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PubMed1991

Expression of a mutant DNA topoisomerase II in CCRF-CEM human leukemic cells selected for resistance to teniposide.

Nuclear extracts from teniposide (VM-26)-resistant sublines of the human leukemic cell line CCRF-CEM have decreased levels of DNA topoisomerase II catalytic activity and decreased capacity to form drug-stabilized covalent protein-DNA complexes. The ATP concentration required for equivalent activity in a DNA-unknotting assay is 2- to 8-fold higher in nuclear extracts from drug-resistant cell lines as compared with the parental line. When adenosine 5'-[beta,gamma-imido]triphosphate is substituted for ATP in complex-formation assays, no significant change is seen with drug-sensitive cells, but a 50-65% reduction is seen with VM-26-resistant cells. Collectively, these results indicate that an alteration in ATP binding may be involved in the resistance phenotype. Therefore, we identified regions of the topoisomerase II sequence that conform to previously identified nucleotide-binding sites. Starting with cDNA as the template we determined the sequence of the topoisomerase II mRNA surrounding these sites by sequencing DNA fragments produced by the polymerase chain reaction. In the region corresponding to the consensus B ATP-binding sequence described by Walker et al. [Walker, J. E., Saraste, M., Runswick, M. J. & Gay, N. J. (1982) EMBO J. 1, 945-951], the cDNA from the two VM-26-resistant sublines contained an altered sequence having a G----A base change. This base substitution results in the replacement of the conserved arginine at position 449 with a glutamine. Hybridization with allele-specific oligonucleotides confirmed the presence of both the normal and the altered sequence in the resistant cell lines, whereas only the normal sequence was found in the sensitive CEM cells. A chemical mismatch cleavage procedure for the detection of mispaired bases in DNA duplexes identified no other alterations in the 5' third of the mRNA coding sequence, which contains the complete ATP-binding domain of topoisomerase II. The presence of mRNA encoding topoisomerase II with Gln449 correlates both with the presence of a topoisomerase II protein whose interaction with ATP is altered and with increased resistance to the cytotoxicity of VM-26.

Alleles↗
PubMed1987

Etoposide (VP16) and teniposide (VM26): novel anticancer drugs, strongly mutagenic in mammalian but not prokaryotic test systems.

The mutagenic effect of the antineoplastic drugs VP16 (etoposide; 4'-demethylepipodophyllotoxin-ethylidene-beta-D-glucopyranoside) and VM26 (teniposide; 4'-demethylepipodophyllotoxin-thenylidene-beta-D-glucopyr ano side) in mammalian and prokaryotic test systems have been compared. Both VP16 and VM26 which interact with mammalian DNA topoisomerase II, are strongly mutagenic in Chinese hamster ovary cells as indicated by the induction of mutations at the hypoxanthine-guanine phosphoribosyl transferase and adenosine kinase loci, and production of DNA strand breaks and sister-chromatid exchanges. Mouse L cells treated with these drugs also show a large dose-dependent (0.05-0.2 microgram/ml for VM26 and 0.5-1.5 micrograms/ml for VP16) increase in the frequency of 6-thioguanine-resistant mutants and extensive fragmentation of cellular DNA. In contrast to the results obtained with mammalian cells, VP16, which was extensively investigated, showed no increase in revertant frequencies in the Salmonella typhimurium strains TA98 and TA100 at concentrations up to greater than 500 micrograms/plate, in either the absence or presence of an exogenous rat liver activation system. However, a very weak mutagenic response to VP16 and VM26 (less than 2-fold increase in revertant frequency) at very high drug concentrations was observed in the strain TA102. VP16 also failed to show any mutagenic response (up to greater than 500 micrograms/ml) in an excision repair-proficient Escherichia coli strain 113/143 employing two different forward mutation detection systems [viz. ability to grow in galactose (Gal+) or in presence of 5-methyltryptophan], which are capable of detecting various types of genetic lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effects of VM26 (teniposide), a specific inhibitor of type II DNA topoisomerase, on SV40 DNA replication in vivo.

Simian Virus 40 (SV40) infected cells were pulse labeled with (3H) thymidine and chased either in the absence or in the presence of the cytotoxic drug VM26 (teniposide). We investigated the structure of labeled SV40 DNA and found that VM26 had no significant effect on replicative chain elongation but strongly inhibited the conversion of late replication intermediates to mature DNA daughter molecules. The late replicative SV40 DNA intermediates which accumulate in VM26 treated cells contained essentially full length labeled DNA strands. These newly synthesized strands were not part of two catenated interlocked SV40 monomers suggesting that the block occurred prior to the final ligation reaction. Since VM26 is known to be a specific inhibitor of DNA topoisomerase II we conclude that this enzyme is dispensable for the chain elongation of replicating SV40 DNA, but that it is essential for the termination of SV40 DNA replication cycles.

Animals↗
PubMed1985

Phase II study of teniposide (VM-26) in multiple myeloma.

From September 1979 to December 1983, a phase II trial with teniposide (VM-26) in multiple myeloma (MM) was conducted at our institution. Of the 30 patients entered, 25 were evaluable for response, 12 previously treated with M-2 protocol and 13 previously untreated elderly (greater than or equal to 70 years) patients. A median of nine cycles (range 1-21) of VM-26 was administered. Seven responses (28%) according to Myeloma Task Force criteria were observed with a median duration of 4 months (range 2-12+). Four responses (33%) were observed in the 12 previously treated patients. Overall toxicity was mild. VM-26 seems an active drug in MM, without significant toxicity even in elderly patients.

Adult↗
PubMed1990

Phase II study of teniposide (VM26) in cutaneous T-cell lymphomas.

A Phase II study of teniposide (VM26) in cutaneous T-cell lymphoma (CTCL) was performed in 15 patients affected by stage III, IV according to TNM (mycosis fungoides or Sézary syndrome). All patients were pretreated, and VM26 was administered at a dose of 100 mg/m2 weekly for at least 3 weeks. Objective responses were observed in 40% of the patients, with two complete responses lasting 26 and 46 months. The drug was well tolerated in elderly patients and deserves further evaluation either for inclusion in first-line combination regimens or for palliative treatment in heavily pretreated or elderly patients.

Adult↗
PubMed1993

Combination chemotherapy with teniposide (VM26) and carboplatin in small cell lung cancer.

Seventy patients with previously untreated histologically proven small cell lung cancer (SCLC) were treated with a combination of teniposide 60 mg/m2 intravenously (i.v.) on days 1 through 5 and carboplatin 400 mg/m2 i.v. on day 1 every 28 days for six courses. Patients with limited stage disease, (LD) who achieved a response, subsequently received 2,000 cGy prophylactic cranial and 3,000 cGy involved field thoracic radiotherapy. Of the 70 patients, 62 were evaluable for response: 47 patients (76%) achieved an objective response; 14 of 29 patients (48%) with LD had a complete response (CR), with a partial response (PR) plus CR rate of 76%. Seven of 33 patients (21%) with extensive disease (ED) achieved a CR, with a combined PR and CR rate of 76%. Median time to progression (TTP) for all responders was 292 days (42 weeks). Median duration of survival for all LD patients was 415 days (59 weeks). Survival for LD patients was 88% at 6 months, 61% at 12 months, and 29% at 18 months. Median survival duration for all patients in the study was 311 days (44 weeks), with a survival of 79% at 6 months, 44% at 1 year, and 16% at 18 months. Myelosuppression was the main toxicity, with World Health Organization (WHO) grade 3 or 4 infection occurring in 33% of patients. Two patients died of pneumonia, one complicated by renal failure, and another suffered cardiac arrest related to treatment. The high activity of this drug combination justifies its use as a first-line treatment of previously untreated SCLC.

Adult↗
PubMed1997

The clinical impact of teniposide in the treatment of elderly patients with small-cell lung cancer.

Teniposide (VM26) has been claimed to be active with a moderate toxicity in elderly patients affected by small-cell lung cancer (SCLC). Twenty-two patients with SCLC older than 65 years received VM26 as first-line chemotherapy at a dose of 60 mg/m2 on 5 consecutive days every 3 weeks. Age distribution ranged from 67 to 80 years (median 72 years). Fourteen patients were men and eight were women. Twelve patients had limited disease (LD) and ten extensive disease (ED). One patient (LD) had a complete response, and four (3 LD, 1 ED) achieved a partial response for an overall response rate of 22.7% (95% CI 6-40%). The most frequent toxicity was myelosuppression: 20 and 15% of patients had grade 3 leukopenia and thrombocytopenia, respectively. Our results seem to suggest that VM26 by this schedule is moderately effective in elderly patients with SCLC, and it cannot be recommended as a routine treatment.

Aged↗
PubMed1992

Activity of etoposide (VP-16) and teniposide (VM-26) in exponential and plateau phase human tumor cell cultures.

The effects of etoposide (VP-16) and teniposide (VM-26) have been evaluated in human epidermoid carcinoma cells (A431, ME180 and HEp3) grown as exponential and plateau phase cultures. A significant increase in resistance to both these chemotherapeutic agents was observed in unfed plateau compared with exponential phase cells. The large differences in cell killing could not be explained by cell cycle specific toxicities resulting from variations in the cell cycle distributions. Rather the differences in the treatment efficacies probably reflect the 5- to 15-fold increase in the proportion of quiescent cells measured in the plateau phase cultures. These findings suggest that non-proliferating cells in tumors may be preferentially spared in treatments utilizing VP-16 and VM-26.

Autoradiography↗
PubMed1995

Effect of cyclosporine on teniposide pharmacokinetics and pharmacodynamics in patients with renal cell cancer.

Five patients with metastatic renal cell cancer (RCC) entered this study. The patients received two courses of teniposide (VM26) (200 mg/m2/24 h i.v.) after which no objective response was observed: three patients had stable disease (SD) and two had progressive disease. Cyclosporine (CsA) (5 mg/kg/2 h followed by 30 mg/kg/48 h i.v.) was then added (VM26/CsA) and at least another two courses were administered. Pharmacokinetic and pharmacodynamic parameters were analyzed. CsA increased the area under curve (AUC) of VM26 in four out of five patients; on average, the variation in the paired AUC of VM26 was 41%. Nadir granulocyte count was lower (average 650/mm3, ranging from < 100 to 1800/mm3) after VM26/CsA than after VM26 (average 1260/mm3, ranging from 200 to 2100/mm3) (p < 0.01). Bilirubin concentration in the serum was increased after VM26/CsA compared with VM26 (p < 0.05). Finally, after two courses of VM26/CsA, four patients had stable disease and one patient had a minor response. In conclusion, the ongoing pilot study indicates that CsA affects both the pharmacokinetics and the pharmacodynamics of VM26.

Aged↗
PubMed1999

Effect of cyclosporin A on protein binding of teniposide in cancer patients.

We investigated the effect of cyclosporin A (CSA) on protein binding of teniposide (VM26) in 16 patients with metastatic renal cell carcinoma receiving i.v. VM26 alone over 24 h (total dose, 200 mg/m2) and in association with CSA (5 mg/kg/2 h followed by 30 mg/kg/48 h i.v.). CSA was used in an attempt to overcome multidrug resistance. The unbound fraction (%fu) of VM26 was significantly (p=0.04) higher in the cycles with CSA (median 0.8; range 0.4-1.9) than in the cycles with VM26 alone (median 0.5; range 0.1-1.6). Both total VM26 area under curve concentration (AUC0-infinity) and free VM26 AUC0-infinity increased after treatment with CSA, but the median increase in free AUC0-infinity was higher (2.7-fold) than total AUC0-infinity (1.5-fold) (p = 0.04). Bilirubin was significantly (p<0.01) increased after CSA but no association was observed between bilirubin level and %fu of VM26. Albumin was in the normal range after both VM26 alone and VM26 plus CSA. The nadir of absolute neutrophil count (ANC) after VM26 plus CSA (median 700/microl, range <100-2860/microl) was lower than after VM26 alone (median 1900/microl, range 200-6000/microl) (p = 0.0007). The median percentage of ANC compared to the pretreatment value (ANC nadir/ANC pretreatment x 100) was 39.0% (range 3.1-98.8%) in the cycles with VM26 alone and 16.9% (range 1.4-97.9%) (p = 0.007) after VM26 plus CSA. Percentage change of neutrophils significantly correlated with free AUC0-infinity VM26 in the cycles with VM26 alone and VM26 plus CSA (p = 0.04, r = -0.53 and p = 0.04, r = -0.52, respectively). Only a trend which failed to reach significance was observed between total AUC0-infinity VM26 and percentage change of neutrophils in the cycles with VM26 alone and in association with CSA (p = NS, r = -0.33 and p = 0.055, r = -0.49, respectively). In conclusion, patients treated with CSA had higher systemic exposure to unbound VM26.

Adult↗
PubMed1999

The cost-effectiveness of paclitaxel (Taxol) + cisplatin is similar to that of teniposide + cisplatin in advanced non-small cell lung cancer: a multicountry analysis.

A large randomized clinical trial in advanced, previously untreated, non-small cell lung cancer (NSCLC) patients revealed better response rates and better tolerance for paclitaxel+cisplatin (TAXCIS) compared to teniposide+cisplatin (TENCIS). Since economic evidence is receiving increasing attention in health care, we conducted an economic evaluation based on the trial results in The Netherlands, Belgium, France and Spain. The evaluation was based on (i) differences in drug costs, (ii) differences in chemotherapy administration and (iii) the economic consequences of significantly different clinical outcomes in the trial: anemia, thrombocytopenia, neutropenia, neuropathy and arthralgia/myalgia. Data regarding medical resource utilization were obtained from clinician interviews using a Delphi technique and validated by patient charts analysis. Differences in medical management occurred across countries, but TAXCIS was cost-additive in all countries, i.e. the extra cost of chemotherapy was only partially compensated by savings in medical resource use, resulting in a net cost per patient of US$2311. In the trial, TAXCIS therapy produced a 37% response rate compared to 26% for TENCIS. The cost per extra responder for TAXCIS is on average US$21011, which is comparable to the cost per responder obtained with TENCIS (US$27266). Thus, the cost-effectiveness of TAXCIS, expressed in cost per responder, is similar to the cost-effectiveness obtained with TENCIS.

Antineoplastic Agents↗
PubMed1988

VM-26 (teniposide)-induced hypersensitivity and degranulation of basophils in children.

During a 7 year period, 16 episodes of VM-26 (teniposide) hypersensitivity occurred in our Department of Pediatrics. Eight of these (50%) were observed in neuroblastoma patients, of whom a total of 22 children had been treated with VM-26. The predominant signs were facial edema, flushing, urticaria, bronchospasm, tachycardia, and hypotension. All children with hypersensitivity recovered, but four of them were critically ill. No risk factors were found. In order to elucidate the mechanism of the hypersensitivity episode further, and to identify a possible allergen, histamine release from basophil leukocytes was performed by use of a glass microfiber method. Blood samples from nine cases reacting to VM-26, eight controls (children exposed to VM-26 without any hypersensitivity reactions), and 12 healthy children without previous exposure were challenged with VM-26 alone and with its vehicle, cremaphor. In all samples, it was found that VM-26 degranulated basophils, whereas no histamine release was seen after challenge with cremaphor. The reaction was dose-dependent, and not IgE-mediated, since IgE depletion of the cells did not abolish histamine release after VM-26 challenge.

Adolescent↗
PubMed1991

Teniposide, dexamethasone and continuous-infusion cyclophosphamide in advanced refractory myeloma.

Twenty-one patients with advanced refractory myeloma (nine primary unresponsive to melphalan, 12 relapsed and resistant to first-line salvage therapy) received monthly 7 d courses of cyclophosphamide by continuous infusion, associated with teniposide and dexamethasone. Six patients died within 2 months from start of treatment, before receiving an adequate trial. Among the 15 evaluable patients, there were eight objective responses and three improvements (decrease of monoclonal protein greater than 50% or greater than 30%, respectively). After a median follow-up of 10 months, all responding patients are alive and none of them is still relapsed. In heavily pretreated patients, ineligible for more aggressive approaches, cyclophosphamide by continuous-infusion exerted a good antineoplastic activity without increasing toxicity.

Adult↗
PubMed1992

Apoptotic cell death triggered by camptothecin or teniposide. The cell cycle specificity and effects of ionizing radiation.

We have previously observed that the DNA topoisomerase I inhibitor camptothecin (CAM), or DNA topoisomerase II inhibitors teniposide (TEN) and amsacrine (m-AMSA) trigger endonucleolytic activity in myelogenous (HL-60 or KG1), but not lymphocytic (MOLT-4) leukaemic cell lines. DNA degradation and other signs of apoptotic death were seen as early as 2-4 h after cell exposure to these inhibitors. Cells replicating DNA (S phase) were selectively sensitive whereas cells in G1 were resistant; the sensitivity of G2 or M cells could not be assessed in these studies. The present studies were aimed at revealing whether DNA repair replication induced by ionizing radiation can sensitize the cells, and to probe the sensitivity of cells arrested in G2 or M, to these inhibitors. The data show that gamma-irradiation (0.5-15 Gy) of HL-60 cells does not alter their pattern of sensitivity, i.e. G1 cells, although engaged in DNA repair replication, still remain resistant to CAM compared with the S phase cells. Likewise, irradiation of MOLT-4 cells also does not render them sensitive to either CAM or TEN, regardless of their position in the cell cycle. Irradiation, however, by slowing the rate of cell progression through S, increased the proportion of S phase cells, and thus made the whole cell population more sensitive to CAM. HL-60 cells arrested in G2 either by irradiation or treatments with Hoechst 33342 or doxorubicin appear to be more resistant to CAM relative to S phase cells. Also resistant are cells arrested in M by vinblastine. The data suggest that some factor(s) exist exclusively in S phase cells, which precondition them to respond to the inhibitors of DNA topoisomerases by rapid activation of endogenous nuclease(s) and subsequent death by apoptosis. HL-60 cells in G1, G2 or M, or MOLT-4 cells, regardless of the phase of the cycle, appear to be protected from such a mechanism, and even induction of DNA repair replication cannot initiate DNA degradation in response to DNA topoisomerase inhibitors. These data, together with the evidence in the literature that topoisomerase I may be involved in DNA repair, suggest that a combination of these inhibitors with treatments that synchronize cells in the S phase and/or recruit quiescent cells to proliferation, including radiation, may be of value in the clinic.

Apoptosis↗
PubMed1989

Cytotoxic effects of teniposide combined with cis-diammine-dichloroplatinum (II) on the in vitro Lewis lung carcinoma model: influence of the treatment schedule.

The interactions between cis-diammine-dichloroplatinum (CDDP) and teniposide (VM26) have been studied in vitro on a Lewis lung carcinoma culture in terms of span, order of exposure or time delay between both drugs. When the cells were simultaneously exposed to VM26 and CDDP for 24 h, a supra-additive effect was observed (P less than 0.001). When the cells were first incubated with VM26, the cytotoxicity was emphasized (P less than 0.02), whereas after a prior exposure to CDDP, only an additive effect was noticed. For a short exposure to the drugs (1 h), we noticed an enhancement of the cytotoxic effect when the cells were first exposed to VM26, principally when the time delay between epipodophyllotoxin and CDDP was 0 or 1 h (P less than 0.001). The sequence in which VM26 was given before CDDP induced a significant increase of the cytotoxic effect, whatever the span of exposure.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Ionizing radiation and teniposide increase p21(waf1/cip1) and promote Rb dephosphorylation but fail to suppress E2F activity in MCF-7 breast tumor cells.

Ionizing radiation and the topoisomerase II inhibitor, teniposide (VM-26) both increase levels of the cyclin dependent kinase inhibitor, p21(waf1/cip1) and promote dephosphorylation of the retinoblastoma tumor suppressor protein, Rb, in MCF-7 breast tumor cells, perturbations associated with suppression of the activity of the transcription factor, E2F. However, studies using an E2F binding site-luciferase reporter plasmid transfected into MCF-7 cells failed to demonstrate a reduction in E2F activity in response to VM-26 or to ionizing radiation. In contrast, E2F activity (both basal and E1A stimulated) could be suppressed by transfection with a plasmid expressing Rb, indicating that the capacity of E2F to bind to Rb and to be inactivated by Rb is functionally intact in MCF-7 cells. These findings in MCF-7 breast tumor cells suggest that E2F activity may not be directly susceptible to modulation by endogenous p21(waf1/cip1) and Rb.

Antineoplastic Agents, Phytogenic↗
PubMed1993

Integration of simian virus 40 into cellular DNA occurs at or near topoisomerase II cleavage hot spots induced by VM-26 (teniposide).

Inhibition of DNA topoisomerase II in simian virus 40 (SV40)-infected BSC-1 cells with a topoisomerase II poison, VM-26 (teniposide), resulted in rapid conversion of a population of the SV40 DNA into a high-molecular-weight form. Characterization of this high-molecular-weight form of SV40 DNA suggests that it is linear, double stranded, and a recombinant with SV40 DNA sequences covalently joined to cellular DNA. The majority of the integrants contain fewer than two tandem copies of SV40 DNA. Neither DNA-damaging agents, such as mitomycin and UV, nor the topoisomerase I inhibitor camptothecin induced detectable integration in this system. In addition, the recombination junctions within the SV40 portion of the integrants correlate with VM-26-induced, topoisomerase II cleavage hot spots on SV40 DNA. These results suggest a direct and specific role for topoisomerase II and possibly the enzyme-inhibitor-DNA ternary cleavable complex in integration. The propensity of poisoned topoisomerase II to induce viral integration also suggests a role for topoisomerase II in a pathway of chromosomal DNA rearrangements.

Animals↗
PubMed1990

Pharmacokinetics of intrapleural versus intravenous etoposide (VP 16) and teniposide (VM 26) in patients with malignant pleural effusion.

The pharmacokinetics of etoposide (VP 16) and teniposide (VM 26) were studied after intrapleural administration to 3 patients with lung cancer and malignant pleural effusion. Comparison with the kinetic behavior of intravenously infused VP 16 and VM 26 in the same patients suggests that intrapleural drug delivery achieves higher and longer-lasting pleural concentrations, thus providing a theoretical basis for the palliative treatment of malignant pleural effusions. Although no systemic toxicity was observed after intrapleural administration of either drug, 1 of the 3 patients developed a transient asymptomatic hemorrhagic pleurisy during the first 2 days after the drug, alerting to the possible local toxicity of such treatment.

Aged↗