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PubMed2006

Development of a novel nitro-derivative of noscapine for the potential treatment of drug-resistant ovarian cancer and T-cell lymphoma.

We have shown previously that an antitussive plant alkaloid, noscapine, binds tubulin, displays anticancer activity, and has a safe pharmacological profile in humans. Structure-function analyses pointed to a proton at position-9 of the isoquinoline ring that can be modified without compromising tubulin binding activity. Thus, many noscapine analogs with different functional moieties at position-9 were synthesized. Those analogs that kill human cancer cells resistant to other antimicrotubule agents, vincas and taxanes, were screened. Here, we present one such analog, 9-nitro-noscapine (9-nitro-nos), which binds tubulin and induces apoptosis selectively in tumor cells (ovarian and T-cell lymphoma) resistant to paclitaxel, vinblastine, and teniposide. 9-Nitro-nos treatment at doses as high as 100 microM did not affect the cell cycle profile of normal human fibroblasts. This selectivity of 9-nitro-nos for cancer cells represents a unique edge over the other available antimitotics. 9-Nitro-nos perturbs the progression of cell cycle by mitotic arrest, followed by apoptotic cell death associated with increased caspase-3 activation and appearance of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. Thus, we conclude that 9-nitro-nos has great potential to be a novel therapeutic agent for ovarian and T-cell lymphoma cancers, even those that have become drug-resistant to currently available chemotherapeutic drugs.

Antimitotic Agents↗
PubMed1997

Characterization of DNA topoisomerase activity in two strains of Mycoplasma fermentans and in Mycoplasma pirum.

DNA topoisomerases (topos) are essential enzymes that participate in many cellular processes involving DNA. The presence of the DNA-gyrase genes in various mycoplasmas has been reported elsewhere. However, the characterization of DNA topo activity in mycoplasmas has not been previously undertaken. In this study, we characterized the topo activity in extracts of Mycoplasma fermentans K7 and incognitus and in Mycoplasma pirum, as well as in partially purified extract of M. fermentans K7. The topo activity in these microorganisms had the following properties. (i) The relaxation of supercoiled DNA was ATP dependent. (ii) ATP independent relaxation activity was not detected. (iii) Supercoiling of relaxed topoisomers was not observed. (iv) The relaxation activity was inhibited by DNA gyrase and topo IV antagonists (novobiocin and oxolinic acid) and by eukaryotic topo II (m-AMSA [4'-(9-acridylamino)methanesulfon-m-anisidide]) and topo I antagonists (camptothecin). Other eukaryotic topo II antagonists (teniposide and etoposide) did not affect the topo relaxation activity. (v) Two polypeptides of 66 and 180 kDa were found to be associated with the mycoplasma topo activity. These results suggest that the properties of the topo enzyme in these mycoplasma species resemble those of the bacterial topo IV and the eukaryotic and the bacteriophage T4 topo II. The findings that mycoplasma topo is inhibited by both eukaryotic topo II and topo I antagonists and that m-AMSA and camptothecin inhibited the growth of M. fermentans K7 in culture support our conclusion that these mycoplasma species have topo with unique properties.

DNA Topoisomerase IV↗
PubMed1988

Camptothecin, a specific inhibitor of type I DNA topoisomerase, induces DNA breakage at replication forks.

The structure of replicating simian virus 40 minichromosomes, extracted from camptothecin-treated infected cells, was investigated by biochemical and electron microscopic methods. We found that camptothecin frequently induced breaks at replication forks close to the replicative growth points. Replication branches were disrupted at about equal frequencies at the leading and the lagging strand sides of the fork. Since camptothecin is known to be a specific inhibitor of type I DNA topoisomerase, we suggest that this enzyme is acting very near the replication forks. This conclusion was supported by experiments with aphidicolin, a drug that blocks replicative fork movement, but did not prevent the camptothecin-induced breakage of replication forks. The drug teniposide, an inhibitor of type II DNA topoisomerase, had only minor effects on the structure of these replicative intermediates.

Animals↗
PubMed1992

Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer.

OBJECTIVE: To investigate the incidence and aetiology of secondary leukaemia after childhood cancer in Britain. DESIGN: Cohort study and a case-control study. SETTING: Britain and population based National Register of Childhood Tumours. SUBJECTS: Cohort of 16,422 one year survivors of childhood cancer diagnosed in Britain between 1962 and 1983, among whom 22 secondary leukaemias were observed. A case-control study of 26 secondary leukaemias observed among survivors of childhood cancer diagnosed in Britain between 1940 and 1983; 96 controls were selected matched for sex, type of first cancer, age at first cancer, and interval to diagnosis of secondary leukaemia. MAIN OUTCOME MEASURES: Dose of radiation averaged over patients' active bone marrow and total accumulated dose of epipodophyllotoxins, alkylating agents, vinca alkaloids, antimetabolites, and antibiotics (mg/m2) given for the original cancer. RESULTS: Cumulative risk of secondary leukaemia within the cohort did not exceed 0.5% over the initial five years beyond one year survival, except that after non-Hodgkin's lymphomas 1.4% of patients developed secondary leukaemia. Corresponding figure for patients treated for non-Hodgkin's lymphomas in the early 1980s was 4%. The relative risk of secondary leukaemia increased significantly with exposure to epipodophyllotoxins and dose of radiation averaged over patients' active bone marrow. Ten patients developed leukaemia after having an epipodophyllotoxin-teniposide in nine cases, etoposide in one. Chromosomal translocations involving 11q23 were observed relating to two secondary leukaemias from a total of six for which there were successful cytogenetic studies after administration of an epipodophyllotoxin. CONCLUSIONS: Epipodophyllotoxins acting alone or together with alkylating agents or radiation seem to be involved in secondary leukaemia after childhood cancer.

Alkylating Agents↗
PubMed2000

Human DNA-Topoisomerases - Diagnostic and Therapeutic Implications for Cancer.

Topoisomerases constitute a family of highly conserved essential enzymes, which exist in all investigated living pro- and eukaryotic cells. They are indispensable for the control of DNA topology. Humans possess 4 types of topoisomerases, i. e. topoisomerase (topo) I, II, III and V. Topo I, a 100-kDa protein, is a member of the type-I enzyme group (type IB). Functionally, it is an ATP-independent DNA single-strand endonuclease and ligase that functions mainly during transcription but also during DNA replication. Topo II belongs to the type-II enzymes and is represented in humans by 2 highly homologous isoforms, alpha (170 kDa) and beta (180 kDa). Contrary to topo I, the 2 topo II isoforms are ATP-dependent double-strand endonucleases and ligases. Topo I and the beta-form of topo II are expressed in a proliferation-independent manner, whereas topo IIalpha is cell-cycle-regulated. Because of the crucial role of topoisomerases for the maintenance and replication of DNA during proliferation, cells become highly vulnerable when these functions are lost. Consequently, a wide range of drugs with cytostatic effects are topo inhibitors. Topo I inhibitors in clinical use belong to the camptothecin family, e. g. topotecan and irinotecan. Topo IIalpha inhibitors are constituents of most chemotherapeutic protocols and form a large heterogeneous group. It includes clinically used compounds such as the podophyllotoxin analogues etoposide and teniposide, the anthracyclines daunorubicin, doxorubicin and idarubicin, the anthracenedione mitoxantrone and amsacrine. Recently, substances with dual specificity that inhibit both topo I and topo IIalpha have been found. The clinical relevance of these new compounds remains to be established. Specific inhibitors of topo IIbeta have not been described yet. The majority of topo inhibitors interfere with the religation step in the normal action of the enzymes, which leads to a stabilisation of the so-called cleavable complex. This results in DNA single-strand breaks in the case of topo I or double-strand breaks in the case of topo II. DNA single-strand breaks due to topo I inhibition are converted into double-strand breaks in the course of DNA replication. Such topo-mediated DNA strand breaks likely induce repair or apoptosis mechanisms via p53 and/or p21(WAF1/Clip1). As a consequence, while topoisomerases are required for proliferation, proliferation is also essential for efficacious topo inhibition. The cell-cycle-dependent expression of topo IIwas also successfully used for prognostic evaluations of survival in patients with cancer. Copyright 2000 S. Karger GmbH, Freiburg

Journal Article↗
PubMed1992

Reactivity of P-glycoprotein monoclonal antibodies in childhood cancers.

P-Glycoprotein (P-gp), the product of the mdr-1 gene, is implicated in the development of chemoresistance in a variety of, mostly adult, cancers. Its role in paediatric tumours, most of which are non-epithelial in origin, has yet to be fully elucidated. A study was undertaken to investigate reactivity of two P-gp monoclonal antibodies (MAbs), JBS-1 and MRK16, recognising cytoplasmic and surface epitopes, respectively, of the P-gp molecule, in a variety of newly diagnosed and relapsed childhood cancers. P-gp was not expressed in any of 36 tumours examined (neuroblastoma 13, nephroblastoma 12, rhabdomyosarcoma 6, lymphoma 3, teratoma 1, Ewings 1), 14 of whom had chemoresistant disease. Reactivity to both MAbs was also investigated in patients with acute leukaemia. Out of 10 diagnostic acute lymphoblastic leukaemia (ALL) samples, a positive reaction with JSB-1 was observed in 1 patient who failed to remit on standard induction therapy and in 3 of 6 patients in ALL relapse, only 1 of whom showed low grade positivity with MRK16. Both MAbs reacted positively in 1 patient with acute non-lymphocytic leukaemia (ANLL) at diagnosis who achieved remission with teniposide and cytosine arabinoside, but relapsed 7 months later and was again positive with both Mabs. JSB-1 also showed varying degrees of positivity in 4 out of 4 other patients in ANLL relapse. It would therefore appear that P-gp is unlikely to mediate chemoresistance in most solid tumours of childhood, but may well play a major role in the development of chemoresistance in acute leukaemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Anticancer therapy as a pediatric pharmacodynamic paradigm.

A series of clinical pharmacokinetic and pharmacodynamic studies of anticancer drugs has been conducted in children with cancer. Since these drugs typically have narrow therapeutic indices, frequently producing toxicities at dosages required for therapeutic effects, they represent an exemplary class of drugs for pediatric pharmacodynamic studies. Reviewed herein are pediatric pharmacokinetic studies of teniposide and high-dose methotrexate, which demonstrate age-related differences in the disposition of these two highly active anticancer drugs, and pharmacodynamic studies which demonstrate a relation between the disposition of these drugs and their clinical effects (efficacy and toxicity) in children with acute lymphocytic leukemia.

Antineoplastic Agents↗
PubMed2005

High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS.

Doxorubicin-based immunochemotherapy, with interferon, has been shown to improve survival in patients with advanced follicular lymphoma. High-dose chemotherapy with stem-cell support is effective in follicular lymphoma in relapse but remains controversial as a first-line therapy. In a randomized study using a purged autologous stem-cell support, we compared these 2 approaches in patients with advanced follicular lymphoma. Newly diagnosed advanced follicular lymphoma patients (172 patients) were randomly assigned either to an immunochemotherapy regimen (cyclophosphamide, doxorubicin, teniposide, prednisone, and interferon) or to a high-dose therapy followed by purged autologous stem-cell transplantation. Compared with the patients who received chemotherapy and interferon, patients treated with high-dose therapy had a higher response rate (69% vs 81%, P = .045) and a longer median event-free survival (not reached vs 45 months). This did not translate into a better survival rate due to an excess of secondary malignancies after transplantation. The Follicular Lymphoma Prognostic Index identified a subgroup of patients with a significantly higher event-free survival rate after high-dose therapy. Autologous stem-cell transplantation cannot be considered as the standard first-line treatment of follicular lymphoma for patients younger than 60 years old with a high tumor burden.

Adult↗
PubMed1985

Unexpectedly severe toxicity from intensive early treatment of childhood lymphoblastic leukemia.

In early 1984, we treated 13 consecutive patients with acute lymphoblastic leukemia (ALL) using an induction regimen of rapidly rotated combinations of prednisone, vincristine, asparaginase, teniposide (VM-26), cytosine arabinoside, and high-dose methotrexate (MTX) followed by leucovorin rescue. The intent of this clinical trial, designated Total Therapy Study XI, is to test the hypothesis that greater initial leukemia cell kill will decrease opportunities for the development of drug-resistant mutants, with resultant improvement in the length of disease-free survival. Five patients experienced life-threatening gastrointestinal toxicity within three weeks of the start of treatment. One died. Three other patients had severe abdominal pain, abdominal distention, diarrhea, and weight loss, but not gastrointestinal bleeding. In the remaining five patients, toxicity was rapidly reversible, and each child was able to complete the planned course of chemotherapy. The study was then amended to switch high-dose MTX from the induction phase to the consolidation phase, allowing at least one week for mucosal recovery. Among the next 28 patients who were treated, none showed evidence of severe gastrointestinal toxicity. Patients now receive high-dose MTX alone as consolidation therapy and are tolerating it adequately. Drug timing should be examined critically when intensified multiple-agent regimens are being devised for initial treatment of ALL.

Adolescent↗
PubMed1985

Etoposide (VP-16) with prednisone and vincristine for the treatment of refractory acute lymphoblastic leukemia.

Fifty children with acute lymphoblastic leukemia (ALL) in first to fifth relapse were treated with a three-drug reinduction regimen consisting of prednisone (40 mg/m2/d for seven days), vincristine (1.5 mg/m2 on day 1) and etoposide (VP-16, 250 mg/m2 on days 1 through 3). The intent was to assess the efficacy of VP-16 in an otherwise conventional reinduction plan, especially in patients who had previously received teniposide (VM-26), the close congener of VP-16. Among the 46 patients who received at least two courses of the therapy, 16 (0.34) achieved complete remission. Seven others showed improvement in their bone marrow status. Each child had been heavily pretreated with prednisone and vincristine, and 14 had received VM-26. That seven patients judged to be clinically resistant to VM-26 had complete responses to prednisone-vincristine-VP-16 indicates that prior treatment with one podophyllotoxin derivative does not preclude responses to the other. We are uncertain about the pharmacologic basis of these results but suggest that the increased dosage and more frequent administration of VP-16, relative to that of VM-26, was sufficient to overcome apparent resistance to the latter compound. Remission durations ranged from one to eight months (median, four months), emphasizing the need to devise more effective continuation therapy, including investigational agents such as the epipodophyllotoxins.

Acute Disease↗
PubMed1986

Etoposide and cytosine arabinoside combination chemotherapy for refractory acute lymphocytic leukemia in childhood.

Eighteen children with refractory acute lymphocytic leukemia (ALL) who had been heavily pretreated, were treated with combination etoposide and cytosine arabinoside (ara-C) chemotherapy. Seventeen of these 18 patients were in their first to third relapses; the remaining patient had never responded to induction therapy. The drug combination of etoposide followed by ara-C was administered as an intravenous (IV) infusion twice a week for two consecutive weeks, a total of four doses. The dosage was 150 mg/m2/dose for each drug. Seven (39%) of the 18 patients attained a complete remission (CR) and three (17%) attained a partial remission (PR). Complete response was obtained in two of eight patients in first marrow relapse, and in five of nine patients in second and third relapse. Five patients achieved a CR after one course of therapy and two achieved a CR after two courses of therapy. Of three patients who had previously received teniposide, two attained a CR with this combination. The duration of these responses was brief with a median of 1 month, ranging from 0.5 to 3 months, with the exception of one case, which has been in remission for 2.5 + months. Although myelosuppression was observed, none of the patients died from infection or bleeding. Allergic reaction with fever and rash was observed in two patients. The efficacy of the etoposide and ara-C combination for refractory childhood ALL is encouraging in several current reinduction regimens.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

LNH-84 regimen: a multicenter study of intensive chemotherapy in 737 patients with aggressive malignant lymphoma.

From July 1984 to September 1987, 737 patients with aggressive malignant lymphoma (ML) were treated by an intensive regimen (LNH-84) comprising three or four courses of doxorubicin, 75 mg/m2; cyclophosphamide, 1,200 mg/m2; vindesine, 2 mg/m2 x 2; bleomycin, 10 mg x 2; and prednisolone, 60 mg/m2 x 5 (ACVB), consolidation with high-dose methotrexate, ifosfamide, etoposide, asparaginase, and cytarabine, and a randomized late intensification with two courses of cytarabine, cyclophosphamide, teniposide, bleomycin, and prednisone (AraCVmB). Four hundred forty-two patients had intermediate-grade ML, 221 highgrade ML, and 74 unclassified ML. Most of the patients had advanced disease: stage IIE (23%), III (13%), or IV (47%); 38% disseminated nodes; 38% two or more extranodal sites; and 41% a tumoral mass greater than 10 cm. Five hundred fifty-three patients (75%) went into complete remission (CR), 63 (9%) into partial remission, 62 (8%) failed to respond, and 59 (8%) died during ACVB courses, 17 of them from progression of the disease. With a median follow-up of 23 months, the estimated 2-year overall survival time to failure (TTF), and time to relapse (TTR) survival are 67%, 56%, and 67%, respectively. Patients receiving a late intensification had the same relapse rate as the other patients. A persistent fibronecrotic mass was found in 150 patients (20%) and did not influence the relapse rate. Toxicity was mainly neutropenia and infection during the ACVB courses, with 40 patients (5%) dying from septic complications while responding to treatment. Fifty-three percent of the patients had a neutropenia less than 0.500 x 10(9)/L, 58% fever (6% grade 4), and 49% a documented infection (8% grade 4). These results obtained with the LNH-84 regimen demonstrate that this therapeutic scheme is an effective treatment for aggressive ML.

Adolescent↗
PubMed1990

Expression of the multidrug resistance, MDR1, gene in neuroblastomas.

Metastatic neuroblastoma is a childhood malignancy that is frequently responsive to chemotherapy with doxorubicin, vincristine, and teniposide (VM26), among other drugs, but in the majority of treated patients, the tumor recurs during or after chemotherapy. In this work, we have examined the hypothesis that the development of resistance to chemotherapy in neuroblastoma might be related to the expression of the human MDR1 gene, which encodes a multidrug transporter that functions as an energy-dependent drug efflux pump. RNA samples from 49 neuroblastomas were analyzed, including 31 from untreated and 18 from treated patients. MDR1 RNA was detectable in the majority of treated and untreated tumors using a sensitive, semiquantitative slot blot assay. Of the samples from treated patients, five of 18 were found to have high MDR1 RNA levels, whereas only three of 31 from untreated patients had high MDR1 levels, a statistically significant difference (P less than .01). These results show that high levels of MDR1 RNA are often associated with resistance to chemotherapy in neuroblastoma and suggest that they may contribute to this resistance. Many of the neuroblastoma samples were also evaluated for N-myc amplification but there was no correlation between N-myc copy number and the level of MDR1 mRNA expression.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Pharmacodynamics in cancer therapy.

Our understanding of anticancer pharmacodynamics, and the relationships between pharmacologic measurements and clinical effects, has grown markedly in recent years due to advances in analytical and computational technology. Although methotrexate plasma levels have been empirically used to guide leucovorin dosing during high-dose methotrexate therapy, there has been no other standard use of therapeutic drug monitoring in oncology. More recently, investigators have attempted to titrate precisely the dose of antineoplastic agents based on previously derived models and real-time analysis of plasma drug or tissue concentrations. Studies have been completed or are in progress using hexamethylene bisacetamide, etoposide, teniposide, fluorouracil (FUra), and cytarabine (ara-C). Future studies will focus on optimal sampling strategies, analysis of intermediate biochemical end points, combination chemotherapy, modulation by colony-stimulating factors, and more sophisticated pharmacodynamic models.

Antineoplastic Agents↗
PubMed1990

A new treatment protocol for childhood non-Hodgkin's lymphoma: preliminary evaluation.

Between November 1986 and July 1988, 21 consecutively diagnosed children with nonlocalized abdominal lymphoma (Murphy's stage III and IV without CNS disease) were eligible for treatment with a multidrug chemotherapy schedule. The induction phase was the same for all (fractionated cyclophosphamide, intermedian-dose methotrexate [Mtx], vincristine [Vcr], and prednisone). After that the children were randomized to repeat the same scheme or intercalate teniposide (VM26) plus cytarabine (AraC) with the induction-phase scheme. All of them were treated for only 6 months. The protocol approved to be very effective with 85% remission in all the children and 94% survival in patients surviving the induction phase. The toxicity was acceptable, also considering the characteristics of our population (malnourished children). The group VM26 and AraC had few hospital admissions in spite of the small number of children because they received VM26 and AraC as outpatients. The sale purpose of the present study is to report that with a few simple procedures such as hydration, alkalinization, and drug fractionation, the chemotherapy schemes used can bring about a dramatic improvement in short-term survival.

Adolescent↗
PubMed1991

Phase I-II study of two consecutive courses of high-dose epipodophyllotoxin, ifosfamide, and carboplatin with autologous bone marrow transplantation for treatment of adult patients with solid tumors.

We describe a phase I-II study of two consecutive 5-day courses of a three-drug regimen of ifosfamide (IFM), carboplatin (CBDCA), and either etoposide (VP-16) (regimen 1) or teniposide (VM-26) (regimen 2) in high doses together with autologous bone marrow transplantation (ABMT), for previously treated patients with ovarian carcinoma (OC), germ cell tumors (GCT), gestational trophoblastic disease (GTD), or oat cell carcinoma (OCC). Forty-four patients entered the study. Two patients with OC received regimen 1, and 22 were given regimen 2. Sixteen patients with GCT, two with GTD, and two with OCC were treated with regimen 1. Six patients (13%) died of toxicity. Nephropathy and esophagitis were the dose-limiting toxic effects. The maximum-tolerated doses (MTDs) were 1,500 and 200 mg/m2/d for 5 days for IFM and CBDCA, respectively, in combination with VP-16 250 mg/m2/d for 5 days (regimen 1), and 150, 1,500, and 200 mg/m2/d for 5 days for VM-26, IFM, and CBDCA, respectively (regimen 2). The response rate of patients with OC was 78% (complete response [CR], 14%). For patients previously resistant to chemotherapy, the response rate was 70%. There were no long-term disease-free survivors among patients with OC. The response rate of patients with GCT was 60% (CR, 33%). All responders with GCT were resistant to previous chemotherapy. Unmaintained CRs lasted 2, 6, 8+, 27+, and 37+ months. Of the two patients with GTD, one with previous resistance to chemotherapy attained a CR of 18+ months. One patient with OCC attained a CR lasting 6 months. The regimen possesses great antitumor activity. It produced CRs of long duration in a number of patients with GCT and GTD who were previously resistant to chemotherapy.

Adult↗
PubMed1991

Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study.

We assessed tumor cell DNA content (ploidy) and N-myc gene copy number as predictors of long-term disease-free survival in 298 children with neuroblastoma. Diploid tumor stem lines were identified in 101 patients (34%), clonal hyperdiploid abnormalities in 194 (65%), and hypodiploid stem lines in three (1%). In children with widely disseminated tumors at diagnosis (stage D), ploidy had a highly age-dependent influence on prognosis. Among infants (less than 12 months) treated with cyclophosphamide-doxorubicin, hyperdiploidy was closely associated with long-term disease-free survival (greater than 90% of cases), while diploidy invariably predicted early treatment failure (P less than .001). Similarly, in children 12 to 24 months of age who were treated with cisplatin-teniposide and cyclophosphamide-doxorubicin, diploidy uniformly predicted early failure, whereas half of the children with hyperdiploidy achieved long-term disease-free survival (P less than .001). There was no relationship between ploidy and treatment outcome in children older than 24 months with stage D tumors who had a very low probability of long-term disease-free survival (less than 10%). N-myc gene amplification was detected in 37 (25%) of the 147 tumors tested, with the remainder showing single-copy levels of the gene. N-myc gene amplification was more frequent in diploid than in hyperdiploid tumors (23 of 57 v 14 of 87, P = .001) and predicted a high likelihood of early treatment failure. In children younger than 2 years with disseminated neuroblastoma, tumor cell ploidy and N-myc gene copy number provide complementary prognostic information that will distinguish patients who can be cured on current regimens from those who require new treatment strategies.

Age Factors↗