspring as manifested by abnormal neuroendocrine responses to restraint stress. However, the differences between the nicotine and saline controls were sometimes as great as between the non-injected controls and the saline controls. Thus, any conclusions drawn about the long-term effects of prenatal nicotine on neuroendocrine responsivity to stress must be tempered by the influence of the repeated injection procedure.

Adrenocorticotropic Hormone↗
PubMed1993

Myelodysplastic syndrome after cisplatin therapy.

Therapy-related myelodysplastic syndrome (tMDS) and acute nonlymphocytic leukemia (tANLL) are known late complications of cytotoxic drug therapy for hematologic malignancies, solid tumors, and nonmalignant conditions. The alkylating agents are often the causative agents, but a few reports have implicated cisplatin as an etiologic agent. Cisplatin has a significant impact on the treatment of a number of malignant neoplasms, including testicular and ovarian cancer, and is a part of several clinical trials for squamous cell carcinoma of the head and neck region. Given its increasing use, a complication as significant as tMDS is potentially important. In this article, the authors describe the case of a patient who had myelodysplastic syndrome develop after successful treatment for laryngeal cancer with cisplatin. The treatment included cisplatin in combination with 5-fluorouracil, followed by radiation therapy. The authors also present a review of articles in the literature regarding tMDS and tANLL occurrence after treatment with cisplatin-containing regimens. The authors conclude that cisplatin can be a leukemogenic agent. The drug may potentiate the leukemogenic effects of other alkylating agents and drugs that inhibit topoisomerase II action.

Anemia, Sideroblastic↗
PubMed1993

Autologous bone marrow transplant in acute myeloid leukemia in first remission.

PURPOSE: The Eastern Cooperative Oncology Group conducted a prospective study of postremission high-dose chemotherapy and autologous bone marrow transplantation (autoBMT) in a group of uniformly treated adults with de novo acute myeloid leukemia (AML) to evaluate whether intensive, myeloablative therapy in first complete remission (CR) could improve the disease-free survival. PATIENTS AND METHODS: After initial CR was induced by the combination of daunorubicin, cytarabine, and thioguanine, patients not eligible for allogeneic bone marrow transplantation (alloBMT) were offered autoBMT. Within a median of 2 months after CR, and without intervening postremission therapy, bone marrow was obtained, purged by exposure to 4-hydroperoxycyclophosphamide (4-HC), and cryopreserved. High-dose therapy consisted of oral busulfan over 4 days (16 mg/kg total) followed by intravenous (IV) cyclophosphamide 50 mg/kg daily for 4 days. The cryopreserved marrow was then reinfused. RESULTS: Of the 39 patients scheduled for autoBMT, four relapsed before transplantation. Two of the 35 (6%) transplant patients died of transplant-related complications, and 11 (33%) relapsed a median of 8 months after marrow reinfusion. No relapse has occurred after 24 months posttransplant. With a median follow-up of 31 months, the median disease-free survival period for all 39 patients has not been reached; however, 54% +/- 16% of patients are projected to be alive and disease-free at 3 years. CONCLUSION: Long-term, disease-free survival after autoBMT in AML seems to be better than the outcome after conventional-dose postremission therapy and rivals the results of alloBMT.

Adolescent↗
PubMed1992

Varying intensity of postremission therapy in acute myeloid leukemia.

The Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial in patients less than or equal to 65 years old (median, 44 years) to determine whether increasing the intensity of postremission therapy in acute myeloid leukemia (AML) would improve the outcome. After uniform induction therapy, patients in complete remission (CR) who were less than 41 years old and who had a histocompatible sibling underwent allogeneic bone marrow transplantation (alloBMT) (54 patients). The remainder of patients in CR were randomized to receive either 2 years of continuous outpatient maintenance therapy with cytarabine and 6-thioguanine (83 patients) or a single course of inpatient consolidation therapy consisting of 6 days of high-dose cytarabine plus 3 days of amsacrine (87 patients). The median duration of follow-up is now 4 years, and patients are included in the analyses of outcome regardless of whether they relapsed before starting the intended treatment. Four-year event-free survival (EFS) was 27% +/- 10% for consolidation therapy versus 16% +/- 8% for maintenance therapy (P = .068) and 28% +/- 11% versus 15% +/- 9% (P = .047) in patients less than 60 years old. The outcome for patients receiving alloBMT was compared with the subset of patients less than 41 years old who received consolidation therapy (N = 29) or maintenance therapy (N = 21). Four-year EFS was 42% +/- 13% for alloBMT, 30% +/- 17% for consolidation therapy, and 14% +/- 15% for maintenance therapy. AlloBMT had a significantly better EFS (P = .013) than maintenance therapy, but was not different from consolidation therapy. In patients less than 41 years old, 4-year survival after alloBMT (42% +/- 14%) did not differ from consolidation therapy (43% +/- 18%), but both were significantly better than maintenance therapy (19% +/- 17%), P = .047 and .043, respectively. The mortality rate for maintenance therapy was 0%, consolidation therapy, 21%; and alloBMT, 36%. Consolidation therapy caused an especially high mortality rate in the patients greater than or equal to 60 years old (8 of 14 or 57%). The toxicity of combined high-dose cytarabine and amsacrine is unacceptable, especially in older patients, and alternative approaches to consolidation therapy such as high-dose cytarabine alone need to be tested. In AML, a single course of consolidation therapy or alloBMT after initial CR produces better results than lengthy maintenance therapy. Although EFS and survival of alloBMT and consolidation therapy do not differ significantly, a larger number of patients need to be studied before concluding that they are equivalent.

Acute Disease↗