Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topotecan (TPT, 9-dimethylaminomethyl-10-hydroxycamptothecin) is the first topoisomerase I-directed cytotoxic agent to enter clinical trials in the United States in two decades. The effect of P-glycoprotein (Pgp) overexpression on TPT cytotoxicity was examined in CHRC5 (colchicine-resistant) and AuxB1 (parental) Chinese hamster ovary cells. Examination of the IC50 values observed in colony-forming assays revealed that the CHRC5 cells were 15-fold (SD, +/- 3; n = 3) resistant to TPT after a 1-h exposure and 3.2-fold (SD, +/- 1.4; n = 4) resistant in continuous exposure experiments. Band depletion immunoblotting revealed that 4-fold higher concentrations of extracellular TPT were required to induce the formation of topo I-DNA complexes in CHRC5 cells as compared to AuxB1 cells. To assess the role of Pgp in this resistance, drug accumulation and cytotoxicity assays were repeated in the absence and presence of quinidine. Addition of quinidine enhanced TPT accumulation (measured by high-performance liquid chromatography) and diminished the IC50 for TPT to a greater extent in CHRC5 cells than in AuxB1 cells. To examine whether similar effects could be detected in Pgp-expressing human cells, MCF-7/Adriar breast cancer cells and KG1a human acute myelogenous leukemia cells were examined. Quinidine or verapamil enhanced TPT accumulation in both of these cell lines but had no effect in parental MCF-7 cells or a variety of human leukemia cell lines that do not overexpress Pgp. Cytotoxicity measurements performed by counting the number of surviving cells (MCF-7/Adriar) or employing a modified, highly stable tetrazolium dye reduction assay (leukemia cell lines) revealed that quinidine diminished the IC50 for TPT in the Pgp-overexpressing cell lines but not in the control lines. These results suggest that Pgp overexpression diminishes TPT accumulation and TPT cytotoxicity in hamster and human cells. It should be stressed, however, that these effects were substantially smaller than the effects of Pgp overexpression on the accumulation and cytotoxicity of the anthracycline daunorubicin and the epipodophyllotoxin etoposide in the same cell lines.
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PMID:Effect of P-glycoprotein expression on the accumulation and cytotoxicity of topotecan (SK&F 104864), a new camptothecin analogue. 134 48

The apoptosis-associated DNA strand breaks were detected in situ, in individual leukemic cells in peripheral blood and bone marrow of over 110 patients with different types of leukemia (ALL, AML, CML in blastic crisis, APL), prior to and during routine chemotherapy. The DNA strand breaks were labeled with digoxigenin- or biotin-conjugated dUTP in the reaction catalyzed by exogenous terminal deoxynucleotidyl transferase, and the cells, counterstained for DNA, were analyzed by bivariate flow cytometry. The proportion of cells with DNA strand breaks prior to therapy, most likely reflecting spontaneous apoptosis, varied from 0.1 to 16%, but in the large majority of cases was below 3%. Administration of drugs of different classes, which included DNA topoisomerase I (Topotecan) and II (mitoxantrone, VP-16) inhibitors, antimetabolite (ara-C) or microtubule poison (Taxol), all triggered the appearance of cells with extensive DNA breakage, typical of apoptosis, to up to 80%. The peak of the response, measured as maximal percent of cells with DNA strand breaks, which varied between individual patients by as much as factor 10, was generally seen between 8 to 24 h after the initial administration of DNA topoisomerase inhibitors, and somewhat later (48-72 h) during the response to Taxol or ara-C. Thus, the data show that the response to treatment with a variety of drugs, in terms of induction of apoptosis, can be conveniently measured by the present method. The prognostic value of the apoptotic index, before, as well as during treatment, is being estimated for each type of leukemia, in the ongoing prospective studies.
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PMID:Apoptotic cell death during treatment of leukemias. 807 83

We used single-strand conformation polymorphism (SSCP) analysis of p53 exons 4-8 to screen for possible mutations in 25 pediatric de novo leukemias with translocations of the MLL gene at chromosome band 11q23. Of the 25 patients, 21 were infants. Fifteen cases were acute myeloid leukemia (AML), eight were acute lymphoblastic leukemia (ALL), and two cases were biphenotypic. Nineteen cases were studied at diagnosis and six at time of relapse. p53 mutations were absent in all 19 cases studied at the time of diagnosis. The only mutation was a TGC-->TTC transversion (cys-->phe) at codon 141 in exon 5 in a case of infant ALL at relapse that occurred by subclone evolution after MLL gene translocation. We previously showed that p53 mutations are also absent in pediatric treatment-related leukemias with MLL gene translocations. The absence of p53 mutations at initial transformation may suggest that the anti-apoptotic effect of mutant p53 is not important in leukemias with MLL gene translocations. Alternatively, exogenous DNA damage may be the common feature in treatment-related and de novo cases. Since MLL gene translocations may occur through DNA repair and wild-type p53 is central to DNA repair, the absence of p53 mutations raises the possibility that wild-type p53, not mutant p53, may be important in the genesis of leukemias with these translocations.
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PMID:Potential role for wild-type p53 in leukemias with MLL gene translocations. 954 37

Topotecan and retinoids are among the most promising agents being evaluated for the treatment of acute myelogenous leukemia (AML), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEB-t). Single-agent topotecan is similar to single-agent ara-C, but may be superior in patients with poor-prognosis chromosome abnormalities (ie, -5,-7). Topotecan plus ara-C is equivalent to topotecan alone in chronic myelomonocytic leukemia (CMML), but significantly more effective in RAEB and RAEB-t. Compared with single-agent ara-C, the complete remission (CR) rate with topotecan plus ara-C is comparable, although it offers special advantages in patients with the -5,-7 karyotype. In patients with poor-prognosis cytogenetics, the combination of cyclophosphamide, ara-C, and topotecan, plus all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF) appears favorable. In a recent study of triple-agent chemotherapy using fludarabine, ara-C, and idarubicin, with or without ATRA and G-CSF, median survival among poor-prognosis patients was 6-7 months, but those who received ATRA did better than those who did not, primarily because it improved survival in those who did not achieve CR. G-CSF produced higher CR rates but had no effect on survival or disease-free survival.
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PMID:New agents for the treatment of acute myelogenous leukemia: focus on topotecan and retinoids. 977 88

The National Comprehensive Cancer Network (NCCN) guidelines for patients with myelodysplastic syndromes (MDS) list myelosuppressive chemotherapy as an option for patients who have MDS with International Prognostic Scoring System (IPSS) scores of "intermediate" or "high." Myelodysplastic syndromes with these IPSS scores have an unfavorable natural history. Topotecan is a myelosuppressive drug that interacts with topoisomerase I and that has been used in the treatment of refractory AML. Its use in MDS has recently received considerable publicity. This paper reviews M. D. Anderson's results with topotecan and topotecan + ara-C in patients with MDS, focusing on comparisons of the results with ara-C and ara-C + fludarabine +/- idarubicin. While it is clear that the drug can produce complete responses, it is less clear that it differs from these other regimens. On average, complete response and survival rates are similar following administration of topotecan + ara-C or the other regimens. On the other hand, among patients with abnormalities of chromosomes 5 and/or 7, complete response rates are higher following topotecan + ara-C than for ara-C alone, or other ara-C combinations. The improvement in complete response rate among patients with abnormalities of chromosomes 5 and/or 7 has not resulted in an improvement in their survival (actuarial median about 6 months), largely reflecting a poor outcome following complete response. Indeed, the frequency of relapse in these patients suggests that any inherent increase in antileukemia activity in patients with abnormalities of chromosomes 5 and/or 7 is minimal. Given the overall results, topotecan +/- ara-C should not be regarded as standard therapy for MDS. The drug is nonetheless interesting and attempts to add to its efficacy are in progress.
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PMID:Incorporating new modalities into guidelines. Topotecan for myelodysplastic syndromes. 1002 4

Prolonged exposure to a topoisomerase I inhibitor may increase expression of topoisomerase II, making cells more susceptible inhibitors of that enzyme. This study was undertaken to establish the maximum tolerated dose (MTD) of a topotecan/topoisomerase II inhibitor sequential combination that may be active in acute leukemia, and to evaluate the effects of in vivo exposure to topotecan on topoisomerase II levels in leukemic blast cells as measured by image cytometry. Patients who were eligible for this phase I study had relapsed or refractory acute myeloid leukemia (< or = 2 prior regimens) or CML blast crisis (0 or 1 prior regimen). Topotecan was given as a 5 day continuous i.v. infusion and was to be escalated through three levels (1.5, 1.75 and 2.0 mg/m2 day), followed by etoposide at two dose levels (100 and 150 mg/m2) i.v. bolus days 6, 7 and 8. Topoisomerase IIalpha levels in leukemic blasts from bone marrow were measured by image cytometry prior to starting treatment, on day 5 of topotecan infusion and on day 28; and daily during topotecan in peripheral blood blasts. Dose-limiting toxicity was seen in two of six patients at the first dose level (topotecan 1.5 mg/m2/day, etoposide 100 mg/m2/day; > or = grade 3 mucositis in both cases). This cohort was expanded to 10 patients; no further non-hematologic dose-limiting toxicity was observed, but given the extent of toxicity seen, further dose escalation was judged not to be feasible. Topo IIalpha levels increased in peripheral blood blasts during the first 72 h of topotecan infusion and returned to near baseline by day 5, whereas levels appeared to decrease in bone marrow blasts by day 5 compared to pretreatment. One complete hematologic and cytogenetic remission in a patient with CML blast crisis was observed in the 10 patients evaluable for response. The sequential administration of topotecan 1.5 mg/m2/day continuous infusion for 5 days followed by etoposide 100 mg/m2/day x 3 is the recommended phase II dose for this schedule. Topotecan increases topo IIalpha expression in vivo in leukemia cells, but levels of the enzyme are cell cycle dependent. Pharmacodynamic evaluation of the sequential or combination administration of novel antileukemic agents may help improve treatment strategies in acute leukemia.
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PMID:Phase I trial of sequential topotecan followed by etoposide in adults with myeloid leukemia: a National Cancer Institute of Canada Clinical Trials Group Study. 1008 24

Although the prognosis for adults with acute myelogenous leukemia (AML) has improved over the past 10 years, overall results remain modest. Current research areas in the treatment of AML include dose-intensive therapy and stem-cell transplantation (SCT), immunotherapy, modulation of leukemia resistance (eg, multidrug resistance [MDR] Inhibitors), differentiation therapy (eg, retinolds), exploitation of different disease pathophysiology (eg, angiogenesis inhibitors, apoptosis-inducing agents), targeted therapy (eg, monoclonal antibodies, gene therapy), and the development of additional active chemotherapeutic agents with different mechanisms of action. Topotecan, a topoisomerase-I Inhibitor, may potentially enhance the activity of standard induction chemotherapy with cytosine arabinoside (cytarabine) and topoisomerase-II inhibitors. Topotecan is being investigated as salvage and front-line therapy for AML in combination with etoposide, cytarabine, or cyclophosphamide. The role that topotecan will eventually play In the treatment of AML is not yet clear, but encouraging results from triple combination induction therapy In patients with unfavorable prognoses warrant further investigation.
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PMID:New developments in the treatment of acute myeloid leukemia: focus on topotecan. 1062 25

Topotecan is a topoisomerase I inhibitor with significant activity in patients with myelodysplastic syndrome and chronic myelomonocytic leukemia. Pre-clinical data suggest a synergistic activity with DNA damaging agents such as cyclophosphamide, where topotecan might prevent the repair of cyclophosphamide-induced DNA damage. We thus designed a combination including cyclophosphamide 500 mg/m2 every 12 hours given on days 1 to 3; topotecan 1.25 mg/m2/day by continuous infusion on days 2 to 6, and cytosine arabinoside (ara-C) 2 g/m2 over 4 hours daily for 5 days on days 2 to 6 (CAT). Sixty six (63 evaluable) patients were treated. Fifty two patients had refractory (n=12) or relapsed (n=40) acute myelogenous leukemia (AML), and eleven had acute lymphocytic leukemia (ALL) (refractory n=3, relapsed n=8); their median age was 57 years (range, 18 to 79 years). Eleven patients (17%) achieved a complete remission (CR), and two patients (3%) had a hematologic improvement (HI; met all criteria for CR except for platelets < 100x10(9)/L), for an overall response rate of 20%. Responses occurred in 12 of 52 AML patients (23%), including 10 CR (19%) and 2 HI (4%), and in 1 of 11 patients with ALL (9%). Myelosuppression was universal; there were 23 episodes of pneumonia or sepsis and 18 episodes of fever of unknown origin complicating 74 courses of CAT. Non-hematologic toxicity was mostly gastrointestinal, including nausea, vomiting, diarrhea and mucositis, but was severe in only 8%. In summary, the CAT regimen is well tolerated and has significant anti-leukemia activity which warrants further investigation.
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PMID:Cyclophosphamide, ara-C and topotecan (CAT) for patients with refractory or relapsed acute leukemia. 1078 92

Few chemotherapy agents have demonstrated activity in patients with myelodysplastic syndromes (MDS) and supportive management remains the standard of care. An increasing number of new drugs in development are being directed at specific molecular or biological targets of these diseases. Topotecan, a topoisomerase I inhibitor, has shown single-agent activity and is now being combined with other agents, including cytarabine. The aminothiol amifostine induces responses in about 30% of patients; however, its role is still being clarified. Agents that inhibit histone deacetylase and target DNA hypermethylation, thus permitting derepression of normal genes, include 5-azacytidine, decitabine, phenylbutyrate, and depsipeptide. Arsenic trioxide has demonstrated impressive activity in acute promyelocytic leukemia and preclinical data suggest the potential for activity in MDS. UCN-01 is a novel agent that inhibits protein kinase C and other protein kinases important for progression through the G1 and G2 phases of the cell cycle. Dolastatin-10 has extremely potent in vitro activity against a variety of tumor cell lines. Since its dose-limiting toxicities include myelosuppression, it is being studied in acute myelogenous leukemia (AML) and MDS. Ras may play a role in MDS, and activation of this gene and its signaling pathways may require farnesylation. Several farnesyl transferase inhibitors are now available for study in patients with MDS. An increasing body of data suggests a possible role for angiogenesis in MDS, and several antiangiogenesis agents are in clinical trials, including thalidomide, SU5416, and anti-vascular endothelial growth factor (VEGF) antibodies. Development of new drugs and regimens will be facilitated by recently developed standardized response criteria. Future clinical trials should focus on rational combinations of these agents and others with the goal of curing patients with MDS.
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PMID:Novel therapeutic agents for the treatment of myelodysplastic syndromes. 1104 23

Single-agent topotecan is an active drug in chemotherapy-naive MDS and CMML and, to a lesser degree, in refractory/relapsed acute leukemias, low-/intermediate-grade lymphoma, and myeloma. Its combination with cytosine arabinoside induces complete remissions in high-risk MDS/CMML. A triple-combination regimen of cyclophosphamide, cytosine arabinoside, and topotecan (CAT) was extensively tested in refractory/relapsed as well as in untreated AML. By proving effective in inducing complete remission in newly diagnosed AML at rates comparable to those achieved by anthracycline-cytosine arabinoside regimens, for example, CAT offers a useful treatment alternative. Topotecan combined with paclitaxel is promising in low-/intermediate-grade lymphomas. The activity of topotecan justifies further evaluation of topotecan-containing combination regimens, particularly in MDS/CMML and acute leukemias.
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PMID:Topotecan (hycamptin) and topotecan-containing regimens in the treatment of hematologic malignancies. 1119


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