Biomedical subjects

F M Uckun

Publications and source records attributed to F M Uckun.

At least 109 records · Page 6Linked to original sources

PubMed2000

Role of PRKCM (PKCmu) in radiation-induced increase of JUN proto-oncogene mRNA levels in B-lineage lymphoid cells.

Exposure of cells to ionizing radiation results in both activation of protein kinase C (PRKC, also known as PKC) and induction of transcription of the JUN proto-oncogene. PRKC plays a pivotal role in radiation-induced JUN expression, since inhibition of PRKC abrogates the JUN signal. However, the specific PRKC isoforms involved in radiation-induced elevation of JUN mRNA levels have not been identified. Here we demonstrate that in DT40 B-lineage lymphoid cells, the mu isoform of PRKC (PRKCM) is critical for the response of JUN to ionizing radiation. The zinc chelator, 1, 10-phenanthroline, abrogated induction of JUN after exposure to ionizing radiation, indicating that this PRKCM-mediated response is also dependent on zinc.

Animals↗

PubMed2000

Cathepsin inhibition induces apoptotic death in human leukemia and lymphoma cells.

We examined the effects of cathepsin inhibitor 1 (CATI-1), a selective inhibitor of cysteine cathepsins, on human leukemia and lymphoma cells. CATI-1 induced apoptosis in all 12 cell lines tested. Apoptosis of CATI-1-treated leukemia/lymphoma cells was caspase-independent, p53-independent, BAX-independent as well as MAP kinase-independent. Our findings provide unprecedented experimental evidence that cathepsins play a pivotal role for the survival of human leukemia/lymphoma cells. Therefore, cathepsin inhibitors may provide the basis for new treatment programs against leukemia and lymphoma.

Apoptosis↗

PubMed2000

Clinical significance of deletions of chromosome arm 6q in childhood acute lymphoblastic leukemia: a report from the Children's Cancer Group.

We have compared outcome for 167 (9.0%) children with a del(6q) and 1713 (91%) children without a del(6q) treated on Children's Cancer Group (CCG) risk-adjusted treatment protocols for acute lymphoblastic leukemia (ALL). Thirty-three patients had a del(6q) as the sole aberration; 22 patients had a del(6q) only as a secondary abnormality. Thirty-six cases had a del(6q) and high hyperdiploidy (>50 chromosomes). Six patients with a del(6q) also had +16 and 8 patients had loss of a sex chromosome. Frequent recurring breakpoints were q13, q15, q21, q23, and q25. Patients with a del(6q) were more likely to have T-lineage ALL (p < 0.001), a mediastinal mass (p = 0.01), and higher WBC counts (p = 0.04), although only half of these patients were classified as poor risk. Event-free survival at 6 years was similar for patients with or without a del(6q), with estimates of 77% (SD = 5%) and 74% (SD = 2%), respectively (p = 0.44). This finding was also observed within NCI poor and standard risk groups. Thus, cytogenetically detectable del(6q) is not associated with adverse risk in pediatric ALL.

Antineoplastic Agents↗

PubMed2000

Histamine as an autocrine regulator of leukemic cell proliferation.

We examined leukemic lymphocyte precursors from ALL patients as well as immortalized ALL cell lines for cytoplasmic histamine expression. The histamine levels ranged from 10.8 pg/10(6) cells to 82.2 pg/10(6) cells in ALL cell lines (N=4) and from 12.5 pg/10(6) cells to 1235.4 pg/10(6) cells for primary leukemic cells from ALL patients (N=13). The presence of histamine in the cytoplasm of these ALL cells was also confirmed by immunostaining using a polyclonal rabbit anti-histamine antibody. Notably, the histamine receptor blocker diphenhydramine inhibited the clonogenic growth of ALL cells by >90% prompting the hypothesis that histamine may be an autocrine regulator of ALL cell proliferation. Our study suggests that histamine receptor blockers may therefore be useful for the treatment of therapy-refractory ALL.

Adolescent↗

PubMed2000

Apoptosis-inducing vanadocene compounds against human testicular cancer.

We systematically assessed the cytotoxic effects of five metallocene dichlorides containing vanadium (vanadocene dichloride), titanium (titanocene dichloride), zirconium (zircodocene dichloride), molybdenum (molybdocene dichloride), and hafnium (hafnocene dichloride) as the central metal atom and 19 other vanadocene complexes. These compounds were tested against the human testicular cancer cell lines Tera-2 and Ntera-2 using both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and apoptosis assays. Notably, only the vanadium(IV)-containing metallocenes exhibited significant cytotoxicity against Tera-2 and Ntera-2 cells and induced apoptosis within 24 h. Vanadocenes with dithiocyanate [VCp2(SCN)2 x 0.5 H2O] and diselenocyanate [VCp2(NCSe)2] as ancillary ligands were identified as the most potent cytotoxic compounds. Vanadocenes, especially the lead compound VCp2(NCSe)2, may be useful in the treatment of testicular cancer.

Apoptosis↗

PubMed2000

Bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) as a novel apoptosis-inducing anticancer agent.

In a systematic effort to identify a potent anticancer agent, we synthesized 15 oxovanadium(IV) complexes and examined their cytotoxic activity against 14 different human cancer cell lines. The oxovanadium compounds included mono and bis ancillary ligands of 1,10-phenanthroline (phen) [VO(phen), VO(phen)2, VO(Me2-phen), VO (Me2-phen)2, VO(Cl-phen), VO(Cl-phen)2, VO(NO2-phen), VO(NO2-phen)2], 2,2'-bipyridyl (bipy) [VO(bipy), VO(bipy)2, VO(Me2-bipy), VO(Me2-bipy)2], and 2-2'-bipyrimidine(bipym) [VO(bipym) and VO-(bipym)2], linked via nitrogen atoms, and 5'-bromo-2'-hydroxyacetophenone (acph) [VO(acph)2], linked via oxygen donor atom. The mono-chelated [VO(Me2-phen), compound 3] and bis-chelated-phen[VO(Me2-phen)2, compound 4] complexes were the most potent oxovanadium compounds and killed target cancer cells at low micromolar concentrations. Notably, the dimethyl substitution of the phenanthroline rings was essential for the anticancer activity of both compound 4 [VO(Me2-phen)2] and compound 3 [VO(Me2-phen)] because unsubstituted bis-chelated and mono-chelated phen oxovanadium(IV) complexes [VO(phen), compound 1, or VO(phen)2, compound 2] were less active. Addition of a chloro or nitro group to the phen complexes did not significantly improve the cytotoxic activity of the unsubstituted oxovanadium(IV) complexes. Irrespective of the ligands, bis-chelated phenanthroline containing compounds showed better activity than the mono-chelated phenanthroline containing complexes. The marked differences in the cytotoxic activity of oxovanadium(IV) complexes containing different heterocyclic ancillary ligands suggest that the cytotoxic activity of these compounds is determined by the identity of the five-member bidentate ligands, as well as the nature of the substitutents on the heterocyclic aromatic rings. Our results presented herein provide experimental evidence that oxovanadium compounds induce apoptosis in human cancer cells. Oxovanadium compounds, especially the lead compound VO(Me2-phen)2, may be useful in the treatment of cancer.

Antineoplastic Agents↗

PubMed2000

Z-Phe-Gly-NHO-Bz, an inhibitor of cysteine cathepsins, induces apoptosis in human cancer cells.

An increasing number of studies indicate that cysteine cathepsins contribute to cancer progression, invasion, and metastasis. Here we provide experimental evidence that the cathepsin inhibitor Z-Phe-Gly-NHO-Bz induces rapid apoptotic death in human cancer cell lines. Notably, the Z-Phe-Gly-NHO-Bz-induced apoptosis exhibited independence of p53, caspases, and mitogen-activated protein (MAP) kinases. Taken together, our results prompt the hypothesis that cysteine cathepsin(s) is a universal survival factor for cancer cells, and its inhibition leads to cancer cell apoptosis. The exquisite sensitivity of human cancer cells to CATI-1 indicates that this compound and its derivatives may provide the basis for new treatment programs against a broad spectrum of malignancies.

Apoptosis↗

PubMed2000

Calpain inhibitor II induces caspase-dependent apoptosis in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells as well as some solid tumor cells.

Calpain is a calcium-dependent cysteine protease that is implicated in calcium-dependent cell death, and calpain inhibitors are generally considered as inhibitors of apoptosis. To the contrary, in the present study, we found that calpain inhibitor II (CPI-2) triggers rapid apoptosis in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) cells. All target cell lines were killed by CPI-2, including: ALL-1, a multidrug-resistant BCR-ABL fusion transcript-positive t(9;22) pro-B ALL cell line; RS4;11, a highly radiation-resistant MLL-AF4 fusion transcript-positive t(4;11) pre-pre B ALL cell line; RAMOS, a highly radiation-resistant and p53-deficient Burkitt's lymphoma cell line; DAUDI, a Burkitt's leukemia/lymphoma cell line; NALM-6, a pre-B ALL cell line; and JURKAT and MOLT-3, two T-lineage ALL/NHL cell lines. CPI-2-induced apoptosis in LYN-deficient and BTK-deficient subclones of the DT-40 lymphoma B cell line as effectively as it did in wild-type DT-40 cells. Thus, CPI-2-induced apoptosis is not dependent on the protein tyrosine kinases LYN or BTK. Notably, caspase inhibitor I effectively inhibited CPI-2-induced apoptosis, suggesting that the inhibition of a CPI-2-susceptible protease results in caspase activation, leading to apoptosis in ALL/NHL cells. Unlike the high calpain-expressing ALL/NHL cell lines, myeloid leukemia cell lines HL-60/AML, K562/CML, and U937/AMML, or solid tumor cell lines BT-20/breast cancer, PC-3/prostate cancer, U373/glioblastoma, and HeLa/epitheloid cancer, were not susceptible to the cytotoxicity of CPI-2. Taken together, our results identify calpain as a new molecular target for the treatment of ALL and NHL. CPI-2 and its analogues represent a promising new class of antileukemia/lymphoma agents that deserves further development.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2000

Residual bone marrow leukemic progenitor cell burden after induction chemotherapy in pediatric patients with acute lymphoblastic leukemia.

We used highly sensitive multiparameter flow cytometry and blast colony assays to quantify the leukemic progenitor cell (LPC) burden of postinduction chemotherapy bone marrows from newly diagnosed and relapsed pediatric patients with acute lymphoblastic leukemia (ALL). Of 890 newly diagnosed patients, 243 (27%) had detectable LPC in the postinduction bone marrow samples with an average (mean +/- SE) LPC content of 22+/-9 LPC/10(6) mononuclear cell (MNC; range, 0-7199/10(6) MNC; median, 0/10(6) MNC). By comparison, 24 of 50 (48%) patients with relapsed ALL had detectable LPC in their postinduction bone marrow specimens (P = 0.003), and their average LPC content was 202+/-139 LPC/10(6) MNC. Fewer patients with B-lineage ALL (170 of 786; 22%) than patients with T-lineage ALL (73 of 104; 70%) harbored residual LPC in their postinduction bone marrow specimens (P < 0.0001). This correlation with immunophenotype was independent of the National Cancer Institute risk classification. Similarly, 19 of 44 (43%) patients with relapsed B-lineage ALL versus 5 of 6 (83%) patients with relapsed T-lineage ALL harbored residual LPC in their postinduction bone marrow specimens (P = 0.09). Among newly diagnosed patients, those with high-risk ALL seemed to have larger numbers of residual LPC in their bone marrow after induction chemotherapy than those with standard risk ALL (53+/-26, n = 286 versus 7+/-1, n = 604, P = 0.04). LPC of patients with standard risk ALL who had a slow early marrow response at day 7 seemed to be more resistant to the three-drug induction chemotherapy than patients who had a rapid early marrow response. Overall, the order of chemosensitivity of LPC was: newly diagnosed standard risk B-lineage > newly diagnosed higher risk B-lineage > newly diagnosed standard risk T-lineage > newly diagnosed higher risk T-lineage > relapsed B-lineage > relapsed T-lineage. Notably, LPC- patients whose end-of-induction remission bone marrow specimens had zero LPC had an excellent early event-free survival outcome. Within the standard and high-risk subsets, LPC- patients had a 2.6-fold lower and 2.4-fold lower incidence of events, respectively, than LPC+ patients. At 6 months, 12 months, as well as 24 months, the ranking order for better event-free survival was: standard risk, LPC- > high risk, LPC- > standard risk, LPC+ > high risk, and LPC+.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Treatment of allergic asthma by targeting janus kinase 3-dependent leukotriene synthesis in mast cells with 4-(3', 5'-dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97).

4-(3',5'-Dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97) is a rationally designed potent inhibitor of Janus kinase (JAK)-3. Treatment of mast cells with WHI-P97 inhibited the translocation of 5-lipoxygenase (5-LO) from the nucleoplasm to the nuclear membrane and consequently 5-LO-dependent leukotriene (LT) synthesis after IgE receptor/FcepsilonRI crosslinking by >90% at low micromolar concentrations. WHI-P97 did not directly inhibit the enzymatic activity of 5-LO, but prevented its translocation to the nuclear membrane without affecting the requisite calcium signal. WHI-P97 was very well tolerated in mice, with no signs of toxicity at dose levels ranging from 5 microg/kg to 50 mg/kg, and LD(10) was not reached at a 50 mg/kg dose level when administered as a single i. p. or i.v. bolus dose. Therapeutic WHI-P97 concentrations, which inhibit mast cell leukotriene synthesis in vitro, could easily be achieved in vivo after the i.v. or i.p. administration of a single nontoxic 40 mg/kg bolus dose of WHI-P97. Notably, WHI-P97 showed promising biological activity in a mouse model of allergic asthma at nontoxic dose levels. Treatment of ovalbumin-sensitized mice with WHI-P97 prevented the development of airway hyper-responsiveness to methacholine in a dose-dependent fashion. Furthermore, WHI-P97 inhibited the eosinophil recruitment to the airway lumen after the ovalbumin challenge in a dose-dependent fashion. Further development of WHI-P97 may therefore provide the basis for new and effective treatment as well as prevention programs for allergic asthma in clinical settings.

Animals↗

PubMed2000

SPIKET and COBRA compounds as novel tubulin modulators with potent anticancer activity.

Agents that either promote or inhibit tubulin polymerization exhibit anticancer activity by disrupting normal mitotic spindle assembly and cell division as well as inducing apoptosis. Recently identified novel agents that target tubulin include synthetic spiroketal pyrans (SPIKET), targeting the spongistatin binding site of beta-tubulin, and COBRA compounds, targeting a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P caused tubulin depolymerization in cell-free turbidity assays and exhibited potent cytotoxic activity against cancer cells as evidenced by destruction of microtubule organization, and prevention of mitotic spindle formation in human breast cancer cells. Molecular modeling studies predicted a high-affinity interaction of the first COBRA compounds, COBRA-0 and COBRA-1, with a unique hydrophobic binding site on alpha-tubulin located between the GTP/GDP binding site and the M-loop. Further studies showed that COBRA-1 inhibited GTP-induced tubulin polymerization in cell-free tubulin turbidity assays. Treatment of human breast cancer and brain tumor (glioblastoma) cells with COBRA-1 caused destruction of microtubule organization and apoptosis. COBRA-1 activated the pro-apoptotic c-Jun N-terminal kinase (JNK) signal transduction pathway. COBRA and SPIKET compounds represent two new classes of tubulin targeting agents that show promise as anticancer drugs.

Animals↗

PubMed1999

N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea as a potent inhibitor of NNI-resistant and multidrug-resistant human immunodeficiency virus-1.

The thiophene-ethyl thiourea (TET) compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (compound HI-443) was five times more potent than trovirdine, 1250 times more potent than nevirapine, 100 times more potent than delavirdine, 75 times more potent than MKC-442, and 50 times more potent than AZT against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation. HI-443 was almost as potent against the NNI-resistant HIV-1 strain A17 with a Y181C mutation as it was against HTLV(IIIB). The activity of HI-443 against A17 was ten times more potent than that of trovirdine, 2083 times more potent than that of nevirapine, and 1042 times more potent than that of delavirdine. HI-443 inhibited the replication of the NNI-resistant HIV-1 strain A17 variant with Y181C plus K103N mutations in RT with an IC50 value of 3.3 microM, whereas the IC50 values of trovirdine, nevirapine, and delavirdine were all >100 microM. These findings establish the novel thiophene containing thiourea compound HI-443 as a novel NNI with potent antiviral activity against NNI-sensitive, NNI-resistant and multidrug-resistant strains of HIV-1.

Anti-HIV Agents↗

PubMed1999

Inhibitor of HIV-1 reverse transcriptase: N'-(5-bromo-2-pyridyl)-N-[2-(2,5-dimethoxyphenyl)ethyl]thiourea.

The crystal structure of the title compound, C16H18Br-N3O2S (HI-236), a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase, revealed an intramolecular hydrogen bond between a thiourea N atom and the pyridyl-N atom [N-H...N = 2.671 (3) A, graph-set motif S1(1)(6)] that imparts a more rigid conformation to the molecule. A second hydrogen bond between a thiourea N atom and the thiocarbonyl-S atom [N-H2...S = 3.403 (2) A, graph-set motif R2(2)(8)] was observed between inversion-related molecules of HI-236. The first-level hydrogen-bond graph-set notation for HI-236 was determined to be S1(1)(6)R2(2)(8).

Crystallography, X-Ray↗

PubMed1999

Deguanylation of human immunodeficiency virus (HIV-1) RNA by recombinant pokeweed antiviral protein.

Modeling studies, combined with the molecular docking of the trinucleotide GGG into the active site of the deadenylating RNA N-glycosidase pokeweed antiviral protein (PAP), indicated that a guanine base can fit into the active site pocket of PAP without disturbing its unique geometry and is sandwiched between residues Tyr(72) and Tyr(123) very much like an adenine base. The guanine base can form two specific hydrogen bonds with the active site residues Ser(121) and Val(73) and the attached negatively charged phosphate groups can entertain stabilizing electrostatic interactions with two clusters of positively charged patches on the PAP surface formed by Lys(210) and Arg(179) from one side and Arg(122) and Arg(135) from the other side of the active site. These observations prompted the hypothesis that the RNA depurinating activity of PAP may not be restricted to adenine residues and PAP should be capable of deguanylating ribosomal and viral RNA as well. This hypothesis was experimentally confirmed by direct demonstration that guanine base is released from both ribosomal and HIV-1 RNA after treatment with purified recombinant PAP using quantitative high performance liquid chromatography. Recombinant PAP released adenine and guanine residues at a 1:1 ratio from HIV-1 RNA and at an approximately 3:1 (adenine:guanine) ratio from Escherichia coli ribosomal RNA. At a concentration of 5 microM, recombinant PAP released 263 +/- 10 pmol of adenine and 100 +/- 11 pmol of guanine from 1 microgram of E. coli ribosomal RNA (16S + 23S) within 4 h of treatment. By comparison, 138 +/- 12 pmol of adenine and 143 +/- 10 pmol of guanine were released from 1 microgram of HIV-1 RNA under identical treatment conditions (5 microM recombinant PAP, 4 h treatment). The deguanylation of the ribosomal and viral RNA targets by recombinant PAP was concentration-dependent and is abolished by alanine substitutions of the catalytic active site residues Tyr(72) and Tyr(123). To our knowledge, these findings provide the first evidence that PAP can deguanylate both ribosomal and viral RNA.

Adenine Nucleotides↗

PubMed1999

N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea and N'-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-chloropyridyl)]-thiourea as potent inhibitors of multidrug-resistant human immunodeficiency virus-1.

We have replaced the pyridyl ring of trovirdine with an alicyclic cyclohexenyl, adamantyl or cis-myrtanyl ring. Only the cyclohexenyl-containing thiourea compound N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]- thiourea (HI-346) (as well as its chlorine-substituted derivative N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-chloropyridyl)]- thiourea/HI-445) showed RT inhibitory activity. HI-346 and HI-445 effectively inhibited recombinant RT with better IC50 values than other anti-HIV agents tested. The ranking order of efficacy in cell-free RT inhibition assays was: HI-346 (IC50 = 0.4 microM) > HI-445 (IC50 = 0.5 microM) > trovirdine (IC50 = 0.8 microM) > MKC-442 (IC5 = 0.8 microM) = delavirdine (IC50 = 1.5 microM) > nevirapine (IC50 = 23 microM). In accord with this data, both compounds inhibited the replication of the drug-sensitive HIV-1 strain HTLV(IIIB) with better IC50 values than other anti-HIV agents tested. The ranking order of efficacy in cellular HIV-1 inhibition assays was: HI-445 = HI-346 (IC50 = 3 nM) > MKC-442 (IC50 = 4 nM) = AZT (IC50 = 4 nM) > trovirdine (IC50 = 7 nM) > delavirdine (IC50 = 9 nM) > nevirapine (IC50 = 34 nM). Surprisingly, the lead compounds HI-346 and HI-445 were 3-times more effective against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation (as well as additional mutations involving the RT residues 74V,41L, and 215Y) than they were against HTLV(IIIB) with wild-type RT. HI-346 and HI-445 were 20-times more potent than trovirdine, 200-times more potent than AZT, 300-times more potent than MKC-442, 400-times more potent than delavirdine, and 5000-times more potent than nevirapine against the multidrug resistant HIV-1 strain RT-MDR. HI-445 was also tested against the RT Y181C mutant A17 strain of HIV-1 and found to be >7-fold more effective than trovirdine and >1,400-fold more effective than nevirapine or delavirdine. Similarly, both HI-346 and HI-445 were more effective than trovirdine, nevirapine, and delavirdine against the problematic NNI-resistant HIV-1 strain A17-variant with both Y181C and K103N mutations in RT, although their activity was markedly reduced against this strain. Neither compound exhibited significant cytotoxicity at effective concentrations (CC50 >100 microM). These findings establish the lead compounds HI-346 and HI-445 as potent inhibitors of drug-sensitive as well as multidrug-resistant stains of HIV-1.

Aminopyridines↗

PubMed1999

Targeting Janus kinase 3 in mast cells prevents immediate hypersensitivity reactions and anaphylaxis.

Janus kinase 3 (JAK3), a member of the Janus family protein-tyrosine kinases, is expressed in mast cells, and its enzymatic activity is enhanced by IgE receptor/FcepsilonRI cross-linking. Selective inhibition of JAK3 in mast cells with 4-(4'-hydroxylphenyl)-amino-6, 7-dimethoxyquinazoline) (WHI-P131) blocked the phospholipase C activation, calcium mobilization, and activation of microtubule-associated protein kinase after lgE receptor/FcepsilonRI cross-linking. Treatment of IgE-sensitized rodent as well as human mast cells with WHI-P131 effectively inhibited the activation-associated morphological changes, degranulation, and proinflammatory mediator release after specific antigen challenge without affecting the functional integrity of the distal secretory machinery. In vivo administration of the JAK3 inhibitor WHI-P131 prevented mast cell degranulation and development of cutaneous as well as systemic fatal anaphylaxis in mice at nontoxic dose levels. Thus, JAK3 plays a pivotal role in IgE receptor/FcepsilonRI-mediated mast cell responses, and targeting JAK3 with a specific inhibitor, such as WHI-P131, may provide the basis for new and effective treatment as well as prevention programs for mast cell-mediated allergic reactions.

Anaphylaxis↗

PubMed1999

Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: A report from the Children's Cancer Group.

Cytogenetic abnormalities of chromosome arm 9p occur frequently in children with acute lymphoblastic leukemia (ALL). We analyzed 201 such cases (11%) in 1,839 children with newly diagnosed ALL treated between 1989 and 1995 on risk-adjusted protocols of the Children's Cancer Group (CCG). The majority of patients (131; 65%) with a 9p abnormality were classified as higher risk. Nearly all patients had complex karyotypes; most cases had deletions of 9p, add/der(9p), a dicentric involving chromosome arm 9p, and/or balanced translocations and inversions involving 9p. Event-free survival (EFS) estimates at 6 years for patients with and without a 9p aberration were 61% (standard deviation [SD] = 5%) and 76% (SD = 2%; P <.0001). In addition, patients with a 9p abnormality had an increased cumulative incidence of both marrow (P =.04) and central nervous system (P =.0001) relapses. Overall survival also was significantly worse for patients with an abnormal 9p (P <.0001). These effects were most pronounced in standard-risk patients (age 1 to 9 years with white blood cell count <50,000/microL): 6-year EFS of 61% (SD = 9%) versus 80% (SD = 2%; P <.0001). Also, a 9p aberration was an adverse risk factor for B-lineage, but not T-lineage patients. The effect of 9p status on EFS was attenuated, but maintained in a multivariate analysis of EFS after adjustment for Philadelphia chromosome status, age, white blood cell (WBC) count, sex, race, and ploidy group (P =.01). Thus, abnormalities of chromosome arm 9p identify a subgroup of standard-risk patients with increased risk of treatment failure.

Child↗

PubMed1999

Alpha-cyano-N-(2,5-dibromophenyl)-beta-hydroxybut-2-enamide.

The title compound, C11H8Br2N2O2 (LFM-A13), is the first reported BTK-specific tyrosine kinase inhibitor and the first antileukemic agent targeting BTK (Bruton's tyrosine kinase). The crystal structure showed that the molecule adopts an approximately planar conformation aided by an intramolecular hydrogen bond formed between the hydroxyl group and the amide carbonyl group. The dihedral angle between the phenyl ring and the plane defined by the N-C-C=C-CH3 group is 8.2 (6) degrees. The crystal packing shows an additional weak intermolecular hydrogen bond between the hydroxyl group and the amide carbonyl-O atom of the centrosymmetrically related molecule.

Agammaglobulinaemia Tyrosine Kinase↗