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 631 records · Page 35Linked to original sources

PubMed1999

Chemotherapy of non-small-cell lung cancer: role of erythropoietin in the management of anemia.

Main mechanisms involved in the development of chemotherapy-induced anemia are the direct bone marrow damage and the renal impairment with a secondary deficient production of erythropoietin. The first mechanism is induced by almost all cytotoxic drugs whilst the second one has been demonstrated with cisplatin treatment. NSCLC patients are generally treated with platinum-based chemotherapy and then both mechanisms are involved in the development of anemia which can be, as a consequence, more frequent and more severe compared to other cancer patients. Chemotherapy regimens such as MVP (mitomycin, vindesine, platin), cisplatin-etoposide and cisplatin-teniposide induce grade > or = 2 anemia in 64%, 46% and 83% of patients, respectively, with grade 3-4 anemia occurring in 29%, 15% and 24% of patients. New chemotherapy regimens are also associated with a high incidence of anemia. Carboplatin-paclitaxel induces grade 3-4 anemia in 34% of patients and 30% of patients need blood transfusions. Similarly, 33% of patients treated with cisplatin-gemcitabine require blood transfusions. Erythropoietin is able to correct anemia in nearly 60%-80% of patients receiving platinum-based chemotherapy and in nearly 40% of patients treated with regimens without platinum compounds, leading to a reduction in blood transfusion requirement. Moreover, erythropoietin is able to prevent anemia development in cancer patients. Due to the high incidence of anemia, erythropoietin may represent an important tool in the supportive care of NSCLC patients. Erythropoietin use is mainly limited by the economic cost and then efforts should be made to identify the subset of patients in whom this supportive therapy is cost-effective. Patient and disease characteristics, factors predicting the probability to be transfused as well as factors predicting the response to erythropoietin can be useful in selecting patients likely to benefit from erythropoietin therapy.

Anemia↗

PubMed1993

Various inhibitors of DNA topoisomerases diminish repair-specific DNA incision in UV-irradiated human fibroblasts.

A function for topoisomerases I and II in DNA excision repair can be postulated from the organization of the mammalian chromosome, involving nucleosomal structures and matrix-attached DNA loops. To analyse this function we determined UV-induced DNA incision in confluent human fibroblasts in the presence of 16 inhibitors of topoisomerases I and II which belonged to at least five different drug categories, based on their mechanism of action. Dose-response experiments were performed, analysed by linear regression and the concentrations at which DNA-incising activity was reduced to 50% were calculated (K50 values). The majority of these values represent concentrations for which interfering cell toxicity could be excluded. K50 concentrations, which were determined by extrapolating dose-response data, may hit the toxicity range, nevertheless, we deem our K50 scale useful for making biochemical comparisons. With respect to topoisomerase I, camptothecin and topotecan diminished repair-specific DNA incision to a small extent, whereas distamycin, which binds to the minor groove of DNA, caused a stronger effect. With respect to topoisomerase II the results were as follows. (i) The DNA intercalator ethidium bromide decreased DNA-incising activity at rather low concentrations, which indicates marked inhibitory potency. Quinacrine was less effective. (ii) Inhibitors intercalating and binding to the 'cleavable' DNA-topoisomerase complex (m-AMSA, mitoxantrone, doxorubicin and daunorubicin) strongly suppressed reparative DNA incision. (iii) Only small effects were observed using several drugs which act by trapping the 'cleavable' DNA-enzyme complex, namely nalidixic acid and oxolinic acid. In contrast, etoposide and teniposide inhibited post-UV DNA cleavage sizeably. (iv) Merbarone had to be applied at very high concentrations to reduce UV-induced DNA incision. (v) Novobiocin, an inhibitor of the ATPase subunit of topoisomerase II, markedly diminished repair-specific DNA cleavage. A comparison of the K50 values for DNA incision with those for DNA repair synthesis (1) shows that the majority of the investigated drugs inhibited both repair parameters. There were, however, differences in the concentrations required to achieve the 50% inhibition level. The results are best explained by assuming that in UV-irradiated human fibroblasts the 180 kd form of topoisomerase II is a target enzyme for inhibitors which suppressed repair and that this isozyme is involved in steps preceding repair-specific DNA incision.

Antineoplastic Agents↗

PubMed1989

Resistance to drugs associated with the multidrug resistance phenotype following selection with high-concentration methotrexate.

To study patterns of resistance at extreme but nevertheless clinically relevant drug concentrations, we developed a series of methotrexate-selected CCRF-CEM sublines, all of which were highly resistant to this antifolate (relative resistance, 10(2)- to greater than 10(5)-fold). The least methotrexate-resistant subline was completely sensitive to drugs associated with the multidrug resistance phenotype. However, more highly methotrexate-resistant sublines were significantly cross-resistant to vincristine, vinblastine, and dactinomycin (maximum relative resistance, 40-fold). These sublines were not cross-resistant to doxorubicin, daunorubicin, and teniposide. Regression analysis indicated that relative resistance to methotrexate was correlated with relative resistance to vincristine (r = 0.96) and vinblastine (r = 0.99). Such cross-resistance in highly methotrexate-resistant cells may have important clinical implications.

Antineoplastic Agents↗

PubMed1991

Adjuvant intravesicular pharmacotherapy for superficial bladder cancer.

In 1990, bladder cancer, excluding carcinoma in situ, was estimated to contribute 49,000 cases of cancer. In men 75 years old or older, it became the fifth leading cause of cancer deaths. Of patients with bladder cancer, 75%-80% initially present with superficial bladder tumors. Treatment of these tumors has three objectives: 1) to eradicate existing disease, 2) to provide prophylaxis against tumor recurrence, and 3) to avoid deep invasion into the muscle layers of the bladder. Transurethral resection is the primary treatment to eradicate superficial bladder tumors, but 40%-80% of these tumors recur. Because of these high recurrence rates, adjuvant intravesicular pharmacotherapy with cytotoxic and immunomodulatory drugs has gained widespread use. The past two decades of clinical investigations in superficial bladder cancer have provided valuable information on the biology and treatment of the disease. Multivariate analyses have indicated that tumor grade and stage are the most important prognostic variables commonly available to the clinician to identify the patient at greatest risk of developing muscle-invasive or metastatic bladder cancer. These studies have also identified groups at low risk for tumor recurrence and invasive bladder cancer. Randomized trials have shown that recurrence rates are decreased by adjuvant intravesicular pharmacotherapy with a number of drugs: bacillus Calmette-Guérin vaccine (BCG), doxorubicin, ethoglucid (Epodyl), mitomycin-C, teniposide, and thiotepa. However, few studies indicate that adjuvant intravesicular pharmacotherapy can prevent progression to invasive bladder cancer in the high-risk patient with superficial bladder cancer. Additional clinical trials are needed to determine whether such therapy can prevent invasive and metastatic bladder cancer and improve disease-free survival in this group. In addition, the identification of tests (e.g., monoclonal antibody tests, chromosomal analyses, and tumor marker assays) that can help to identify high-risk patients is needed to better develop therapeutic strategies for superficial bladder cancer.

Antineoplastic Agents↗

PubMed1993

Report of the Cancer Therapy Evaluation Program monitoring plan for secondary acute myeloid leukemia following treatment with epipodophyllotoxins.

BACKGROUND: Recent reports have documented the occurrence of treatment-related acute myeloid leukemia (AML) following therapy with epipodophyllotoxins. These reports have led to growing concern among oncologists, which could lead to premature abandonment of these agents at a time when the relationship between cumulative dose of epipodophyllotoxin and risk of treatment-related AML has not been determined. PURPOSE: Because of the increasingly important role of epipodophyllotoxins in the treatment of several types of adult and pediatric tumors, the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of treatment-related AML following epipodophyllotoxin treatment. METHODS: We identified 12 NCI-supported Cooperative Group clinical trials in which patients with solid tumors are being treated with epipodophyllotoxins at different cumulative doses. One trial is using a moderate dose of teniposide (900 mg/m2), and 11 trials are using etoposide at a low dose (< 1500 mg/m2), a moderate dose (1500-3999 mg/m2), or a high dose (> or = 4000 mg/m2). Cases of treatment-related AML and treatment-related myelodysplastic syndrome (MDS) (hereafter referred to as treatment-related AML/MDS) occurring in these trials are reported to CTEP, with initial analysis for each cumulative dose group triggered by the reporting of four cases of treatment-related AML/MDS in that group. For each analysis, total patient follow-up for the group is determined and cumulative 6-year incidence rate is calculated. RESULTS: Three cases of treatment-related AML and one case of treatment-related MDS (with documented monosomy 7) were reported in a group of 207 patients who received etoposide at a low cumulative dose. The calculated 6-year rate of development of treatment-related AML/MDS was 3.2% (95% upper confidence interval bounded by 7.2%). CONCLUSIONS: The 6-year cumulative rate of treatment-related AML/MDS (3.2%) is within the range previously reported for alkylator-based regimens that did not include epipodophyllotoxins. IMPLICATIONS: Previous reports have suggested that higher cumulative doses of alkylators are associated with increased risk of treatment-related AML, and a critical goal of the monitoring plan is to determine whether a similar relationship exists for the epipodophyllotoxins. Estimates will be developed for leukemogenic risk for the moderate- and high-cumulative-dose groups when four cases of treatment-related AML/MDS have been identified within each group.

Acute Disease↗

PubMed1999

Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus.

BACKGROUND: Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine, and those with homozygous deficiency in thiopurine S-methyltransferase (TPMT) enzyme activity have an extreme sensitivity to this drug as a result of the accumulation of higher cellular concentrations of thioguanine nucleotides. We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes. METHODS: We compared, by use of statistical modeling, 6-mercaptopurine pharmacology and tolerance in 180 patients who achieved remission on St. Jude Children's Research Hospital Protocol Total XII composed of weekly methotrexate (40 mg/m(2)) and daily oral 6-mercaptopurine (75 mg/m(2)) given for 2.5 years, interrupted every 6 weeks during the first year for treatment with either high-dose methotrexate or teniposide plus cytarabine. Statistical tests were two-sided. RESULTS: Erythrocyte concentrations of thioguanine nucleotides (pmol/8 x 10(8) erythrocytes) were inversely related to TPMT enzyme activity (P<.01), with averages (+/- standard deviations) of 417 (+/-179), 963 (+/-752), and 3565 (+/-1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and homozygous-deficient (n = 2) patients, respectively. There was complete concordance between TPMT genotype and phenotype in a subset of 28 patients for whom TPMT genotype was determined. There were no sex differences in thioguanine nucleotide concentrations (P =.24), TPMT enzyme activity (P =.22), or average weekly prescribed dose of 6-mercaptopurine (P=.49). The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest among patients homozygous for mutant TPMT (100%), intermediate among heterozygous patients (35%), and lowest among wild-type patients (7%) (P<.001), with average (+/- standard deviation) final weekly 6-mercaptopurine doses of 72 (+/-60), 449 (+/-160), and 528 (+/-90) mg/m(2), respectively. Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations. CONCLUSION: We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait.

Antimetabolites, Antineoplastic↗

PubMed1995

Genotoxicity of 17 gyrase- and four mammalian topoisomerase II-poisons in prokaryotic and eukaryotic test systems.

The genotoxic potency of certain classes of topoisomerase II poisons is correlated with their affinity to the topoisomerase protein rather than with the presence of 'classical' structural alerts for DNA reactivity: bacterial topoisomerase II poisons (specifically named gyrase inhibitors) are highly genotoxic in prokaryotic systems; mammalian topoisomerase II poisons are potent mutagens/clastogens in eukaryotic systems. Studies with bacterial, lower eukaryotic and mammalian genotoxicity tests were performed to draw structure-activity conclusions and address risk-benefit considerations for the class of quinolone gyrase inhibitors. All 17 gyrase inhibitors investigated in this study showed genotoxic activity in Salmonella typhimurium strain TA102 and the SOS test. The genotoxic and the toxic activities increased in a highly parallel fashion from the parent compounds, nalidixic acid and oxolinic acid, to the new generation fluoroquinolones. Generally, the most potent fluoroquinolones also show clear-cut positive effects in eukaryotic test systems, although at concentrations 100-1000-fold higher than those effective in bacteria and also 100-1000-fold higher than the minimal genotoxic concentrations of antitumour topoisomerase II inhibitors (ellipticine, teniposide, mAMSA) used as reference compounds. However, subtle structural modifications of the quinolones can strongly diminish the preferential genotoxicity in the prokaryotic test systems.

Animals↗

PubMed1992

Alternating chemotherapy for small-cell lung cancer. A twelve-week schedule of six drugs.

We have treated sixty-two patients (21 with limited disease, 41 with extensive disease), on an outpatient-basis schedule of six drugs administered weekly for twelve weeks. Cyclophosphamide, 400 mg/m2, adriamycin, 20 mg/m2 and vincristine, 2 mg, full dose, were administered during weeks 1, 5 and 9; cisplatin, 50 mg/m2 and etoposide, 100 mg/m2 during weeks 2, 6 and 10; adriamycin and vincristine at the same doses during weeks 3, 7 and 11; methotrexate 30 mg/m2, during weeks 4, 8 and 12. After the first 28 patients vincristine was replaced by teniposide (VM-26) due to neurotoxicity. The overall response rate was 64.5% (complete remission 13 p., partial remission 27 p.). Toxicity grade 3-4, mainly nausea and vomiting or neutropenia, was recorded in 17 patients. Alopecia grade 1-2 was universal. One toxic death occurred from sepsis. The overall survival was 8 months (range 1-40), (95% CL: 53-77%); 8 months in limited disease (range 1-40), and 7 months in extensive disease (range 1-23). Time to treatment failure was 6 months (7 limited disease, 5 extensive disease). In conclusion, the results of this alternating schedule are poorer than those attained with standard, high-dose treatments, mainly in limited disease, but could be a less toxic option for patients with extensive disease.

Adult↗

PubMed1992

Prospective study with combined low-dose chemotherapy and zidovudine in 37 patients with poor-prognosis AIDS-related non-Hodgkin's lymphoma. French-Italian Cooperative Study Group.

The French-Italian Cooperative Study Group included patients with poor-prognosis AIDS-related non-Hodgkin's lymphoma (NHL), defined as those with performance status (PS) > or = 3 and/or opportunistic infections (OI), in a prospective study with a 50% reduced-dose combination chemotherapy regimen: CHVmP-Vincristine-bleo (cyclophosphamide 300 mg/m2 i.v. day 1, doxorubicin 25 mg/m2 i.v. day 1, teniposide 30 mg/m2 i.v. day 1, prednisone 20 mg/m2 per os days 1-5, vincristine 2 mg i.v. day 15, and bleomycin 10 mg i.v. day 15), given every 21 days for eight cycles, and concomitant zidovudine 500 mg per os per day. The aims of this combined treatment were to reduce bone marrow toxicity and infectious complications related to chemotherapy (with a low-dose chemotherapy regimen), and to control the HIV and related infectious complications (with zidovudine therapy). Thirty-seven patients entered this prospective study. At the time of the NHL diagnosis, 41% of the patients had asymptomatic HIV infection, 27% had ARC and 32% had already had CDC-defined diagnoses of AIDS. The median CD4+ cell count was 35 mm3. Only 29 patients are evaluable for response, since 8 received only one cycle of chemotherapy. Fifteen of 29 (52%) patients obtained objective responses, with only 4 (14%) achieving complete remissions (CR) of 1, 4, 14 and 29+ months. Three (16%) CRs were achieved in 19 evaluable patients included in the study because of poor PS, and only one CR was observed in 10 evaluable patients with histories of OI, either alone or with poor PS. The most common side effect was bone marrow toxicity with 2 related toxic deaths.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Therapy-related acute myeloid leukemia secondary to inhibitors of topoisomerase II: from the bedside to the target genes.

In the past five years, several groups have reported acute myeloid leukemia (AML) often monoblastic, as a complication of chemotherapy regimens including the epipodophyllotoxins, etoposide and teniposide. This syndrome is distinct clinically, pathologically and cytogenetically from classical therapy-related myelodysplasia and AML. There is also evidence that other topoisomerase II inhibitors, such as the intercalating agents (including doxorubicin, mitoxantrone, and actinomycin D) may be leukemogenic. Furthermore, there may be further interactions from concomitant topoisomerase II inhibitors and alkylating agents. Topoisomerase II inhibitors induce DNA cleavage and other chromosomal aberrations, including sister chromatid exchanges. These clastogenic abnormalities are not fully understood, and may be specific for each cytotoxic agent. Work is in progress to clone breakpoints such as the t(9;11) and t(8;21) and the use of the resultant DNA probes will enhance our understanding of the leukemogenic process. Given the potential diversity in patients with secondary leukemia, cytogenetic studies should be mandatory for both enhancing our knowledge base and guiding treatment in individual patients. Clinicians must also be wary of the leukemogenic potential of 'dose-intense' regimens including agents such as etoposide and doxorubicin.

Acute Disease↗

PubMed1987

Intraarterial mitomycin-C for recurrent brain metastases.

Fifteen consenting patients with brain metastases recurrent after cranial irradiation were treated with intraarterial mitomycin-C, 15 mg/m2, administered in a total final volume of 100 ml 0.45% saline over 20 min through a transfemoral catheter with a 0.2-mu in-line filter. There were 2 early deaths (one probably drug-related). Of the 13 evaluable patients, 6 (46%) responded, with both computed tomography (CT) scan and neurological improvement. Median response duration was 25 weeks, and median survival of all 15 patients was 17 weeks. Neurological, ocular, and local skin toxicity were dose-limiting. The degree of toxicity was comparable to that we have noted with other intracarotid regimens, and it appears to be less toxic when infused into the vertebral artery than are most other drugs (although experience is still limited and caution still needs to be exercised). We do not recommend that this replace or be added to cranial irradiation as front-line treatment of brain metastases, but we feel that it is an effective and reasonably well-tolerated regimen for treatment of brain metastases that have recurred after cranial irradiation. We are currently initiating studies of intraarterial mitomycin-C combined with intraarterial cisplatin and teniposide (VM-26) as treatment for recurrent brain metastases.

Adolescent↗

PubMed1998

Effects of 1,2-naphthoquinones on human tumor cell growth and lack of cross-resistance with other anticancer agents.

The sensitivity of human tumor and rat prostate tumor cells to a series of naphthoquinones, including tricyclic compounds of the beta-lapachone and dunnione families as well as 4-alkoxy-1,2-naphthoquinones, was evaluated. To better understand the mechanism of cytotoxicity of 1,2-naphthoquinones, the roles of various resistance mechanisms including P-glycoprotein, multidrug resistant associated protein, glutathione (GSH) and related enzymes, altered topoisomerase activity, and overexpression of genes that control apoptosis (bcl-2 and bc-xL) were studied. MCF7 cells were most sensitive to the naphthoquinones with IC50 values ranging from 1.1 to 10.8 microM, as compared to 2.5 to >32 microM for HT29 human colon, A549 human lung, CEM leukemia and AT3.1 rat prostate cancer cells. MCF7 ADR cells, selected for resistance to adriamycin (ADR), displayed cross-resistance to the tricyclic 1,2-naphthoquinones. Drug efflux via a P-glycoprotein mechanism was ruled out as a mechanism of resistance to 1,2-naphthoquinones, since KB-V1 cells expressing high levels of P-glycoprotein and the KB-3.1 parent line were equally sensitive to these compounds. Any resistance of the tricyclic naphthoquinones noted in ADR-resistant cells appeared to relate to the GSH redox cycle and could be circumvented by exposure to buthionine sulfoximine or by changing the structure from a tricyclic derivative to a 4-alkoxy-1,2-naphthoquinone. The 1,2-naphthoquinones were found to be cytotoxic against CEM/VM-1 and CEM/M70-B1 cells that were selected for resistance to teniposide or merbarone, respectively. In addition, cells overexpressing bcl-2 or bcl-xL proteins were as sensitive to 1,2-naphthoquinones as were control cells. Because of their effectiveness in drug-resistant cells, these agents appear to hold promise as effective chemotherapeutic agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Altered DNA-cleavage activity of topoisomerase II from WEHI-3B leukemia cells with specific resistance to ciprofloxacin.

In order to investigate the mechanisms of drug resistance arising in tumor cells, we investigated the capacity of fluoroquinolones to inhibit the in vitro growth of WEHI-3B monomyelocytic leukemia cells and then we established a variant of this line (currently maintained in the absence of drug). The line, named WEHI-3B/CPX, expresses a specific resistance to ciprofloxacin (CPX; resistance index=17.3+/-2.2), and does not show cross-resistance with other fluoroquinolones, camptothecin and topoisomerase II inhibitors such as doxorubicin, etoposide and teniposide. Although a little decrease in intracellular accumulation of CPX is observed in WEHI-3B/CPX cells, these cells do not express MDR or LRP markers, and the resistance is not circumvented by verapamil. Purified nuclear extracts from WEHI-3B and WEHI-3B/CPX cells were tested for topoisomerase I catalytic activity and checking in vitro topoisomerase I sensitivity to CPX and camptothecin inhibition, but no difference was observed. As the treatment with CPX showed that the resistant cell line suffers a significantly lower number of breaks in the DNA molecule we also addressed our investigations to the topoisomerase II-dependent DNA cleavage that, in the resistant clone, was found dramatically less susceptible to be enhanced by CPX both in pre-strand and post-strand DNA passage conditions. WEHI-3B/CPX cells do not express any character of multidrug resistance and represent a rare case of specific drug resistance to CPX. The specific resistance to CPX observed in these cells is related to a functional decrease of topoisomerase II cleavage activity. It could be consequent to a decreased binding affinity of CPX for the topoisomerase II--DNA complex or to a decreased affinity or specificity of topoisomerase II for its DNA cleavage sites.

Animals↗

PubMed1993

Autologous bone marrow transplantation in childhood acute lymphoid leukemia with use of purging.

INTRODUCTION: Chemotherapy alone is rarely curative for children with recurrent acute lymphoid leukemia (ALL). Although allogeneic bone marrow transplantation has been reported to provide disease-free survival rates of from 40 to 70%, its application is severely limited by the lack of sibling donors. The use of autologous bone marrow transplantation (ABMT) allows the application of therapy of comparable intensity to a larger number of patients. A potential problem associated with transplanting autologous marrow, the reinfusion of residual leukemic cells in the harvested marrow, can be addressed through purging. The most widely used purging techniques involve either immunologic or pharmacologic techniques. PATIENTS AND METHODS: Since 1980, the Dana-Farber Cancer Institute has had an active autologous bone marrow transplantation program for children with recurrent ALL. Sixty-six children underwent autologous marrow transplants with a conditioning regimen consisting of teniposide, cytarabine, cyclophosphamide, and total body irradiation. This was followed by infusion of autologous marrow purged with two monoclonal antibodies directed against CD9 and CD10 and complement. RESULTS: Twelve patients died of acute complications, 26 experienced relapse of ALL, one patient had acute myeloid leukemia 6 years after marrow transplant, and 27 remain in continuous complete remission. The event-free survival rate was 47% for patients with a first remission of at least 2 years, as compared with a rate of 10% for those with a shorter first remission. Since 1989, we have used a new conditioning regimen consisting of fractionated total body irradiation followed by high-dose etoposide and cyclophosphamide for patients with a short first remission. For the first 11 patients, the event-free survival rate is 61%. LITERATURE REVIEW: We reviewed reports of 552 patients with ALL who underwent ABMT at 17 centers. To our knowledge, only four series, including our own, were limited to pediatric patients. Some form of purging was used in 483 (87%) patients. Although conditioning regimens varied greatly, more than 80% of patients received at least total body irradiation and cyclophosphamide. Failure of engraftment was reported in only three patients. The rates of disease-free survival in these series clustered between 25-35%. The most common cause of treatment failure after ABMT was relapse, which occurred in 40-85% of patients. Early deaths from toxicity occurred in 5-21% of patients. Two studies attempted to compare the results of allogeneic and autologous bone marrow transplantation by using the same conditioning regimen for all. Neither series reported significant differences in overall survival.

Bone Marrow Purging↗

PubMedDate not supplied

Therapeutic trial for infant acute lymphoblastic leukemia: the Pediatric Oncology Group experience (POG 8493).

PURPOSE: Despite improved event-free survival of older children with acute lymphocytic leukemia (ALL), infants <1 year of age continue to have a very poor prognosis. A new therapy designed specifically for infants with ALL was initiated. PATIENTS AND METHODS: From 1984 until 1990, 82 eligible infants <1 year of age were entered on a Pediatric Oncology Group (POG) protocol 8493 for infant ALL. Compared to older patients, infants at diagnosis had more overt CNS leukemia (26%), higher initial WBC count (56% >50,000/microl), and a higher likelihood of CD-10 (CALLA) negative lymphoblasts (55%). A translocation involving chromosome 11 at band q23 was detected in 27 of 64 cytogenetically informative cases. Treatment was based upon two institutional pilot studies utilizing chemotherapy doses based upon body weight. Important components included remission induction with cyclophosphamide (Ctx), vincristine (Vcr), cytosine arabinoside (Ara-C), and prednisone (Pred) (COAP); consolidation therapy with teniposide (VM-26) and Ara-C; and continuation therapy with alternating pulses of COAP with VM-26/Ara-C separated by a methotrexate (Mtx) and 6-mercaptopurine (6-MP) backbone plus CNS therapy consisting of standard triple intrathecal therapy (TIT) (Mtx/hydrocortisone/Ara-C), which avoided the use of radiotherapy in this population. RESULTS: Seventy-six infants achieved a complete remission (93%). Fifty patients have relapsed: 35 isolated marrow relapses, five isolated CNS relapses, eight combined marrow and CNS relapses, and two other relapses. Actuarial event-free survival was 28% (SE = 5%) at 4 years. Infants >274 days (9 months) at diagnosis had a better outcome than those <274 days. CONCLUSIONS: This study represents a modest outcome improvement in comparison to previous experience with ALL for infants treated on POG trials. More effective therapy is still needed for infants with ALL.

Age Factors↗

PubMed1999

Interspecies variability and drug interactions of clozapine metabolism by microsomes.

Cytochrome P450 expression in liver is influenced by several factors, including species, sex and strain. We compared metabolism formation of clozapine in different species (rat, mouse, guinea-pig, dog, monkey and man) so as to choose between species to further validate interaction studies. Liver microsomes of male and female Sprague-Dawley rats, hairless rats, OF1 mice, Balb C mice and Dunkin-Hartley albino guinea-pigs, male beagle dogs, male cynomolgus monkeys and man were used to investigate in vitro metabolism of clozapine. This process was dependent on the presence of NADPH and on the presence of microsome protein. In addition, we observed the formation of desmethyl- and N-oxide metabolites, with the rate of formation of each of these compounds varying with species, sex and strain of microsomes incubated. The desmethyl- and N-oxide metabolites formed were statistically greater in male than in female rats, mice in the two strains studied, as well as for the guinea-pigs. Levels of desmethyl clozapine formed were high for the rats and no significant difference in clozapine biotransformation was observed between Sprague-Dawley and hairless rats. For man, the formation of metabolites of clozapine was comparable with guinea-pig, dog and monkey. In addition, we screened the effect of 52 molecules, representative of 11 different therapeutic classes, on the metabolism of clozapine by rat liver microsomes. We found that most of the calcium channel blockers (diltiazem, felodipine, isradipine, lacidipine, nicardipine and nitrendipine), antifungals (ketoconazole, miconazole) and two anticancer drugs (paclitaxel, teniposide) caused more than 50% inhibition of clozapine metabolism in vitro. The extent of inhibition was increased in a concentration-dependant manner. Complementary clinical and pharmacokinetic studies should be performed to confirm these results.

Animals↗

PubMed1999

Assessment of drugs against Cryptosporidium parvum using a simple in vitro screening method.

A rapid semi-quantitative screening method was devised for assessing the anticryptosporidial and cytotoxic effects of putative chemotherapeutic compounds. The method is suitable as an initial rapid screening procedure from which compounds demonstrating anticryptosporidial activity can be identified for further analysis. It has the advantages of speed, low cost and concurrent assessment of anticryptosporidial and cytotoxic effects and allows accurate determination of minimum lethal concentrations. Of the 71 compounds screened, six completely inhibited cryptosporidial growth at 1 microM (monensin, salinomycin, alborixin, lasalocid, trifluralin and nicarbazin) and a further eight showed significant anticryptosporidial activity at 1 or 20 microM (halquinol, bleomycin, suramin, mitomycin, doxycycline hydrochloride, toltrazuril, chloroquine phosphate and teniposide). Twelve compounds were found to have some degree of cytotoxicity at 1 microM and a further 12 at 20 microM.

Animals↗

PubMed1994

Gene transfer of drug resistance genes. Implications for cancer therapy.

Two general approaches to the gene therapy of cancer have been proposed: (1) strategies that use exogenous genes to modify cancer cells so that they are less malignant or more susceptible to host defenses or to killing by exogenous agents; and (2) approaches that modify host cells so that they are more effective in eliminating cancer cells or more resistant to agents that are used to treat cancer. In both cases, the development of vectors that encode in vivo selectable phenotypes, such as drug resistance, would be extremely valuable because of the inherent inefficiency of gene transfer and the potential of such vectors to protect normal tissues against toxic agents. To allow the selection of cells in vivo that have been transduced with vectors for gene therapy, we have utilized the human multidrug resistance (MDR1) gene. The product of this gene is a 170,000-dalton glycoprotein known as P-glycoprotein, which acts as an energy-dependent efflux pump for a great many cytotoxic anticancer drugs, including doxorubicin, daunorubicin, etoposide, teniposide, actinomycin D, and taxol. Vectors encoding an MDR1 cDNA are able to transduce many cell types, including bone marrow cells, with high efficiency to allow selection of drug resistance in vitro and in vivo in mouse models. Thus, it should be possible to protect the bone marrow of patients undergoing intensive chemotherapy by transduction of their bone marrow with MDR1 vectors. Furthermore, the ability to select for the presence of the MDR1 cDNA in vivo means that it can be used to introduce otherwise nonselectable genes into the bone marrow for therapy of cancer and other diseases.

3T3 Cells↗