UMLS:C0023473 - FACTA Search

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Query: UMLS:C0023473 (chronic myeloid leukemia)
18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Residual disease remains a major problem in the treatment of human neoplasia. To effectively monitor minimal leukemic activity after bone marrow transplantation (BMT), we used a competitive polymerase chain reaction (PCR) amplification technique to quantify expression of the characteristic bcr-abl fusion message in patients with chronic myelogenous leukemia (CML). Quantitative results were obtained between the 0.001% and 0.1% level in control experiments. This represents a significant advantage over cytogenetic and Southern blotting techniques routinely used to diagnose CML, which may not be sensitive below the 1% level. To illustrate the potential clinical usefulness of the quantitative PCR strategy, we compared results of bcr-abl messenger RNA expression with those obtained using cytogenetic and Southern blotting techniques, in a study of consecutive BM and peripheral blood (PB) samples from two CML patients at high risk for relapse after BMT. One patient received a syngeneic transplant during the chronic phase of the disease and relapse was apparent at the molecular level 4.5 months after BMT, while the patient was in complete clinical remission. The second patient was treated with an allogeneic BMT during the accelerated phase of the disease. A slow, but progressive decrease in bcr-abl expression was observed during the first 12 months after BMT, and expression was undetectable thereafter. Our results indicate that the competitive PCR technique can be used to monitor disease activity in patients at high risk of relapse, while the patients are in complete clinical remission, which should facilitate the early detection of relapse or the identification of progressive disappearance of leukemic activity. The approach used may serve as a model for the study of residual disease in an increasing number of other hematologic malignancies that express cancer-specific RNAs.
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PMID:Molecular quantification of residual disease in chronic myelogenous leukemia after bone marrow transplantation. 154 52

Tiazofurin, 2-beta-D-ribofuranosylthiazole-4-carboxamide, is cytotoxic to murine and human tumor cells. In earlier Phase-I/-II trials performed in other centers in patients with solid tumors, the drug was given mainly as a 10-min bolus or as a continuous i.v. infusion for 5 days. These protocols were associated with serious side effects, including neurotoxicity, pleuropericarditis, and occasional myelosuppression. In our study, 26 patients with end-stage leukemia were treated with tiazofurin with 1-hr daily i.v. infusions, resulting in lower incidence and less severity of side effects. In this group, 7 attained complete remission and 7 showed hematologic responses. Out of 12 evaluable patients with myeloid blast crisis of chronic granulocytic leukemia, 10 (83%) responded to therapy, with 6 attaining complete response. We present pharmacokinetic parameters of our clinical study and examine some of the reasons for the lower toxicity found in our trials. In leukemic patients during and after infusion at doses of 1,100, 2,200 and 3,300 mg/m2 tiazofurin peak plasma concentrations were 245, 441 and 736 microM, respectively, values one-half of those calculated from other reports with a 10-min bolus administration. In our 1-hr infusion method, biphasic pharmacokinetics were noted with alpha t1/2 and beta t1/2 of 0.5 and 6.2 hr, and tiazofurin was eliminated at a faster rate than in previous trials with continuous infusion. The area under the curve with our 1-hr infusion was 52% of that reported for the same dose given by continuous infusion. Our 1-hr infusion method and prompt and effective treatment of side effects enabled us to administer higher doses and larger total amounts of tiazofurin in longer treatment cycles than in any previous trials elsewhere. Tiazofurin therapy using 1-hr infusion may be feasible for other carefully selected types of malignancies.
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PMID:Clinical pharmacokinetic study of tiazofurin administered as a 1-hour infusion. 156 87

Eight cases of Philadelphia positive acute leukemia (Ph+AL) were compared with 13 cases of Ph+ chronic myelogenous leukemia in blast crisis (BC) and 10 cases of Ph negative acute lymphoblastic leukemia (Ph-ALL) based on the clinical and molecular biological findings. Distinguishing clinical features were a high leukocyte count (median; 147.9 x 10(3)/microliters) for Ph+AL, and a high incidence of tumor formation and basophilia for BC. A cytogenetic study demonstrated the disappearance or marked reduction of Ph+ metaphases in Ph+AL in remission, while Ph+ cells persisted in BC. The major bcr gene was not rearranged in 4 Ph+AL cases, whereas it was found rearranged in 4 other cases of Ph+ AL and 6 cases of BC. Reverse transcriptase polymerase chain reaction technique demonstrated the presence of minor bcr/abl mRNA in the former three cases, and major bcr/abl mRNA in the latter 4 cases. Remission rates were 63% for Ph+AL, 38% for BC, and 100% for Ph-ALL, and the 50% survival were 12, 5 and 29 months, respectively. It was concluded that Ph+AL can be differentiated from BC by a marked reduction of Ph+ cells at remission, and that the prognosis of Ph+AL is better than BC, but worse than Ph-ALL.
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PMID:[Clinical and molecular biological study of Ph positive acute leukemia: comparison with blast crisis of chronic myelogenous leukemia and Ph negative acute lymphoblastic leukemia]. 163 16

A 36-year-old woman was referred to our hospital because of splenomegaly in February 1989. The leukocyte count was 55,500/microliter without hiatus leukemicus. The leukocyte alkaline phosphatase score was low (29). The bone marrow showed myeloid hyperplasia (24.8% myeloblasts) but no dysplastic change. The karyotype of the bone marrow cells was 46, XX and a diagnosis of Ph1 (-) CML was made. Treatment with VCR, 6MP and prednisolone made 7-month duration chronic phase, but the abnormal karyotype.[46, XX, i(17q)] gradually increased to 100% of bone marrow cells. The patient died in June 1990. The evidence that not only a BCR rearrangement but also messages of BCR/ABL fusion gene were negative made us able to differentiate this case from Ph1(-), BCR(+) CML. The addition of an i(17q) results in partial monosomy of 17q (17q13;p53 gene) and partial trisomy of 17q (17q11.2-12;G-CSF gene). We examined the rearrangement of p53 gene and G-CSF-dependent tumor cell growth in vitro, demonstrating one allelic loss of p53 gene and independent cell growth on G-CSF respectively. It is thought that in Ph1 (-), BCR (-) CML as well as in Ph1 (+) CML, an i(17q) is related to the progression but not to the initiation of these leukemias. However the precise mechanism, including p53 gene inactivation by point mutation, is still to be elucidated.
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PMID:[i(17q) appearing in acute phase in Ph1-negative, BCR-negative CML]. 163 23

Four human chronic myeloid leukemia (CML) cell lines, BV173, K562, KCL-22, and KYO-1, were studied for inactivation of human tumor suppressor gene p53. Southern blotting showed allele deletion in KCL-22 and cytogenetic studies showed a chromosome 17 deletion in KYO-1 but no gross structural abnormalities in the other two lines. Northern blotting showed increased amounts of normal size p53 mRNA in BV-173 and KYO-1, trace amounts in KCL-22, and none in K562. Direct sequencing of p53 cDNA revealed a missense point mutation in KYO-1 and a single base pair deletion consistent with a coding frame shift in KCL-22. Both abnormalities in these myeloid cell lines were located in the highly conserved region of p53. Studies with two monoclonal antibodies showed that the three cell lines with p53 mRNA had readily detectable p53 proteins. In KYO-1 and BV173 cells the p53 protein was located mainly in the nuclei but KCL-22 cells had weak staining in the cytoplasm. Our data support the assumption that inactivation of p53 tumor suppressor function in myeloid blast transformation of CML may result from point mutations or deletions that produce mutant proteins.
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PMID:p53 in chronic myeloid leukemia cell lines. 164 Jul 38

The past year has seen important advances in our understanding of the molecular biology of human cancer. We have learned more about how normal genes with critical functions in growth and development can induce cellular transformation and malignancy if mutated or overexpressed. The finding of such oncogenes in specific human cancers often portends a poor prognosis. We have learned more about tumor suppressor genes, whose loss by mutation, deletion, or translocation can lead to cancer. A series of defects involving both oncogenes and tumor suppressor genes has been shown to characterize the multistep development of a fully malignant colon cancer. We have new insights into the promotion of malignancy by the fused gene product resulting from the chromosomal abnormality diagnostic of one leukemia, chronic myelogenous leukemia. Recently, in acute promyelocytic leukemia, a characteristic chromosomal abnormality has been shown to result in a specific fusion of a nuclear receptor that activates transcription and a previously unknown gene. Most interestingly, a ligand for this rearranged receptor has been shown to be a novel effective treatment for the disease. This review summarizes many of these advances.
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PMID:Oncogenes and clinical oncology. 164 34

The discovery of isozymes (types I and II) of IMP dehydrogenase (IMPDH; EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, has attracted attention as a possible novel approach to cancer diagnosis and selective tumor cell chemotherapy. To elucidate differences in expression and regulation of the two IMPDH isozymes, we examined the steady-state levels of these mRNAs in various types of leukemic cells from patients. Northern blot analysis revealed that type II IMPDH was more active transcriptionally (1.5- to 5.1-fold) in all the leukemic cells examined than in normal lymphocytes, whereas type I expression was similar. The increased expression of type II mRNA in leukemic cells was closely linked with the increase in total IMPDH activity (r = 0.92). When leukemic cells from a patient with chronic granulocytic leukemia in blast crisis were separated into blast-rich and mature leukocyte-rich fractions, the expression of type II mRNA correlated positively with the population of immature leukemic cells, whereas type I expression was unchanged. Treatment of leukemic blasts with 12-O-tetradecanoyl-phorbol-13-acetate for 5 days resulted in a 90% decrease in the expression of type II mRNA with macrophage-like differentiation, while the expression of type I mRNA was relatively stable. These observations suggest that expression of type II IMPDH is stringently linked with immature characteristics of leukemic cells; thus, it should be a selective target for antileukemic chemotherapy.
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PMID:Selective up-regulation of type II inosine 5'-monophosphate dehydrogenase messenger RNA expression in human leukemias. 167 9

Cytogenetic evaluation of patients after bone marrow transplantation (BMT) has provided a standard method of documentation of hematopoietic engraftment. More recently, recombinant DNA technology has also been applied to determine engraftment status. In order to establish the relative utility of these methods in clinical practice we have directly compared the data from cytogenetic and recombinant DNA methods, evaluating engraftment status in 68 BMT recipients. Patients were evaluated pre-transplant, 30, 60, 90, and 180 days after BMT, and yearly thereafter for 1) the presence or absence of the Y chromosome in sex-mismatched allogeneic transplant recipients, 2) the presence or absence of the Philadelphia chromosome [t(9;22)] in patients transplanted for chronic myelogenous leukemia (CML), 3) restriction fragment length polymorphism (RFLP) profiles, and/or 4) clonal rearrangement of the bcr gene. Cytogenetic examination of unstimulated bone marrow and recombinant DNA tests of nucleated peripheral blood or bone marrow cells produce qualitatively similar data in the identification of patient and donor cells and/or normal and tumor cells. Differences in the results obtained by the two analytic methods were most often due to the restricted cell populations evaluable by cytogenetic studies of PHA-stimulated peripheral blood specimens. DNA analyses could frequently be applied at earlier intervals after transplantation and, in cases of graft rejection, when cell counts were low. Although recombinant DNA methods required fewer cells and demonstrated greater sensitivity in detection of minor cell populations in the majority of instances, the cytogenetic evaluation may complement the DNA studies and allow detection of additional chromosomal anomalies.
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PMID:Comparison of molecular and cytogenetic methods in the evaluation of engraftment following allogeneic bone marrow transplantation. 168 32

Immunologic strategies for removal of malignant cells from autologous marrow grafts by "negative selection" (i.e., "purging") requiring multiple specific monoclonal antibodies for each tumor type. "Positive selection" of marrow stem cells for grafting is a possible alternative strategy, using a monoclonal antibody which selectively recognizes lymphohematopoietic stem cells. The human hematopoietic progenitor cell antigen, CD34, is an integral cell membrane glycoprotein of approximately 115 kD, which has been molecularly cloned and sequenced. Although its function has not been determined, the glycoprotein has been characterized biochemically, including preliminary epitope mapping. Collective results from several laboratories indicate that CD34 monoclonal antibodies (My10, BI-3C5, 12.8, etc.) have the appropriate specificity to warrant testing their utility in positive selection for autologous bone marrow transplantation. First, precursors for all human hematopoietic lineages assayed (including most CFU-GM, BFU-E, CFU-MEG, CFU-EO, CFU-MIX or CFU-GEMM, pre-CFU, CFUBLAST, and terminal transferase+ B [and probably T] lymphoid precursors) are CD34+. Second, only 1.5% (mean) of low density human marrow mononuclear cells express CD34; mature human blood and marrow cells are CD34-. Endothelial cells are the only fixed tissue cells which express CD34. Third, the expression of CD34 in malignancies appears to parallel normal cellular expression: of hematopoietic malignancies, some acute leukemias and chronic myelogenous leukemia blasts are CD34+, but chronic lymphois leukemias, lymphomas, myelomas and non-hematopoietic malignancies are uniformly CD34-. Fourth, it appears feasible to isolate CD34+ cells from clinical marrow harvest samples in large scale, using either columns or immunomagnetic microspheres. Fifth, recent studies in very small numbers of non-human primates and human patients suggest that isolated CD34+ cells include the true hematopoietic stem cell, since transplantation of CD34+ cells, into myeloblated recipients results in at least short-term hematopoietic engraftment. It is anticipated that transplantation of CD34+ marrow cells may have broad applicability in clinical bone marrow transplantation.
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PMID:Positive stem cell selection--basic science. 168 54

The increased activity in cancer cells of inosine 5'-monophosphate dehydrogenase (IMP DH, EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, was suggested as a sensitive target for chemotherapy. Tiazofurin (NSC 286193), through its conversion to the active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), is a strong inhibitor of IMP DH. In our clinical trial, tiazofurin caused return to the chronic phase in patients with chronic granulocytic leukemia in blast crisis (Tricot, G.; Jayaram, H.N.; Weber, G.; Hoffman, R. Tiazofurin: Biological effects and clinical uses. Int. J. Cell Cloning 8:161-170; 1990). In K562 human leukemic cells, tiazofurin down-regulated the expression of c-Ki-ras and c-myc oncogenes, which was followed by induced differentiation. We now report down-regulation by tiazofurin of the c-Ki-ras oncogene in a patient with chronic granulocytic leukemia in blast crisis. A single tiazofurin infusion (2,200 mg/m2) on days one and two decreased IMP dehydrogenase activity (the apparent t1/2 was 30 min), GTP concentration (the apparent t1/2 was 6 hr), and expression of ras (the apparent t1/2 was 8 hr) and c-myc (the apparent t1/2 was 38.5 hr) oncogenes in the leukemic cells. No further tiazofurin was given, because on days three and four the chemotherapeutic impact became evident in a tumor-lysis syndrome and the blast cells were cleared from the periphery by day five. The decrease in IMP DH activity, GTP concentration, and expression of c-Ki-ras oncogene were early markers of the successful chemotherapeutic impact of tiazofurin in a patient with chronic granulocytic leukemia in blast crisis.
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PMID:Tiazofurin down-regulates expression of c-Ki-ras oncogene in a leukemic patient. 170 12

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