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Biomedical subjects

N Hamdy

Publications and source records attributed to N Hamdy.

9 recordsLinked to original sources
PubMed1999

Treatment of a de novo fludarabine resistant-CLL xenograft model with bryostatin 1 followed by fludarabine.

WSU-CLL is a de novo fludarabine resistant cell line established from a patient with advanced chronic lymphocytic leukemia (CLL) refractory to chemotherapy including fludarabine (Flud). Our previous studies indicate that bryostatin 1 (Bryo 1) induces differentiation of WSU-CLL and increases the ratio of dCK/5'-NT activity and Bax/Bcl-2. This study tests the hypothesis that Bryo 1-differentiated cells are more susceptible to Flud than the parent WSU-CLL cells. Flud, given sequentially after Bryo 1, in vitro and in vivo animal studies resulted in significantly higher rates of growth inhibition and improved animal survival. Flud at 100 to 600 nM exhibited a dose-dependent growth inhibitory effect on the WSU-CLL cell line. The sequential exposure to Bryo 1 (10 nM for 72 h) followed by Flud (100 nM) resulted in significantly higher rates of growth inhibition than either the reverse addition of these two agents or each agent alone, but was not significantly different than the concurrent addition of Bryo 1 + Flud. Using 7-amino-actinomycin D staining and flow cytometry, apoptosis was seen in 40.8% of cells treated with Bryo 1 (10 nM, 72 h) followed by Flud, compared with Flud (100 nM, 72 h) followed by Bryo 1 (18.1%). To demonstrate that Bryo 1 enhancement of Flud efficacy was not restricted to in vitro culture, we used the WSU-CLL xenograft model in mice with severe combined immune deficiency (SCID). Bryo 1 + Flud at the maximum tolerated doses (75 microg/kg i.p. and 200 mg/kg i.v., respectively) were administered to mice in different combinations. The survival in days, the tumor growth inhibition ratio (T/C), the tumor growth delay (T-C) in days, log10 kill, as well as mean tumor weight (mtw) of mice treated with Bryo 1 followed by Flud, were significantly better than control and other groups. T/C%, T-C, log10 kill and mtw were as follows: Bryo 1 (36.8%, 10 days, 0.8, 375 mg); Flud (100%, 0. 0 day, 0.0, 1130 mg); Bryo 1 + Flud (14.3%, 12 days, 0.95, 288 mg); Bryo 1 followed by Flud (4.6%, 17 days, 1.35, 35 mg); Flud followed by Bryo (40.3%, 10 days, 0.80, 175 mg). We conclude that: i) Bryo 1 sensitizes WSU-CLL cells to Flud and enhances apoptosis; ii) the sequential treatment with Bryo 1 followed by Flud resulted in higher anti-tumor activity compared with either agent alone, in combination, or the reverse addition of these agents and iii) these results are comparable to those of Bryo 1 followed by 2-CdA suggesting common pathway(s) of interaction between Bryo 1 and purine analogues.

Animals↗
PubMed1999

A new tubulin polymerization inhibitor, auristatin PE, induces tumor regression in a human Waldenstrom's macroglobulinemia xenograft model.

Waldenstrom's macroglobulinemia (WM) is an uncommon lymphoproliferative disease which remains incurable with current treatment protocols. We have previously established a permanent WM cell line, WSU-WM, which grows as a xenograft in severe combined immune deficient (SCID) mice. In this study, we investigated the anti-tumor effects of auristatin PE (a structural modification of the marine, shell-less mollusk peptide constituent dolastatin 10). WSU-WM cells were cultured in RPMI-1640 at a concentration of 2x10(5) cells/ml using 24-well plates. Auristatin PE or dolastatin 10 were added to triplicate wells and cell count and viability were assessed after 24, 48 and 72 h. Results showed that both agents were active against WSU-WM, and were able to induce complete growth inhibition at 100 pg/ml. The efficacy of these agents in vivo was evaluated using the WSU-WM SCID mouse xenograft model. Auristatin PE and dolastatin 10 were given i.v. via tail vein at 2.0 mg/kg and 0.2 mg/kg, respectively. The agents were given every second day for three injections which represent the maximum tolerated doses. Tumor growth inhibition (T/C), tumor growth delay (T-C), and log10 kill for auristatin PE and dolastatin 10 were 0%, 18 days, 2.83 and 67%, 2 days, 0.06, respectively. Based on these animal results, dolastatin 10 was inactive while auristatin PE was highly active. We therefore focused further investigation on auristatin PE to understand some of its mechanisms of action. Using two flow cytometry assays, propidium iodide for cell cycle analysis and 7-amino actinomycin D (7AAD) to detect apoptosis, we were able to demonstrate that auristatin PE at 10 pg/ml after 24 h arrested 50% of WSU-MW cells in G2M. Concomitantly, 31% of auristatin PE-treated cells entered apoptosis. By 72 h, greater than 75% of the cells became apoptotic. The activity of auristatin PE should be evaluated in other tumor types and in clinical trials.

Animals↗
PubMed1998

Potentiation of 2-chlorodeoxyadenosine activity by bryostatin 1 in the resistant chronic lymphocytic leukemia cell line (WSU-CLL): association with increased ratios of dCK/5'-NT and Bax/Bcl-2.

The activities of 2-chlorodeoxyadenosine (2-CdA) metabolizing enzymes, deoxycytidine kinase (dCK) and cytosolic 5'-nucleotidase (5'-NT) were measured in control and bryostatin 1 treated CLL cells using an EBV-negative WSU-CLL cell line. This cell line was established from a patient with CLL resistant to fludarabine. The results revealed a significant increase in dCK activity in bryostatin 1 treated cells at 48 and 72 h compared with the control. 5'-NT activity decreased significantly at 48 h. The ratio of dCK to 5'-NT activity was significantly increased in bryostatin 1 treated WSU-CLL cells after 48 h. WSU-CLL cells treated with bryostatin 1 exhibited an increase in the percentage of apoptotic and dead cells from control levels of 16% to 40%. This percentage was further increased to 67% following the addition of 11.2 microM 2-CdA to WSU-CLL cells pretreated with bryostatin 1. Results from Western blot analysis indicate that WSU-CLL cells express high levels of Bcl-2, Bcl-xL and c-myc, and a low level of Bax. p53 in untreated WSU-CLL cells is undetectable. WSU-CLL cells treated with bryostatin 1 showed a significant increase in the ratio of Bax to Bcl-2. To demonstrate that the bryostatin 1 mediated enhancement of 2-CdA efficacy was not restricted to in vitro cell culture, we have studied the tumor growth delay of WSU-CLL xenografts treated with placebo, bryostatin 1, 2-CdA, and bryostatin 1 followed by 2-CdA. SCID mice given bryostatin 1 at 75 microg x kg(-1) x d(-1) for 5 days followed by 30 mg x kg(-1) x d(-1) 2-CdA for 5 days in two cycles, had significantly improved tumor growth delay (P = 0.05). We conclude that bryostatin 1 is not only capable of inducing apoptosis by itself, but also sensitizes de novo resistant WSU-CLL cells to the chemo-therapeutic effects of 2-CdA. The bryostatin 1-induced increased ratio of dCK/5'-NT activity and an increased ratio of Bax/Bcl-2 are at least two mechanisms through which this natural compound is able to potentiate the anti-tumor activity of 2-CdA in otherwise resistant CLL cells.

5'-Nucleotidase↗
PubMed1995

Mutations in the coding region of c-myc occur independently of mutations in the regulatory regions and are predominantly associated with myc/Ig translocation.

Constitutive expression of c-myc resulting from a chromosomal translocation, which juxtaposes c-myc to an immunoglobulin gene, is a pivotal lesion in Burkitt's lymphomas. This deregulated expression of c-myc is associated with mutations in the regulatory regions, i.e. the first exon and the first intron of c-myc in tumors where the chromosomal breakpoint is not itself within the regulatory region. Until recently it was widely believed that the c-myc protein in these tumors is wild type. We have demonstrated that in a fraction of Burkitt's lymphomas from Africa and from the continental USA, and in mouse plasmacytomas, the c-myc gene carries mutations in the coding region. We now show that, occasionally, such mutations are also present in multiple myelomas--tumors which do not carry translocations or amplifications of c-myc. We also show that the frequency of the c-myc coding region mutations in BL is independent of the frequency of mutations in the regulatory region. These results suggest that the mechanisms that induce missense mutations involving the coding region of c-myc may be different from those that lead to mutations in the regulatory regions.

Burkitt Lymphoma↗
PubMed1995

Molecular epidemiology of acute lymphoblastic leukemia in Egypt.

We have characterized immunophenotypically defined acute lymphoblastic leukemia (ALL) in Egypt for rearrangements of the antigen receptor genes, and correlated this with rearrangements of ALL-1 and the presence of p53 mutations. Thirty-nine cases were analyzed for rearrangements of the immunoglobulin (Ig) and T-cell receptor (TCR) genes. All precursor B-cell ALLs (12 cases) contained rearranged Ig heavy-chain (JH) region which was biallelic in 92% of these tumors. In addition to JH rearrangements, TCR delta, beta and gamma rearrangements were observed in 80, 40 and 30% of these cases, respectively. TCR genes were invariably rearranged in T-cell ALLs (11 cases). A small fraction (2/11) of T-cell ALL showed concurrent IgJH rearrangement which was monoallelic. Simultaneous rearrangement of IgJH and TCR genes was also observed in both cases of biphenotypic ALL (coexpressing B and T markers). We observed marked heterogeneity in the pattern of rearrangement of antigen receptor genes in mixed-lineage leukemias (ALL coexpressing myeloid-associated markers), including the retention of germline configuration in two cases. Rearrangements of the ALL-1 gene were confined to the leukemias that demonstrated lineage infidelity. Mutations in p53 were infrequent and were present in only three of 47 ALL cases (6%) analyzed; two of these were mixed-lineage leukemias. These results suggest that mixed-lineage and biphenotypic leukemias accumulate pathogenetic lesions that are distinct from B- and T-cell ALL, and that ALL in developing countries includes molecular entities similar to those in developed countries.

Adolescent↗
PubMed1994

Mutations in the coding region of c-myc occur frequently in acquired immunodeficiency syndrome-associated lymphomas.

We have analyzed 30 cases of high- and intermediate-grade acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma (AIDS-NHL) for mutations in the c-myc coding region. In addition, in these same tumors, we have sought the presence of mutations in a regulatory region within the first c-myc intron defined by the binding to a factor that inhibits c-myc transcription (MYC intron factor, or mif). Mutations in the c-myc coding region were present in 10 of 16 small noncleaved cell lymphoma (SNCL), but in only 3 of 14 other histologic subtypes tested (0/3 large non-cleaved cell, 2/8 immunoblastic, and 1/3 anaplastic large cell lymphomas). Nineteen of the AIDS-NHLs analyzed contained a c-myc rearrangement and in 10 of these the c-myc gene was mutated in its coding region. In contrast, we could detect a mutation in the coding region in only 2 of 8 AIDS-NHL without a c-myc rearrangement. Mutations in the mif region were detected in 5 of 16 SNCL. Among AIDS-NHL carrying mutations in the c-myc coding region, only 4 carried mutations in the regulatory region. These results suggest that the mutations in the coding region of the c-myc protein may either be a consequence of the translocations involving c-myc, or may be necessary only in tumors where c-myc is deregulated as a result of a c-myc/lg translocation.

Base Sequence↗
PubMed1985

Hyperparathyroid bone disease in chronic renal failure.

Much has been learnt over the past 80 years of the pathogenesis and management of hyperparathyroid bone disease in uraemia. Clinically it has changed from a rare disorder of childhood and adolescence to a common and difficult problem in patients maintained on dialysis programmes. Whereas effective treatments are now available for hyperparathyroid bone disease, these are not curative and there is clearly much more work to be done before a full understanding of its pathogenesis, and the best methods of treatment and prevention, can be reached.

Bone Diseases↗
PubMedDate not supplied

Double-blind controlled trial of prostacyclin in cerebral infarction.

Thirty-two patients with acute cerebral infarction received either prostacyclin or placebo intermittently for 65 hours. Pulse and blood pressure were not altered by prostacyclin. After infusion there was no change in infarct volume or cerebral blood flow in either group. After normalisation for starting values, age and site of cerebral infarction there was a greater than 10% improvement in speech in the prostacyclin group, but minimal changes in neurological score or disability status. Age is related to neurological score at 14 days after stroke by decreasing improvement by 6.8% for each additional 10 years. This study has not been able to demonstrate that prostacyclin is effective in the treatment of ischaemic stroke, but due to the sample size the chance of proving this statistically (the power) was small. Similarly any conclusion that prostacyclin is not effective may be wrong because of the Type II error probability being high.

Aged↗