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PubMed1992

Teniposide (VM-26) in brain tumors.

Although teniposide activity in glioma was reported as early as 1971, it is only within the last 2 to 3 years that its effectiveness in small cell lung cancer and, most dramatically, in associated brain metastasis, has undergone long overdue systematic investigation. The drug appears to enjoy preferential uptake by brain-tumor tissue compared with disease-free brain tissue. Single-agent activity of teniposide in astrocytomas has been widely reported but the data are difficult to interpret due to differences among studies in definition of response and response duration. Combination therapy has focused primarily on teniposide with nitrosoureas and, again, definition variations have made it difficult to evaluate data. Similar problems plague trials by one group of investigators who reported that the combination of teniposide with doxorubicin and lomustine resulted in regression or improvement in significant percentages of their patients. While many studies indicate that teniposide has significant potential in treatment of adult glioma, controlled trials are needed to evaluate and optimize the use of this agent.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Investigation of the additive potential of teniposide and vincristine in non-Hodgkin's lymphoma. Australian and New Zealand Lymphoma Group.

Two hundred forty-seven patients with non-Hodgkin's lymphoma were randomized to receive doxorubicin, cyclophosphamide, and prednisolone in combination with vincristine (ACVP) or teniposide (ACTP) or both vincristine and teniposide (ACTVP). ACVP produced 44% complete remissions (CRs) and 32% partial remissions (PRs), whereas ACTP produced 46% CRs and 33% PRs and ACTVP produced 47% CRs and 36% PRs. Survival and relapse-free survival were also comparable for the three arms. The majority (59%) of patients had diffuse large cell lymphoma. Within this group, CR was achieved in 52% and no significant difference was observed in the response rates, survival, or relapse-free survival for the three treatment arms. Toxic effects occurred with equivalent frequency in the three regimens, except for neurotoxicity and myelosuppression. Moderate to severe neurotoxicity occurred in 20% of ACTVP-treated patients and in 8% of ACVP-treated patients but was not seen in any of the ACTP-treated patients (P = 0.0004). Severe myelosuppression occurred in 27% of ACTVP-treated patients and in 22% of ACTP-treated patients but only in 8% of ACVP-treated patients (P = 0.02), indicating an increased risk of myelosuppression for the combinations including teniposide. These results confirm our previous findings that teniposide can replace vincristine in the treatment of non-Hodgkin's lymphoma, with freedom from neurotoxicity and comparable survival and response rates. However, the combined use of teniposide and vincristine in the schedule as described has not increased response rates or survival but has instead added to neurotoxicity.

Actuarial Analysis↗
PubMed1987

Severe hypertensive reactions to teniposide (VM-26) in infants with congenital leukemia.

Two cases of infants with congenital leukemia who had severe, refractory hypertensive reactions to teniposide (VM-26) are described. Patients on a 5 mg/kg twice weekly schedule of teniposide had hypertensive reactions in which their systolic blood pressure was greater than 200 mm Hg after the second dose of teniposide. Hypertension combined with myelosuppression resulted in the patient's death in one case. Although the exact mechanism of this unusual toxicity of teniposide remains unknown, it might be an age-specific problem, considering the very young age of our patients. Meticulous monitoring of vital signs, including blood pressure, is mandatory in leukemic infants receiving teniposide.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Demonstration of a schedule-dependent therapeutic synergism utilizing the interacting drugs methotrexate and teniposide in L1210 leukemia.

When three variables require simultaneous adjustment for treatment optimization, the experimental determination of the optimum treatment becomes more complicated than generally appreciated, especially when one variable is the interval between drug administrations. Molecular pharmacological studies at this institution suggest that teniposide, in doses that are achievable in vivo, blocks methotrexate efflux from cells, enhancing formation of methotrexate polyglutamates which are active retentive forms of the drug. Hence, the combination might show a synergistic effect if teniposide is given at an appropriate time in relation to administration of methotrexate. This paper considers the problem of estimating the optimal dose levels and timing of administration of these drugs in B6D2F1 mice bearing L1210 leukemia in vivo as a model for the analysis of multidrug regimens when time and dose are variables. Because of the complexity of these experiments, an adaptive approach was applied. Three cycles of treatment were given using methotrexate at 0-400 mg/kg, teniposide at 0-60 mg/kg, and an interval of 0-54 hours between the two drugs. The single drugs prolonged median survival up to 24 days under the conditions of these experiments. The combination given simultaneously resulted in median survival of up to 33.5 days, while use of an appropriate interval between drugs prolonged median survival to greater than 50 days. An analysis of the underlying dose-time response gives a much better appreciation of the relationships among the variables. The concept that optimal doses included less methotrexate and more teniposide as the interval between drugs is increased was developed only through modeling. This finding is critical in demonstrating the importance of including all nonnegligible variables in the experimental design if the results are to be considered valid. Confidence regions about the optimum dose and about the response at the optimum provide a sound basis for a claim of therapeutic synergism as demonstrated by use of a scheduling variable in the experiment design. A nonproportional hazards analysis permits the conclusion of nonproportionality and emphasizes the contribution of methotrexate to optimal short-term survival (15-24 days) and teniposide to long-term survival (24-39 days).

Animals↗
PubMed1984

High-performance liquid chromatographic analysis of the semisynthetic epipodophyllotoxins teniposide and etoposide using electrochemical detection.

A high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of two structurally similar and highly active anticancer drugs, etoposide (I) and teniposide (II), and their potential metabolites (hydroxy acid, picrolactone, and aglycone). The assay utilizes electrochemical detection, which imparts specificity and sensitivity sufficient to detect greater than or equal to 20 ng/mL in plasma, urine, and CSF. The mean assay coefficients of variation were 5.1 and 8.1% for teniposide (10 micrograms/mL) and etoposide (5 micrograms/mL), respectively. The extraction efficiencies were 86% for etoposide, 70% for its hydroxy acid metabolite, 66% for teniposide, and 54% for the hydroxy acid of teniposide. The correlation coefficient of the multilevel standard curve was greater than or equal to 0.995 over the concentration range of 0.05-50 micrograms/mL for the parent drugs and metabolites extracted from plasma. This method has been used to determine the concentrations of the parent drugs and their metabolites in the plasma, urine, and CSF of patients with cancer.

Body Fluids↗
PubMed1983

Automated liquid chromatographic analysis of the anti-tumorigenic drugs etoposide (VP 16-213) and teniposide (VM 26).

A method is described for the fully automated analysis of large numbers of 1--2 ml serum and plasma or urine samples containing the anti-tumorigenic drugs etoposide and teniposide and their aglycone. The blood samples are hydrolysed by a proteolytic enzyme, subtilisin A, prior to preconcentration on a small precolumn. The hydrolysis step serves both to release the strongly protein-bound drugs and to prevent clogging of the chromatographic system. On-line preconcentration is carried out with precolumns packed with PRP1, a micro-particulate divinylbenzene-styrene copolymeric sorbent. Chromatography takes place, after column switching, in a C18/methanol--water system. After a post-column clean-up step using continuous extraction with dichloroethane in an autoanalyzer system, native fluorescence of these analytes is used for detection of the drugs. Recovery of etoposide and teniposide from spiked serum and plasma samples was 100%. Calibration curves of etoposide and teniposide typically show correlation coefficients of 0.9994 over a two-to-three order linear range. The detection limit of etoposide is approx. 8 ng per sample. Repeatability was found to be excellent. Unattended overnight routine analysis is possible without any problems. This method, considering optimal sample throughput, reliability and selectivity, competes favourably with existing techniques for the analysis of etoposide and teniposide.

Autoanalysis↗
PubMed1999

Teniposide sometimes effective in brain metastases from non-small cell lung cancer.

In a prospective study we have treated 13 patients with brain metastases from non-small cell lung cancer with intravenous teniposide, at a dose of 150 mg/m2 on days 1, 3 and 5 given every 3 weeks on an out-patient basis. Six of the 13 patients had previously been treated for brain metastases by surgery and/or radiotherapy. Seven patients experienced neurological improvement. Objective response was obtained in 3 patients (23%) (2 PR, 1 CR), and stabilization in 5 patients. Duration of response in the 3 patients with objective response was 16 weeks, 40 weeks and 80 weeks, respectively. In 2 of these patients extracranial disease responded also to teniposide therapy. Although toxicity of teniposide therapy was relatively mild, there was one patient who died as a consequence of leukopenic sepsis. The results demonstrate that teniposide has some activity in de novo as well as recurrent brain metastases from non-small cell lung cancer.

Aged↗
PubMed1992

Mixed micelles as proliposomes for the solubilization of teniposide.

The aqueous solubility of teniposide in detergent and phospholipid mixed micelles was investigated as functions of the detergents and lipids composing the mixed micelles, the molar ratio of detergent to phospholipid, and the total lipid concentration of the system. The polarity, the charge of the phospholipid, and its saturation affected the solubilization potential of the micelles. Physical chemical factors such as the pH, ionic strength, and temperature of the dispersion medium also altered the solubilization capacity of the system. The results are explained by the changes occurring in the critical micelle concentration and packing arrangements of the aggregates. The desired solubility of teniposide can be achieved by adjusting the studied parameters to the optimum values. Teniposide-containing mixed micelles were spontaneously converted to drug-containing vesicles upon aqueous dilution; therefore, the precipitation of the drug was totally eliminated. In conclusion, mixed micelles as proliposomes can be a suitable drug carrier system for insoluble compounds such as teniposide.

Blood Proteins↗
PubMed2000

Differences in mutant p53 protein stability and functional activity in teniposide-sensitive and -resistant human leukemic CEM cells.

We examined p53 protein stability and DNA damage-induced p53-dependent responses in a human leukemic CEM cell line and two teniposide-resistant sublines, CEM/VM-1 and CEM/VM-1-5 ( approximately 40 and 400-fold resistant to teniposide, respectively). Although all cell lines contain the same p53 mutations at codons 175 (Arg-->His) and 248 (Arg-->Gln), the constitutive levels of p53 were progressively increased with the resistance of the cells to teniposide. By pulse-chase experiments, we found that the half-lives of mutant p53 protein were approximately 12, 17, and >30 h in CEM, CEM/VM-1, and CEM/VM-1-5 cells, respectively. The prolonged half-lives of p53 in these cells is consistent with the fact that the protein harbors the indicated mutations. Of note, however, is the fact that the increased p53 protein half-lives in the two drug-resistant cell lines corresponds to a proportional decrease in MDM2 protein levels but an increase in p53-MDM2 binding interactions. This suggests that MDM2-mediated p53 degradation may be altered in our leukemic cell lines. The DNA damage-induced p53 response is fully functional in the drug-sensitive CEM cells containing a mutant p53, but this pathway is attenuated in the drug-resistant cells. Specifically, while the mutant p53 was phosphorylated at serine-15 in response to ionizing radiation in all these cell lines, mutant p53 induction in response to teniposide or ionizing radiation and induction of the p53-target genes, p21 and GADD45 only occurred in the drug-sensitive CEM cells. As assessed by MTT cytotoxicity assay, CEM cells were also significantly more sensitive to ionizing radiation, compared to the drug-resistant cell lines, and this correlated with p53 induction. Collectively, these results suggest that changes in constitutive mutant p53 protein levels, p53-MDM2 binding interactions, and altered regulation of the DNA damage-inducible p53-dependent pathway may play a role in drug- and radiation-responsiveness in these cells.

Antineoplastic Agents↗
PubMed1989

A phase II study with teniposide (VM26) in patients with progressed or relapsed small cell lung cancer (SCLC).

Sixteen patients with advanced small cell lung cancer who relapsed or progressed under first-line therapy, were treated with second-line chemotherapy consisting of: teniposide, 60 mg/m2, i.v. days 1-5, every 3 weeks until further progression. The response rate was: 3 minor responses, 6 stable disease, 5 progressive disease, 1 early death and 1 not evaluable. After the introduction of teniposide, median survival was 4.5 (range 1-11) months, compared to the median survival (2 months, range 1-11) observed in 40 contemporary patients of our series, who relapsed or progressed and subsequently received no treatment. The assessment of the difference was significant: chi-square = 4.05, P less than 0.05. In addition a particular comparison was performed with 15/40 patients who matched according to the major predictive parameters of disease. These patients experienced 2 months (range 1-7) of median survival which was significantly shorter than that of the teniposide treated group (chi-square = 4.48, P less than 0.05). On these bases, teniposide appeared to be effective, but the small size of the study suggests caution in evaluating the results.

Adult↗
PubMed1986

[Mutagenicity tests of etoposide and teniposide].

Mutagenicities of Etoposide (VP 16-213) and Teniposide (VM-26), podophyllotoxin derivatives with antitumor activity, were studied by Rec-assay, Salmonella/microsome reverse mutation assay (Ames' test) and Micronucleus test. In the Rec-assay, both Etoposide and Teniposide showed positive results on B. subtilis H17 rec+ and M45 rec-. They also induced the revertants of S. typhimurium TA 98, TA 1537 and TA 1538, but not of S. typhimurium TA 100, TA 1535 or E. coli WP2 uvrA in the Reverse mutation test. The results were not influenced by the addition of S-9 Mix. In the Micronucleus test, Etoposide and Teniposide induced significantly micronucleated polychromatic erythrocytes of the bone marrow cells in mice; 3.3-4.3% at the doses of 0.75-6 mg/kg and 4.0-6.1% at 0.5-4 mg/kg, respectively. These results indicate that Etoposide and Teniposide are both mutagenic.

Animals↗
PubMed1992

Absolute bioavailability and pharmacokinetics of oral teniposide.

The absolute bioavailability and pharmacokinetics of orally administered teniposide were investigated in 25 patients. All patients received 50 to 60 mg/m2 teniposide intravenously on day 1, before oral administration. Six patients received 60 mg/m2 as a single oral dose on day 8; 5 patients received 60 mg/m2 and 120 mg/m2 as a single oral dose on days 8 and 15, respectively; 5 patients received 120 mg/m2 and 240 mg/m2 as a single oral dose on days 8 and 15, respectively; 6 patients received 60 mg/m2 as a single oral dose on 5 consecutive days from days 8 to 12; and 3 patients received 50 mg/m2 three times a day at 6-hour intervals on day 8. The mean absolute bioavailability was 41.6% +/- 14.2% with a large interindividual variability (range, 19.7% to 71.4%) and a low intraindividual variability (range, 2.8% to 13.9%). At a dose of 240 mg/m2, the bioavailability was decreased, whereas administration of multiple doses on 1 day or 5 consecutive days increased the overall bioavailability. In conclusion, teniposide can be administered orally with a bioavailability comparable with that of etoposide. The schedule dependency of both drugs warrants investigations of oral administration for 21 or more days. A formulation of teniposide capsules of 50 mg or less would be most helpful to facilitate oral administration.

Absorption↗
PubMed1992

Teniposide (VM-26) in ovarian cancer: a review.

Relatively few patients with gynecologic malignancies have been included in trials with teniposide given as a single agent. For 109 patients with advanced ovarian cancer treated with various doses and schedules, an overall response rate of 12% was reported. Most patients were heavily pretreated and presumably had resistant disease. Information about teniposide's activity in combination with other cytotoxic agents, as well as its efficacy in other gynecologic malignancies, is limited. In view of the favorable pharmacologic and toxicity profiles of teniposide and its possible synergism with cisplatin and carboplatin, new treatment strategies are discussed that may have implications for further investigation of the usefulness of teniposide in advanced ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Variability in teniposide plasma protein binding is correlated with serum albumin concentrations.

Teniposide is a widely used anticancer drug that is extensively bound to plasma proteins (greater than 95%). We evaluated the drug's plasma protein binding in nine patients with acute lymphocytic leukemia who were in their first complete remission, and in a second group of nine patients at the time of relapse and subsequently after achieving another complete remission. Plasma protein binding was assessed by equilibrium dialysis, with direct high-performance liquid chromatographic measurement of total and free teniposide. The mean unbound fraction was 0.44% (0.21-0.88%) in the plasma of patients in first remission. It was significantly higher in patients at the time of relapse (mean = 0.86%; range 0.68-1.08%) and after achieving another complete remission (mean = 1.25%; range 0.51-2.11%). Serum albumin values were significantly lower at the time of relapse (mean = 4.6 vs 4.0 mg/dl; p less than 0.014), and decreased further during intensive postremission therapy containing L-asparaginase (mean = 3.2; p less than 0.05). For all 18 patients, a significant negative correlation (r2 = 0.667; p less than 0.001) was found between serum albumin and unbound teniposide, with low albumin being associated with higher unbound fraction. Such patients have higher systemic exposure to unbound (presumably active) teniposide at any given total plasma concentration of the agent.

Adolescent↗
PubMed1985

Allergic reactions to teniposide in patients with neuroblastoma and lymphoid malignancies.

Acute allergic reactions have been reported in 1%-5% of patients receiving teniposide. In a patient population of 82 children with leukemia and lymphoma, we observed only two acute reactions during the infusion of 1707 doses of teniposide. In contrast, 14 of 105 children with neuroblastoma developed acute allergic reactions during the infusion of 665 doses of teniposide. Four rechallenge doses of the drug were given to patients with neuroblastoma after premedication with antiallergic agents. All four doses resulted in repeat reactions. Our data suggest that children with neuroblastoma have a significantly higher incidence of acute reactions to teniposide than patients with other malignancies (P = 0.008), and that these reactions cannot be prevented by premedication with antiallergic drugs.

Child↗
PubMed1993

Teniposide-resistant CEM cells, which express mutant DNA topoisomerase II alpha, when treated with non-complex-stabilizing inhibitors of the enzyme, display no cross-resistance and reveal aberrant functions of the mutant enzyme.

We have examined the effects of a group of DNA topoisomerase II (topo II) inhibitors, merbarone, aclarubicin, SN22995, RP60475F, and fostriecin, in CCRF-CEM cells and two sublines, CEM/VM-1 and CEM/VM-1-5, that were selected for increasing resistance to teniposide (VM-26). The teniposide-resistant sublines have been termed "at-MDR" for altered topo II-associated multidrug resistance. These topo II inhibitors differ from the "classic" inhibitors such as teniposide in that they do not stabilize DNA-topo II complexes. In this study, we found that our at-MDR cell lines express little or no cross-resistance to these "non-classic" topo II inhibitors. Merbarone and SN22995 inhibited VM-26-mediated DNA-topo II complexes in CEM cells only when they were added before VM-26. Since they did not deplete topo II protein, it suggested that these drugs may inhibit topo II activity before the enzyme binds to DNA, thereby preventing stabilization of VM-26-mediated topo II-DNA complexes. Continuous exposure of CEM cells to merbarone, SN22995, or VM-26 caused G2 arrest, as determined by flow cytometry. Likewise, at-MDR cells continuously treated with VM-26 also arrested in G2. By contrast, treatment of at-MDR cells with either merbarone or SN22995 produced a qualitatively different pattern; the at-MDR cells first accumulated in G2 but then escaped the G2 block and proceeded into mitosis with elongated and intertwined chromosomes but failed to divide. Their DNA was re-replicated, however, and the cells eventually accumulated at the 8N DNA stage. Given that both wild-type and mutant topo II alpha alleles are expressed in the at-MDR cells (B. Y. Bugg, M. K. Danks, W. T. Beck, and D. P. Suttle. Expression of a mutant DNA topoisomerase II in CCRF-CEM human leukemic cells selected for resistance to teniposide. Proc. Natl. Acad. Sci. USA, 88: 7654-7658, 1991), we hypothesize that drugs such as merbarone may inhibit the activity of wild-type topo II alpha, allowing the aberrant activity of the mutant enzyme to be revealed during chromosome condensation and sister chromatid segregation.

Cell Cycle↗
PubMed1997

Teniposide (VM-26) as a single drug treatment for patients with extensive small cell lung carcinoma: a Phase II study of the Southwest Oncology Group.

BACKGROUND: Teniposide (VM-26) was reported to have activity in small cell lung carcinoma (SCLC). The authors performed a Phase II study of teniposide as a treatment for patients with previously untreated extensive SCLC. METHODS: The study was open to patients with a histologic or cytologic diagnosis of extensive SCLC who had not received prior radiation or chemotherapy. Patients with hematologic values below normal were considered eligible if the impaired bone marrow function was directly attributable to disease involvement. Treatment consisted of teniposide 60 mg/m2 given intravenously (i.v.) on Days 1-5 every 3 weeks. RESULTS: This study opened on September 15, 1988, closed permanently on November 15, 1990, and accrued 45 patients identified at 19 academic, military, and Community Clinical Oncology Program institutions affiliated with the Southwest Oncology Group. Of the 45 registered patients, 41 were eligible. Twenty eight (68%) were males and 13 (32%) were females; the median age was 64 years (minimum, 46 years; maximum, 83 years). Twenty-four patients (59%) had a performance status (PS) on the Zubrod scale of 0-1 and 17 cases (41%) had a PS of 2. Of the 41 eligible patients, 10 had confirmed partial responses (24%) (95% confidence interval, 12-40%). The median survival was 7 months. The significant toxicities noted were Grade 4 leukopenia and/or granulocytopenia, experienced by 15 patients; 1 of these patients also had Grade 4 hyponatremia. One patient died of a respiratory infection. CONCLUSIONS: When administered according to the dosage and schedule selected for this study (60 mg/m2 i.v. on Days 1-5 every 3 weeks), teniposide as a single agent had modest activity in extensive small cell lung carcinoma. The toxicities observed in this study were acceptable.

Actuarial Analysis↗
PubMed1998

Improved targeting of brain tumors using dexrazoxane rescue of topoisomerase II combined with supralethal doses of etoposide and teniposide.

Dexrazoxane (ICRF-187) is a catalytic inhibitor of the nuclear enzyme DNA topoisomerase II (topo II). It protects cells against topo II poisons, such as etoposide and teniposide, by hindering the DNA cleavage reaction of the target enzyme. We have previously shown that this antagonism also extends to an in vivo model. Thus, ICRF-187 protected mice against supralethal doses of etoposide and amsacrine, and the etoposide LD10 dose increased as much as 3.6-fold when combined with ICRF-187 (B. Holm, Cancer Chemother. Pharmacol., 38: 203-209, 1996). We describe here how scheduling of this drug combination can be optimized and used. Interestingly, ICRF-187 can protect when it is given after etoposide. Although timing is very critical here, ICRF-187 was able to completely protect when given 10 min after etoposide. This rescue principle resembles methotrexate rescue by folinic acid. We also found scheduling to be crucial because ICRF-187 did not protect when etoposide was given once a day for five days, whereas effective protection was seen when etoposide was used three times, once every four days. Similar investigations were performed with teniposide in combination with ICRF-187. The combination with ICRF-187 allowed a 3.4-fold teniposide dose escalation. Such dose escalations could be advantageous in specific situations. One such case is when the tumor is situated in a pharmacological sanctuary, e.g., in the brain. ICRF-187 is hydrophilic and does not cross the blood-brain barrier, whereas the lipophilic etoposide and teniposide do. Therefore, ICRF-187 would protect normal tissues and allow a cytotoxic dose of etoposide to reach the central nervous system (CNS). We therefore studied the combinations using L1210 or EHR2 cells inoculated into the CNS of mice. L1210 presented a leukemic CNS model with leptomeningeal spread and infiltration of liver, spleen, and lymph nodes, whereas EHR2 cells acted as a solid tumor with no evidence of extracerebral disease. In all experiments, the combination of high-dose etoposide and ICRF-187 was significantly superior to an equitoxic dose of etoposide alone. Such superiority was also seen when treatment was given on days 4, 8, and 12 after tumor inoculation. Here etoposide alone resulted in a mean increased life span of 12.3%, whereas the rescue regimen yielded an increase of 47% (P < 0.0001). In conclusion, DNA topo II rescue by catalytic inhibitors is a new strategy enabling significant epipodophyllotoxin dose escalations; in this study, we have demonstrated the superiority of this strategy in two in vivo CNS tumor models. This concept is now being tested in a clinical trial.

Amsacrine↗