SEARCH · PubMed Health

Results for “Teniposide”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 415 records · Page 23Linked to original sources

PubMed1983

Prognostic factors in superficial bladder tumors. A study of the European Organization for Research on Treatment of Cancer: Genitourinary Tract Cancer Cooperative Group.

A randomized clinical trial was performed on 308 patients with stage T1 carcinoma of the bladder to compare the efficacy of transurethral resection alone or followed by bladder instillations of thiotepa or VM-26 (teniposide) for 1 year. With the recurrence rate as the primary end point of interest the data from this trial were used to assess the prognostic importance of the following factors at entry into the study: number of tumors, prior recurrence rate, tumor size, grade, age, treatment group assigned and, finally, the interval between transurethral resection at entry into the study and the start of intravesical treatment. Using multivariate statistical techniques we found that the number of tumors at presentation was the most important prognostic factor followed by, in order of importance, the recurrence rate at entry and the size of the largest tumor. Of particular note was the discovery that patients with less than 1 recurrence per year at entry had a prognosis similar to patients with primary tumors, while those with a higher recurrence rate did uniformly poorly. These results show that patients with stage T1 carcinoma of the bladder form a heterogeneous group and that more aggressive therapy should be considered for patients with a poor prognosis.

Humans↗

PubMed1999

Interaction effects of 5-azacytidine with topoisomerase II inhibitors on CHO cells, as detected by cytogenetic analysis.

Different cell treatment protocols with the hypomethylating agent 5 azacytidine (5-aza C) were used in exponentially growing Chinese hamster ovary (CHO) cells in order to test its influence on the induction of chromosomal aberrations (CAs) induced by topoisomerase II inhibitors, ellipticine (EPC) and teniposide (VM-26). Cells pre-treated with 1 microg/ml 5-aza C for 1 h during the S-phase and post-treated in the last 2 h of incubation with 0.6 microg/ml EPC or 0.04 microg/ml VM-26 showed a reduction of 48% and 45%, respectively, in the frequencies of CAs as compared to the sum value of the frequencies obtained for each drug alone. 5-aza C added to the cultures for the last 2 h before cell fixation after a 30-min pulse treatment with EPC or VM-26 caused a 38% and 28% reduction, respectively. Simultaneous treatments with 5-aza C plus EPC, or 5-aza C plus VM-26 during the last 2 h of incubation (G2-phase), showed a significant effect of CA reduction (24%) only for the combination of 5-aza C + EPC. Preliminary assays with 5-aza C alone added to the cultures at different times demonstrated its effectiveness in inducing chromosome damage during the S-phase. Since S-phase-treated CHO cells showed a higher degree of reduction in the frequencies of CAs induced by EPC and VM-26, we suggest that 5-aza C incorporation into DNA may change the topo II cleavage sites, protecting the DNA from the induction of damage, or that the hypomethylation induced by incorporation of 5-aza C into DNA may change the chromatin structure facilitating the access to DNA repair enzymes. An alternative possibility is that 5-azaC can reactivate methylated genes involved in the repair of DNA double-strand breaks induced by topo II inhibitors.

Animals↗

PubMed1998

Discovery of podophyllotoxins.

This review deals with the historical discovery of particularly important lignan derivatives used in cancer chemotherapy. From isolation of the naturally occurring podophyllotoxin, an inhibitor of microtubule assembly, to hemisynthesis of the clinically important anticancer drugs etoposide and teniposide, it will be demonstrated how the activities and the ability of this class of compounds to inhibit topoisomerase II were discovered by different research teams. By virtue of these discoveries, new hemisynthetic derivatives, with different mechanisms of action, are bringing improvements in the ability to treat cancer.

Animals↗

PubMed1990

Human DNA topoisomerase II: evaluation of enzyme activity in normal and neoplastic tissues.

We have used both a quantitative filter binding assay and a decatenation assay to measure DNA topoisomerase II activity. The filter binding assay, which measures catenating activity, is able to detect topoisomerase II activity at 50-100-fold lower protein concentrations than the decatenation assay. Because of this remarkable sensitivity, we have been able to quantitate topoisomerase II activity in a variety of normal and neoplastic human tissues. The highest level of enzyme activity in normal tissues was found in the spleen and thymus. The highest level of enzyme activity in neoplasms was found in those that clinically behave in an aggressive manner and had a high proliferative status by flow cytometry. Surprisingly, these high topoisomerase II values in the neoplastic specimens are in the same range of values found in normal nonproliferating tissue. Since much previous data indicate that the enzyme is apparently a property of only proliferating cells, this finding might suggest that human tissues contain more than one form of the enzyme. The finding that 35-65% of the topoisomerase II activity in human tissues is resistant to teniposide suggests that more than one enzyme form exists.

Adolescent↗

PubMed1996

Position-specific effects of base mismatch on mammalian topoisomerase II DNA cleaving activity.

To further define the nucleic acid determinants of DNA site recognition by mammalian topoisomerase II, base mismatch effects on the enzyme DNA cleavage activity were determined in a 36-bp synthetic oligonucleotide corresponding to SV40 DNA. DNA cleavage sites induced by topoisomerase II without or with the antitumor drugs teniposide, idarubicin, or amsacrine were mapped using sequencing gels. Selected mismatches were studied, and always one of the two strands had the wild-type sequence. The effects of base mismatches were independent from the studied drugs. Mismatches introduced at the -4, -3, -2, or -1 positions, relative to the enzyme cleavage site, often abolished, or much reduced, DNA cleavage, whereas those at +1 and +2 positions often increased DNA breakage or were without influence. Mismatches at more distant positions, e.g., -7, -8, etc., had no effect. Those at positions -5 and -6 sometimes increased cleavage levels. These effects were always observed at sites already cleaved in the wild-type oligomer; new sites of cleavage were not induced by the studied mismatches. These results were obtained both for the native murine topoisomerase II and for the two recombinant human isozymes. No difference between topoisomerases II alpha(p170) and beta(p180) was seen in their response to mismatches. The results demonstrate that topoisomerase II recognition of the DNA site of cleavage requires fully paired nucleotides at the 3' terminus. Nevertheless, similarly to other DNA strand transferase enzymes, both topoisomerase II isoforms may have a sequence-specific nicking activity at the 5' side of unpaired bases.

Amsacrine↗

PubMed1998

Chemosensitivity of human malignant glioma: modulation by p53 gene transfer.

Loss of wild-type p53 activity is one of the most common molecular abnormalities in human cancers including malignant gliomas. The p53 status is also thought to modulate sensitivity to irradiation and chemotherapy. Here, we studied the effect of a p53 gene transfer on the chemosensitivity of three human glioma cell lines with different endogenous p53 status (LN-229, wild-type; LN-18, mutant; LN-308, deleted), using the murine temperature-sensitive p53 val135 mutant. Expression of mutant p53 enhanced proliferation of LN-308 cells but reduced proliferation in the other cell lines. Expression of wild-type p53 caused reversible growth arrest of all cell lines but failed to induce apoptosis. Growth arrest induced by wild-type p53 was associated with strong induction of p21 expression. Strong induction of BAX expression and loss of BCL-2 expression, which are associated with p53-dependent apoptosis rather than growth arrest, were not observed. Wild-type p53 failed to sensitize glioma cells to cytotoxic drugs including BCNU, cytarabine, doxorubicin, teniposide and vincristine. The combined effects of wild-type p53 gene transfer and drug treatment were less than additive rather than synergistic, suggesting that the intracellular cascades activated by p53 and chemotherapy are redundant. Unexpectedly, forced expression of mutant p53 modulated drug sensitivity in that it enhanced the toxicity of some drugs but attenuated the effects of others. These effects may represent a dominant negative effect of mutant p53 in LN-229 cells which have wild-type p53 activity but must be considered a gain of function-type effect in the other two cell lines which have no wild-type p53 activity. Importantly, no clear-cut pattern emerged among the three cell lines studied. We conclude that somatic gene therapy based on the reintroduction of p53 will limit the proliferation of human malignant glioma cells but is unlikely to induce clinically relevant sensitization to chemotherapy in these tumors.

Amino Acid Substitution↗

PubMed1987

Vidarabin-monophosphate, BCNU, VM26--an in vitro comparative study of active agents in the treatment of malignant human brain tumours.

BCNU (carmustine), VM26 (teniposide) and ARA-A5'P (vidarabin-monophosphate) were compared in their activity against 30 cell lines of primary (N = 21) and metastatic (N = 9) human brain tumours, which were characterized in tissue culture by cytochemical, immunological and cytogenetic criteria. In vivo achievable concentration-time products c X t were correlated with in vitro pharmacokinetic data in order to evaluate in vitro drug sensitivity at relevant exposure doses. A microcytotoxicity assay was employed to screen for drug toxicity in individual tumour cell lines. Following drug exposure and 5 to 8 population doubling times of untreated controls, RNA-synthesis - as a parameter of cell metabolism and proliferation - was determined by incorporation of [5,6-3H]-uridine into cellular RNA (liquid scintillation counting protocol). The cytotoxic effect of each drug on individual cell lines was expressed in terms of a sensitivity index (SI); by these means effects of different drugs on individual tumour cell lines could be compared. Mean sensitivity indices of ARA-A5'P, BCNU and VM26 for primary brain tumour cell lines were 0.59, 0.82 and 0.54. ARA-A5'P and VM26 had almost similar activities against brain tumour cell lines, whereas BCNU was significantly (P less than 0.001) less active. High grade gliomas were less sensitive to all three agents than low grade and infratentorial gliomas. ARA-A5'P was also able to effectively reduce colony formation in brain tumour cell lines. A cross-resistance of ARA-A5'P to either BCNU or VM26 could not be observed. Clearly, ARA-A5'P is an effective drug in treatment of brain tumour cells in vitro.

Adolescent↗

PubMed1991

Comparison of in vitro activity of epipodophyllotoxins with other chemotherapeutic agents in human medulloblastomas.

Surgical specimens from 15 medulloblastoma patients were used to establish early passage cultures. In vitro sensitivity to a battery of cytotoxic agents, including some in current medulloblastoma treatment protocols, was measured. Drug sensitivity was assessed at clinically relevant drug concentrations using the 3H-thymidine uptake method. Tumours were predicted to be sensitive if greater than 37% were killed by exposure to drugs at clinically achievable levels. A poor response to vincristine (Vcr), cis-platin (CDDP), hydroxyurea (HU) or diaziquone (AZQ) (no responders), and cytosine arabinoside (AraC) (1/12), was seen. Nine of ten tumours tested were sensitive to mafosfamide (Mfs); seven out of 12 were sensitive to carmustine (BCNU), 12 of 13 to teniposide (VM-26) and seven of 13 to etoposide (VP16-213). VM-26 was the best of the agents tested with most tumours responding to very low concentrations of drug, suggesting that the role of epipodophyllotoxins in treatment of brain tumours be further investigated. Despite the marked sensitivity of the medulloblastomas to the epipodophyllotoxins, three early passage cultures were much more resistant to these drugs than the average for the group. The basis of this resistance was investigated. Deficient cellular uptake of drug was excluded as a cause of resistance. One resistant early passage culture displayed low cellular activity of topoisomerase II and decreased levels of drug induced enzyme-DNA strand break activity. This was not the case for the other resistant early passage cultures: the basis of resistance in these cells does not appear to be due to any previously reported mechanism.

Alkylating Agents↗

PubMed1996

Differential expression of DNA topoisomerase II alpha and -beta in P-gp and MRP-negative VM26, mAMSA and mitoxantrone-resistant sublines of the human SCLC cell line GLC4.

Sublines of the human small-cell lung carcinoma (SCLC) cell line GLC4 with acquired resistance to teniposide, amsacrine and mitoxantrone (GLC4/VM20x, GLC4/AM3x and GLC4/MIT60x, respectively) were derived to study the contribution of DNA topoisomerase II alpha and -beta (TopoII alpha and -beta) to resistance for TopoII-targeting drugs. The cell lines did not overexpress P-glycoprotein or the multidrug resistance-associated protein but were cross-resistant to other TopoII drugs. GLC4/VM20x showed a major decrease in TopoII alpha protein (54%; for all assays presented in this paper the GLC4 level was defined to be 100%) without reduction in TopoII beta protein; GLC4/AM3x showed only a major decrease in TopoII beta protein (to 18%) and not in TopoII alpha. In GLC4/MIT60x, the TopoII alpha and -beta protein levels were both decreased (TopoII alpha to 31%; TopoII beta protein was undetectable). The decrease in TopoII alpha protein in GLC4/VM20x and GLC4/MIT60x, was mediated by decreased TopoII alpha mRNA levels. Loss of TopoII alpha gene copies contributed to the mRNA decrease in these cell lines. Only in the GLC4/MIT60x cell line was an accumulation defect observed for the drug against which the cell line was made resistant. In conclusion, TopoII alpha and -beta levels were decreased differentially in the resistant cell lines, suggesting that resistance to these drugs may be mediated by a decrease in a specific isozyme.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin.

We conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m(-2) day(-1) to 20 mg m(-2) day(-1) in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection. Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated liver transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m(-2). Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% CI, 0.41-2.61 h). A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m(-2) dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered.

Adult↗

PubMed2000

In vitro drug resistance profiles of adult versus childhood acute lymphoblastic leukaemia.

The difference in the current cure rates between adult and childhood acute lymphoblastic leukaemia (ALL) may be caused by differences in drug resistance. Earlier studies showed that in vitro cellular drug resistance is a strong independent adverse risk factor in childhood ALL. Knowledge about cellular drug resistance in adult ALL is still limited. The present study compared the in vitro drug resistance profiles of 23 adult ALL patients with that of 395 childhood ALL patients. The lymphoblasts were tested by the MTT assay. The group of adult ALL samples was significantly more resistant to cytosine arabinoside, L-asparaginase, daunorubicin, dexamethasone and prednisolone. The resistance ratio (RR) was highest for prednisolone (31.7-fold) followed by dexamethasone (6.9-fold), L-asparaginase (6. 1-fold), cytosine arabinoside (2.9-fold), daunorubicin (2.5-fold) and vincristine (2.2-fold). Lymphoblasts from adult patients were not more resistant to mercaptopurine, thioguanine, 4-HOO-ifosfamide, mitoxantrone and teniposide. There were no significant differences in drug resistance between adult T-cell (T-) ALL (n = 11) and adult common/pre-B-cell (B-) ALL (n = 10). Additionally, adult T-ALL did not differ from childhood T-ALL (n = 69). There were significant differences between adult common/pre-B-ALL and childhood common/pre-B-ALL (n = 310) for prednisolone (RR = 302, P = 0.008), dexamethasone (RR = 20.9, P = 0.017) and daunorubicin (RR = 2.7, P = 0.009). Lymphoblasts from adults proved to be relatively resistant to drugs commonly used in therapy. This might contribute to the difference in outcome between children and adults with ALL.

Adolescent↗

PubMed1990

[Chemotherapy of nonendemic Burkitt's lymphoma].

14 patients (12 men, 2 women, mean age 26.3 [15-47] years) with histologically confirmed Burkitt's lymphoma were subjected between 1984 and 1989 to chemotherapy originally developed for treating lymphomas in children. Treatment consisted of medium doses of methotrexate, cyclophosphamide, teniposide, cytarabine, adriamycin and prednisone, intrathecal administration of methotrexate and if necessary prophylactic or therapeutic irradiation of the cranium. Most of the patients (64%) were in advanced stages of the disease. The rate of complete remissions was 100%. Four patients (29%) had a recurrence. Side effects were leukopenia (WHO grade III and IV) in 71%, grade III anaemia in 43% and grade III-IV thrombopenia in 29% of the patients. Considerable mucositides in 5 of the 14 patients (36%), and in one case a tumour lysis syndrome with transient renal insufficiency were other therapy-induced side effects. These results suggest that this treatment course can be successful also in non-endemic Burkitt's lymphoma in adolescents and adults.

Adolescent↗

PubMed1986

Intensive retreatment of childhood acute lymphoblastic leukemia in first bone marrow relapse. A Pediatric Oncology Group Study.

We devised a plan of intensive chemotherapy to address the problem of inadequate results of treatment in children with acute lymphoblastic leukemia in first bone marrow relapse. Immediately after remission was induced with four conventional drugs, a two-week intensification course of teniposide and cytarabine was given to eradicate subclinical leukemia. Patients in remission were then treated for two years with rapid rotation of pairs of drugs that were not cross-resistant and periodic courses of the same agents used to induce remission. A second complete remission was induced in 31 of the 39 patients in whom response to chemotherapy could be assessed. The probability of maintaining bone marrow remission in these patients for one year was 0.38 +/- 0.19 (95 percent confidence interval); the two-year probability was 0.29 +/- 0.17. Seven patients completed the treatment program, five of whom have been in continuous second complete remission 17 to 20 months after the cessation of therapy. Children whose initial bone marrow remission lasted less than 18 months had significantly poorer responses to retreatment than did those with a longer first remission (P = 0.004). Intensive chemotherapy, as described here, may save half of the children with acute lymphoblastic leukemia in whom bone marrow relapse occurs after a relatively long initial remission.

Adolescent↗

PubMed1993

Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. Groupe d'Etude des Lymphomes de l'Adulte.

BACKGROUND: Interferon alfa and cytotoxic drugs have synergistic effects in patients with non-Hodgkin's lymphoma. In 1986, we designed a clinical trial to evaluate the benefit of concomitant administration of recombinant interferon alfa with a regimen containing doxorubicin in patients with follicular non-Hodgkin's lymphoma. METHODS: The trial involved 242 patients with advanced low-grade follicular non-Hodgkin's lymphoma selected on the basis of clinical, radiographic, and biologic criteria. All patients were treated with a regimen consisting of cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP), given monthly for six cycles and then every two months for one year. After randomization, 123 patients also received interferon alfa-2b at a dosage of 5 million units three times weekly for 18 months. The remaining 119 patients received chemotherapy alone. RESULTS: As compared with the patients treated with CHVP only, the patients treated with CHVP plus interferon alfa had a higher overall rate of response (85 percent vs. 69 percent, P = 0.006), a longer median event-free survival (34 months vs. 19 months, P < 0.001), and a higher rate of survival at 3 years (86 percent vs. 69 percent, P = 0.02). Granulocyte toxicity was greater in the patients treated with CHVP plus interferon alfa than in those treated with CHVP alone. There were no treatment-related deaths. Interferon alfa had to be stopped because of toxic effects (fatigue and hepatitis) in 13 patients (11 percent). CONCLUSIONS: The addition of interferon alfa to a regimen containing doxorubicin increased the rate of response, event-free survival, and overall survival in patients with advanced follicular non-Hodgkin's lymphoma, without serious toxicity, although some patients were unable to tolerate the side effects.

Aged↗

PubMed1986

Role for topoisomerases in the release of DNA into the detergent-soluble fraction of eukaryotic cells.

Detergent-soluble DNA is the fraction (2-4%) of DNA that is released into the supernate upon mild detergent lysis. It is nonmitochondrial in origin. It labels efficiently with deoxy[3H]ribonucleosides and the labeling is prevented by inhibitors of polymerase alpha and ribonucleotide reductase. In previous publications we have characterized detergent-soluble DNA from splenocytes of immunologically activated mice. In this publication we show that incorporation of [3H]thymidine into detergent-soluble DNA is prevented by pretreatment with novobiocin, 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), and teniposide (VM26), three inhibitors of type II topoisomerases. Camptothecin, an inhibitor of type I topoisomerases, also reduces incorporation of [3H]thymidine but only to 50% of control levels. In addition to affecting incorporation of [3H]thymidine, preincubation with the topoisomerase II inhibitors m-AMSA and VM26 alters the amount of DNA recovered in the detergent-soluble fraction. At low concentrations of m-AMSA the amount of detergent-soluble DNA increases somewhat, whereas at higher drug concentrations a marked decrease is observed. Treatment with VM26 results in diminished amounts of DNA being released into the detergent-soluble fraction as well. However, maximal inhibition of detergent-soluble DNA release by VM26 requires the presence of camptothecin. Therefore, we suggest that topoisomerases play an important role in making a small part of lymphocyte chromatin detergent labile. Furthermore, these results are consistent with recent studies demonstrating a role for topoisomerases in yeast replication. Thus, the newly synthesized portion of detergent-soluble DNA may arise as DNA replication intermediates not yet stabilized into mature chromatin.

Aminoacridines↗

PubMed1999

MRP3, an organic anion transporter able to transport anti-cancer drugs.

The human multidrug-resistance protein (MRP) gene family contains at least six members: MRP1, encoding the multidrug-resistance protein; MRP2 or cMOAT, encoding the canalicular multispecific organic anion transporter; and four homologs, called MRP3, MRP4, MRP5, and MRP6. In this report, we characterize MRP3, the closest homolog of MRP1. Cell lines were retrovirally transduced with MRP3 cDNA, and new monoclonal antibodies specific for MRP3 were generated. We show that MRP3 is an organic anion and multidrug transporter, like the GS-X pumps MRP1 and MRP2. In Madin-Darby canine kidney II cells, MRP3 routes to the basolateral membrane and mediates transport of the organic anion S-(2,4-dinitrophenyl-)glutathione toward the basolateral side of the monolayer. In ovarian carcinoma cells (2008), expression of MRP3 results in low-level resistance to the epipodophyllotoxins etoposide and teniposide. In short-term drug exposure experiments, MRP3 also confers high-level resistance to methotrexate. Neither 2008 cells nor Madin-Darby canine kidney II cells overexpressing MRP3 showed an increase in glutathione export or a decrease in the level of intracellular glutathione, in contrast to cells overexpressing MRP1 or MRP2. We discuss the possible function of MRP3 in (hepatic) physiology and its potential contribution to drug resistance of cancer cells.

ATP-Binding Cassette Transporters↗

PubMed2000

SUMO-1 conjugation to human DNA topoisomerase II isozymes.

Topoisomerase I-mediated DNA damage induced by camptothecin has been shown to induce rapid small ubiquitin-related modifier (SUMO)-1 conjugation to topoisomerase I. In the current study, we show that topoisomerase II-mediated DNA damage induced by teniposide (VM-26) results in the formation of high molecular weight conjugates of both topoisomerase IIalpha and IIbeta isozymes in HeLa cells. Immunological characterization of these conjugates suggests that both topoisomerase IIalpha and IIbeta isozymes are conjugated to SUMO-1. The involvement of SUMO-1/UBC9 in the modification of topoisomerase II isozymes is also supported by the demonstration of physical interaction between topoisomerase II and SUMO-1/UBC9. Surprisingly, ICRF-193, which does not induce topoisomerase II-mediated DNA damage but traps topoisomerase II into a circular clamp conformation, is also shown to induce similar SUMO-1 conjugation to topoisomerase II isozymes. In addition, we show that both oxidative and heat shock stresses, which can cause protein damage, rapidly increase nuclear SUMO-1 conjugates. These studies raise the question on whether SUMO-1 conjugation to topoisomerases is an indirect result of a DNA damage response or a direct result because of protein conformational changes.

DNA Topoisomerases, Type II↗

PubMed2001

Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study.

BACKGROUND: The long-term outcome for patients with aggressive non-Hodgkin's lymphoma (NHL) is poor. Consequently, the European Organization for Research and Treatment of Cancer Lymphoma Group designed a prospective randomized trial to investigate whether high-dose chemotherapy plus autologous bone marrow transplantation (ABMT) after standard combination chemotherapy improves long-term survival. METHODS: Patients aged 15-65 years with aggressive NHL received three cycles of CHVmP/BV polychemotherapy (i.e., a combination of cyclophosphamide, doxorubicin, teniposide, and prednisone, with bleomycin and vincristine added at mid-cycle). After these three cycles, patients with a complete or partial remission and at that time no lymphoma involvement in the bone marrow were randomly assigned to the ABMT arm (a further three cycles of CHVmP/BV followed by BEAC [i.e., a combination of carmustine, etoposide, cytarabine, and cyclophosphamide] chemotherapy and ABMT) or to the control arm (five more cycles of CHVmP/BV). All statistical tests are two-sided. RESULTS: From December 1990 through October 1998, 311 patients (median age = 44 years) were registered and received the first three cycles of CHVmP/BV, and 194 patients were randomly assigned to the treatment arms. Approximately 70% (140 patients) of these patients were of low or low-intermediate International Prognostic Index (IPI) risk. After a median follow-up of 53 months, an intention-to-treat analysis showed a time to disease progression and overall survival at 5 years of 61% (95% confidence interval [CI] = 51% to 72%) and 68% (95% CI = 57% to 79%), respectively, for the ABMT arm and 56% (95% CI = 45% to 67%) and 77% (95% CI = 67% to 86%), respectively, for the control arm. Differences between arms were not statistically significant. A subset analysis on IPI risk groups, although too small for reliable statistical analysis, yielded similar results. CONCLUSIONS: Standard combination therapies remain the best choice for most patients with aggressive NHL. We recommend that patients with IPI low or low-intermediate risk not be subjected to high-dose chemotherapy and ABMT as a first-line therapy.

Adolescent↗