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PubMed1985

Pharmacokinetics of teniposide in patients with ovarian cancer.

Pharmacokinetics of teniposide (VM26) after each of three doses were investigated by high-performance liquid chromatographic assay in eight patients with ovarian cancer with normal liver and renal functions. Treatment consisted of a first dose of 100 mg/m2 iv as a 1-hour infusion (Day 1), a second dose of 150 mg/m2 iv as a 1-hour infusion (Day 8), and a third dose of 150 mg/m2 as an approximately 1-day infusion (Day 22). Disappearance of VM26 from plasma followed a biexponential decay pattern. The mean terminal half-life (+/- SE) was 6.9 +/- 0.9 hours after the first dose, 6.1 +/- 0.7 hours after the second dose, and 9.7 +/- 1.4 hours after the third dose. VM26 levels in ascites were lower than those in plasma in the first hours after drug administration, but by 24 hours they were similar or slightly higher. Urinary elimination of VM26 as unchanged drug amounted to less than 10% of the dose.

Adult↗
PubMed1985

Inhibition of 1-beta-D-arabinofuranosylcytosine transport and net accumulation by teniposide and etoposide in Ehrlich ascites cells and human leukemic blasts.

The interactions of the epipodophyllotoxins, teniposide (VM-26) and etoposide (VP-16), with the nucleoside carrier were examined with emphasis on their effects on 1-beta-D-arabinofuranosylcytosine (ara-C) transport and net accumulation. VM-26 inhibited ara-C transport by Ehrlich ascites cells within 1 min of exposure, and inhibition was only partially reversed after 45 min in VM-26-free medium. ara-C transport was slowed by 50% by 7 microM VM-26 or by 35 microM VP-16. Since epipodophyllotoxins were noncompetitive inhibitors, fractional inhibition was independent of the ara-C concentration. Analysis of ara-C transport kinetics revealed only a single saturable transport route, and there was no indication of VM-26-insensitive transport. VM-26, VP-16, and ara-C were competitive inhibitors of the specific binding of nitrobenzylthioinosine to the nucleoside carrier with Ki values of 7.4 microM, 23 microM, and 2.2 microM, respectively. The rate of dissociation of nitrobenzylthioinosine (t 1/2 = 20.6 min) was accelerated by 5 microM ara-C (t 1/2 = 18.5 min) but slowed by 100 microM VM-26 (t 1/2 = 34.6). By these criteria, the interaction of VM-26 with the nucleoside carrier was qualitatively similar to that of dipyridamole. Although VM-26 inhibited ara-C transport, it did not significantly slow the rate of net intracellular accumulation of ara-C by Ehrlich cells, presumably because transport capacity far exceeds the capacity for phosphorylation in these cells. In freshly isolated human leukemic blasts, which have far less nucleoside transport activity, inhibition of ara-C accumulation by VM-26 was dependent on the ara-C concentration. At 1 microM ara-C, a concentration where transport was rate limiting for net uptake, VM-26 inhibited accumulation of ara-C over a 60-min time course. At 50 microM ara-C, transport was in excess, and VM-26 did not slow ara-C metabolism.

Animals↗
PubMed1984

Selection and characterization of L1210 sublines resistant to teniposide (VM-26).

Two spectra of L1210 sublines with gradations of resistance to teniposide (VM-26) were selected by stepwise exposure of cultures to increasing concentrations of the drug. Cultures representing the first spectrum were from 20 times to 1200 times more resistant to VM-26 than were cultures of parental cells. At 24 hr after addition of 22 nM VM-26 to the medium, the growth of cultures of parental cells was inhibited by 50%. Increases in resistance to VM-26 among the sublines coincided with increases in population doubling times. When cells were transferred to drug-free medium, there was a sharp decrease in resistance over the first 10 days; the subsequent decline in resistance, over 2 to 4 months, correlated with a decrease in population doubling times. The second spectrum of resistant sublines arose from the first spectrum after the latter had been maintained for about 1 year on various selective concentrations of VM-26. Resistance to VM-26 by this second group of sublines was from 400 times to over 2000 times greater than that of the parental cell line. Doubling times for these resistant cell populations were similar to the normal rate of the parental cell line. Eight sublines were characterized by two chromosomes with homogeneously staining regions, while the remaining subline had a single chromosome with this anomaly. One of the regions appeared on a submetacentric chromosome in seven of the nine sublines, while the other was on an acrocentric chromosome. These observations indicate that a longer doubling time facilitated selection of increasingly resistant sublines but was not essential for the resistance of sublines in the second spectrum.

Animals↗
PubMed1982

Comparative trial of two teniposide-based combination chemotherapy regimens for the treatment of advanced malignant lymphomas.

One hundred and twenty-three patients with advanced measureable malignant lymphomas resistant to conventional chemotherapy were entered in a prospectively randomized trial of two teniposide (VM-26)-based combination chemotherapy regimens: V-PLAT (VM-26, cisplatin, and prednisone) and V-HEX (VM-26, hexamethylmelamine, and prednisone). Ninety-seven eligible and evaluable patients received protocol therapy. Sixteen percent of the patients had Hodgkin's disease, and 84% had non-Hodgkin's lymphoma. All patients were ambulatory (Eastern Cooperative Oncology Group Performance status 0, 1, or 2), 70% had stage IV disease, 59% had "B" symptoms, and all had failed either two or three previous chemotherapy regimens. Toxicity was mainly hematologic and significantly greater with V-PLAT. Objective tumor responses were seen in nine of 45 patients (20%) treated with V-PLAT (duration, 4-35 + weeks) and in four of 51 patients (8%) treated with V-HEX (duration, 10-65 + weeks). Among the 12 patients with histologically confirmed histiocytic lymphoma treated with V-PLAT, five (42%) experienced objective tumor responses, including two complete responses. Overall median survival was approximately 6 months, with no difference between treatment regimens. Limited antitumor activity of these combination regimens in patients with advanced malignant lymphomas has been demonstrated. However, the objective response rates were not higher than we have previously seen with either VM-26 (22%) or hexamethylmelamine (27%) given in maximum tolerable doses as single agents.

Adult↗
PubMed1983

Activity and pharmacokinetics of teniposide in Lewis lung carcinoma-bearing mice.

The antitumor activity of teniposide (VM26) was investigated in Lewis lung carcinoma (3LL) of the mouse after a single dose of 20 mg/kg iv (given 8 or 14 days after tumor transplant) or after three doses of 6.5 mg/kg iv (given on Days 8, 11, and 14 after tumor transplant) (total dose, 19.5 mg/kg). The single dose resulted in only 25% primary tumor reduction but had marked antimetastatic activity. The repeated doses (6.5 mg/kg x 3) were much more effective, with 85% primary tumor reduction and the apparent disappearance of all metastatic deposits. The pharmacokinetics of VM26 was investigated in 3LL-bearing mice by a high-performance liquid chromatographic assay. At both of the above doses VM26 disappeared from mouse plasma biphasically, with an elimination half-life of about 70 mins. The concentrations in metastases were higher than in primary tumor, where very low levels were found. The highest VM26 levels were found in liver, small intestine, and kidney, and the lowest levels were found in the brain. Excretion of VM26 in urine amounted to less than 5% of the dose.

Animals↗
PubMed1982

Combination chemotherapy for patients with relapsed malignant lymphoma using methyl-GAG and teniposide (VM-26).

We treated 45 patients with advanced malignant lymphoma, using a combination of methyl-GAG and teniposide (VM-26). All patients had received extensive prior treatment with combination chemotherapy with or without irradiation. Both methyl-GAG (600 mg/m2) and VM-26 (100 mg/m2) were administered on Days 1 and 8 of the treatment protocol and, in responding patients, every 2 weeks thereafter. Partial responses occurred in six of 12 patients with Hodgkin's disease and in ten of 31 patients with non-Hodgkin's lymphoma. The median duration of response for all patients was 3 1/2 months (range, 1 1/2-11). There were moderate toxic effects, including nausea, myalgia, weakness, and myelosuppression. Relative to our recent experience with methyl-GAG as a single agent, the addition of VM-26 to methyl-GAG did not produce a superior rate or duration of response in similar, heavily pretreated patient populations with malignant lymphoma; however, the combination caused considerably more myelotoxicity. We conclude that the use of VM-26 with methyl-GAG in this dose schedule offers no advantage over single-agent therapy. Methyl-GAG, when administered on a biweekly schedule, is effective and well-tolerated. This agent should be considered for incorporation into chemotherapy protocols for the therapy of previously untreated patients with malignant lymphoma.

Clinical Trials as Topic↗
PubMedDate not supplied

Small cell lung cancer (SCLC): a randomized trial of cyclophosphamide, adriamycin, vincristine plus etoposide (CAV-E) or teniposide (CAV-T) as induction treatment, followed in complete responders by alpha-interferon or no treatment, as maintenance therapy.

In this phase III, double-random study, we compared CAV-E to CAV-T combination as induction treatment (1st randomization) for SCLC. Subsequently, patients achieving a complete response (CR) were randomized again (2nd randomization) to receive maintenance treatment with alpha-IFN or no treatment. From June 1990 to June 1992, 75 untreated patients were enrolled in this trial. After stratification according to limited disease (LD) or extensive disease (ED), patients were randomized to receive the following treatment: cyclophosphamide 1000 mg/m2, adriamycin 50 mg/m2, vincristine 2 mg, day 1 i.v., plus etoposide (E) 100 mg/m2 (CAV-E: arm-A) or teniposide (T) 60 mg/m2 on day 2, 3, 4 i.v., every 3 weeks (CAV-T: arm-B). LD patients after 3 cycles of treatment received chest radiotherapy and 2 further cycles, whereas ED patients received 5 consecutive cycles. Patients who achieved a CR entered the 2nd randomization receiving a-IFN (3 x 10(6) I.U., i.m. daily x 9 months) or no treatment. A second-line treatment with carboplatin 300 mg/m2 plus E (if T was initially used) or T (if E was initially used) was also scheduled for patients achieving less than CR to induction treatment. Preliminary results are as follows: 75 patients were randomized, 72 were eligible for survival (arm-A = 37 and arm-B = 35) and 60 were fully evaluable for response (arm-A = 34 and arm-B = 26). In patients with LD the overall response rate was 79% (CR 21%) in arm-A vs 92% (CR 50%) in arm-B. In patients with ED, the overall response rate was 80% (CR 33%) in arm-A vs 84% (CR 7%) in arm-B. At a mean observation time of about 1 year (range 1-25 months), median survival of LD patients was 15 months in arm-A and 13 months in arm-B (Chi-square = 1.55; p > 0.05); in ED patients survival was 10.8 months and 8 months respectively (Chi-square = 2.88; p > 0.05). Cumulative survival probability was identical (12 months) in all patients of both arms. Toxicity was mainly haematologic and gastrointestinal: WHO grade 3-4 myelosuppression and vomiting were observed in 20% and 11% respectively, of cycles delivered in arm-A, compared to 19% and 8%, respectively, of cycles in arm-B. Two septic deaths occurred with CAV-T, while 1 patient discontinued treatment due to persistent myelosuppression with CAV-E. After the first and second-line treatment 20 patients showed a CR.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1993

Mitoxantrone, teniposide, chlorambucil and prednisone (MVLP) for relapsed non-Hodgkin's lymphoma. The impact of advanced age and performance status.

Fifty-seven patients with relapsed non-Hodgkin's lymphoma (NHL) of low, intermediate and high-grade malignancy were treated with mitoxantrone, teniposide (Vm26), chlorambucil (Leukeran) and prednisone (MVLP). The median age was 71 years; none of the patients was excluded due to poor performance status (PS). Out of 44 patients with PS (according to WHO) < or = 2, 38 responded with a median progression free survival (PFS) of 21.5 months. Of 13 patients with PS > 2, 6 responded with a median PFS of 8.2 months. Haematopoietic toxicity was related to PS rather than to dose intensity or bone marrow involvement. Three patients died within a short time due to toxicity; another two died later as a result of cardiac failure probably due to accumulated toxicity of adriamycin and mitoxantrone. MVLP chemotherapy is effective and feasible and has only moderate toxicity in patients with relapsed NHL and PS < or = 2, despite advanced age.

Adult↗
PubMedDate not supplied

Factors influencing response to second-line treatment with teniposide (VM26) in patients with progressive small cell lung cancer (SCLC).

Twenty-eight patients with small cell lung cancer (SCLC), 12 with limited (LD) and 16 with extensive (ED) disease, 22 of them relapsed to first-line treatment and 6 not responsive, were treated with a single-agent second-line treatment consisting of teniposide (VM26) 60 mg/m2, i.v. on days 1 to 5, every three weeks, until progression. After a minimum of two courses, we observed no complete response, 7 (LD/ED = 4/3) partial responses (25%), 4 (LD/ED = 2/2) minor responses (14%), and 17 (LD/ED = 6/11) with no change (61%). Median duration of response (partial plus minor) was 3.5 months (range 1-8). Median duration of survival, from VM26 administration, was in LD 6 months (range 2.5-11), in ED 3 months (range 1.5-6) and in all patients 4 months (1.5-11). Correlating the 11 responses with major prognostic variables present in the patients, we observed that KPS > 70, few initial courses of PL/VP16 and response to first-line treatment were significant determinants for successful salvage treatment. This study suggests the need to consider detailed patient characteristics of exposure to previous treatment before prompting new drug phase II studies on SCLC.

Aged↗
PubMed1993

Doxorubicin, vincristine, and actinomycin-D, but not teniposide, require long-lasting uninterrupted verapamil pressure to overcome drug resistance in multidrug-resistant cells.

The cytotoxic efficacy of doxorubicin (DOX), vincristine (VCR), actinomycin-D (ACT-D), and teniposide (VM-26) toward the LoVo and SW948 multidrug-resistant (MDR) cell sublines was significantly enhanced by the concomitant presence of verapamil (VER) during pharmacological treatment (1-h exposure) without, however, achieving a complete reversion of the MDR phenotype. Long-lasting VER in the culture medium, at the end of the combined drug+VER treatment, conferred to DOX, VCR, and ACT-D cytotoxic efficacy roughly similar to that exerted on the drug-sensitive parent cell lines. On the contrary, no enhancement of VM-26 cytotoxic efficacy was derived from continuous VER treatment. Enhancement of DOX, VCR, and ACT-D cytotoxic efficacy requires that VER be present in an uninterrupted manner in the culture medium since brief interruptions (15 to 60 min) in the VER pressure completely counteract any effect. These findings offer new insight into the modalities of pharmacological treatment that MDR cells require to obtain a complete reversion of cellular resistance to the various drug families included in the MDR spectrum.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

A randomized, controlled phase III study of cyclophosphamide, doxorubicin, and vincristine with etoposide (CAV-E) or teniposide (CAV-T), followed by recombinant interferon-alpha maintenance therapy or observation, in small cell lung carcinoma patients with complete responses.

BACKGROUND: Studies of chemotherapy for patients with small cell lung carcinoma (SCLC) have shown that teniposide (T) may have higher activity than etoposide (E). In this randomized, controlled Phase III study, the authors compared cyclophosphamide, doxorubicin, and vincristine (CAV) with E and CAV with T as induction treatments for patients with SCLC. A second objective of the study was to study patients who had achieved complete response (CR). They were considered for a second randomization to maintenance therapy, in which they would receive either recombinant interferon-alpha (rIFN-alpha) or no treatment. METHODS: From June 1990 to December 1995, 140 untreated SCLC patients were enrolled in this study. Patients were stratified by either limited disease (LD) or extensive disease (ED) and randomized to one of two treatment arms. The schedules for both arms included cyclophosphamide 1000 mg/m2 administered intravenously (i.v.), doxorubicin 50 mg/m2 i.v., and vincristine 2 mg i.v. on Day 1. Arm A (CAV-E) involved the addition of E 100 mg/m2 i.v. on Days 2, 3, and 4; Arm B (CAV-T) involved the addition of T 60 mg/m2 i.v. on Days 2, 3, and 4. Courses were repeated every 3 weeks. After 3 courses, patients with LD received chest radiotherapy and 2 additional consolidation courses, whereas patients with ED received 5 consecutive courses only. Patients with CR were considered for the second randomization, which consisted of either maintenance therapy with intramuscular (i.m.) rIFN-alpha-2b, 3 M.U., once a day for 9 months (IFN-alpha arm) or no therapy (control arm). RESULTS: At 5 years from start-up (3-year median observation time and 90% death rate), the study was closed. Results were as follows: 140 patients (71 in Arm A and 69 in Arm B) were eligible for survival analysis; 131 were evaluable for response and toxicity (66 in Arm A and 65 in Arm B), whereas 9 were not (6 early deaths and 3 with protocol violations). Among evaluable patients, 68 showed LD (35 assigned to Arm A and 33 to Arm B); the responses to treatment were 28.5% (10/35) CR and 51% (18/35) partial response (PR) to CAV-E, and 39% (13/33) CR and 39% PR (13/33) to CAV-T. Sixty-three patients showed ED (31 assigned to Arm A and 32 to Arm B); their responses were 22.5% (7/31) CR and 52% (16/31) PR to CAV-E, and 12.5% (4/32) CR and 50% (16/32) PR to CAV-T. Drug-related toxicity was WHO Grade 3-4 myelosuppression in 20% of 292 CAV-E courses and in 27% of 252 CAV-T courses. There were 6 toxic deaths, 1 in Arm A and 5 in Arm B (chi-square = 2.86); 2 patients in Arm A discontinued therapy due to persistent leukopenia and thrombocytopenia. No other remarkable toxicities were observed. Actuarial median survival (MS) was 13.7 months (range, 1.0-62.5 months) for patients with LD receiving CAV-E (Arm A) and 15.2 months (range, 0.5-68.2 months) for those receiving CAV-T (Arm B) (chi-square = 0.89); in patients with ED it was 10.5 months (range, 0.6-30.4 months) and 8.2 months (range, 0.2-24.8 months), respectively (chi-square = 3.42). Overall, MS was 12 months (range, 0.6-62.5 months) in Arm A and 10 months (range, 0.2-68.2 months) in Arm B (chi-square = 0.059). Thirty-nine patients with CR (27.8%) were candidates for the second randomization. Among them, 26 patients (18.5%) complied with the program and were randomized as follows: 14 were assigned to the IFN-alpha arm and 12 to the control arm. Starting from the second randomization, median time to progression was 12 months (range, 3-51 months) for patients in the IFN-alpha arm versus 7 months (range, 1-59 months) for patients in the control arm (chi-square = 0.12). MS was 15 months (range, 5-52.3 months) versus 9 months (range, 2-60.5 months) (chi-square = 0.13). CONCLUSIONS: This study did not show a wide difference in activity and toxicity between CAV-E and CAV-T. The number of patients who entered the second randomization was too small to reach the second study endpoint.

Adult↗
PubMed1998

Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: involvement of NF-kappaB activation in drug resistance.

Brefeldin A, an agent that disrupts protein transport from the endoplasmic reticulum to the Golgi, induces the expression of GRP78 and the activation of nuclear factor (NF)-kappaB in cells. Treatment of cells with brefeldin A causes the development of resistance to topoisomerase II-directed agents, such as etoposide and doxorubicin. In this study, we show that treatment of EMT6 mouse mammary tumor cells with brefeldin A strongly induces GRP78 mRNA (8.5-fold) and resistance to teniposide (VM26). Treatment with okadaic acid causes a minor increase in GRP78 mRNA (2.1-fold) yet still induces resistance to VM26 as effectively as brefeldin A. In contrast, cells treated with castanospermine show a moderate increase in GRP78 mRNA (3.9-fold) but no resistance to VM26. These data imply that GRP78 induction does not mediate the development of drug resistance. An alternative mechanism of drug resistance may involve activation of the transcription factor, NF-kappaB, and we show that both brefeldin A and okadaic acid activate NF-kappaB in EMT6 cells. Furthermore, we demonstrate that treatment with the proteasome inhibitor MG-132 blocks the activation of NF-kappaB and prevents the development of resistance to VM26 induced by brefeldin A. Collectively, these results suggest that the resistance to VM26 in EMT6 cells treated with brefeldin A is mediated by the activation of NF-kappaB rather than the induction of GRP78. Our results also suggest that inhibition of NF-kappaB activation in tumor cells may increase the efficacy of topoisomerase II-directed agents in chemotherapy.

Animals↗
PubMed2006

Topoisomerase II trapping agent teniposide induces apoptosis and G2/M or S phase arrest of oral squamous cell carcinoma.

BACKGROUND: Teniposide (VM-26) has been widely used in the treatment of small cell lung cancer, malignant lymphoma, breast cancer, etc. However, there are few reports on VM-26 against oral cancers. The present study was designed to identify the effect of VM-26 against oral squamous cell carcinoma in vitro, and to provide evidence for the feasibility and effectiveness of VM-26 for application to the patients with oral cancer. METHODS: Human tongue squamous cell carcinoma cell line, Tca8113, was used. Cells were incubated with different concentrations of VM-26 for a variety of time span. Cisplatin (CDDP) was employed as a control reagent. MTT assay was used to assess the inhibitory rate of Tca8113 growth. Flow cytometer (FCM), transmission electronic microscope (TEM) and fluorescence staining were employed for determining the cell apoptotic rate. Cell cycle distribution of Tca8113 incubated with VM-26 was examined by flow cytometer assay. Statistic software (SAS 6.12, USA) was used for one-way ANOVA. RESULTS: The IC50 of VM-26 against Tca8113 cells was 0.35 mg/l and that of CDDP was 1.1 mg/l. The morphological changes of Tca8113 cells were observed with fluorescence microscope and TEM. Apoptotic morphological feature could be found in the nucleus. Apoptotic rate of Tca8113 cells incubated with 5.0 mg/l of VM-26 for 72 hours was 81.67% and cells were arrested at S phase. However, when exposed to 0.15 mg/l of VM-26 for 72 hours, G2/M phase increased from 12.75% to 98.71%, while the apoptotic rate was 17.38%, which was lower than that exposed to 5.0 mg/l of VM-26. CONCLUSION: VM-26 could significantly induce apoptosis of oral squamous cell carcinoma and inhibit cell growth. There may be another pathway to induce apoptosis of oral squamous cell carcinoma cells except for G2/M phase arrest.

Journal Article↗
PubMed1984

Penetration of teniposide (VM-26) into human intracerebral tumors. Preliminary observations on the effect of tumor type, rate of drug infusion and prior treatment with amphotericin B or oral glycerol.

Thirty-four consenting patients received VM-26 50-100 mg/m2 I.V. before surgical resection of intracerebral tumor, and drug was measured using a high pressure liquid chromatographic technique. Sufficient tumor for analysis was obtained from 29 patients. Brain metastases (13 patients) had higher concentrations of VM-26 than did gliomas (13 patients). Concentrations were comparable in brain metastases and meningiomas (3 patients). Prolonged (24 h) infusion of VM-26 did not appear to result in higher tumor drug concentrations in 5 patients than did rapid (1 h) infusion in 24 patients. Pretreatment with Amphotericin-B 10 mg/m2 12 h and 1 h before VM-26 did not appear to have any effect on VM-26 uptake into 4 intracerebral tumors, although data were limited, and VM-26 concentrations were very high in 1 metastasis. Pretreatment with oral glycerol 500 mg/kg 18 h, 12 h, 6 h, and immediately before I.V. VM-26 may have resulted in increased penetration of VM-26 into 9 tumors, although confirmation is required. Amphotericin-B, glycerol, and operative conditions did not appear to alter VM-26 plasma pharmacokinetics.

Amphotericin B↗
PubMed1982

Etoposide (VP16-213) and teniposide (VM26) comparative in vitro activities in human tumors.

In order to determine if any inherent sensitivity differences may exist between VP16-213 and VM26 individual human tumors were grown in vitro and drug sensitivities were determined using the soft agar clonogenic assay method. Only nine of the 34 tumors tested so far showed a differing sensitivity to VP16-213 and VM26 as measured by a 25% or greater colony number reduction. However in none of these tumors did this added reduction result in a 70% decrease over control plate colony numbers. As yet we have been unable to demonstrate any clinically meaningful inherent in vitro sensitivity difference between VP16-213 and VM26 in any tumor type tested.

Antineoplastic Agents↗
PubMed1982

Pharmacokinetics of Teniposide (VM26) and etoposide (VP16-213) in children with cancer.

The clinical pharmacokinetics of VM26 and VP16-213 were assessed in 15 children (median age 10 years) with acute leukemia, using a new high-performance liquid chromatography-electrochemical assay. Pharmacokinetic parameters were calculated by both model-dependent and compartment model-independent methods. These studies demonstrated substantial differences in the central volumes of distribution (VDc), steady-state volumes of distribution (VDss) and systemic clearances (Cls) of VM26 and VP16-213; with the VDc, VDss, and Cls all being smaller for VM26, Systemic clearances determined by model-independent methods were 5.2 +/- 1.0 ml/min/m2 (mean +/- SD) for VM26 and 17.8 +/- 11.2 ml/min/m2 for VP16-213. The major metabolites. detected in serum and urine were the hydroxy acids. Low levels of the picro-lactone isomers were detected in some patients while the aglycones were not detected in the serum or urine of any patients.

Biotransformation↗
PubMed1990

Effects of the lipophilic anticancer drug teniposide (VM-26) on membrane transport.

The epipodophyllotoxin glucopyranosides have previously been shown to interact with membrane lipids and to alter the activity of several lipid-embedded membrane proteins. To determine if these agents are acting as general membrane perturbants, we have further examined their effects on membrane processes in Ehrlich ascites tumor cells. [3H]VM-26 and [3H]VP-16 were taken up rapidly and concentrated within the cells in proportion to their lipophilicity. Neither agent was found to have any significant effect on the influx of L-[3H]leucine or alpha-[3H]aminoisobutyric acid. Likewise, these drugs had no significant effects on the hexose transporter. The nucleoside transporter, which is structurally and functionally similar to the hexose transporter, was dramatically affected, however. VM-26 was a non-competitive inhibitor of equilibrium-exchange influx of cytosine arabinoside in Ehrlich cells with a Ki of 15 microM. Equilibrium-exchange influx increased with temperature in control cells (Q10 = 2) but not in VM-26-treated cells; thus, VM-26 was a more potent inhibitor at higher temperatures. VM-26 also significantly reduced zero-trans influx in Ehrlich, P388, L5178Y, and ML-1 cells, and these effects were immediate in onset. VM-26 inhibited high-affinity binding of the nucleoside transport inhibitor nitrobenzylmercaptopurine riboside (NBMPR), but VM-26 enhanced non-specific NBMPR binding to Ehrlich cells. The apparent specificity of the epipodophyllotoxins for the nucleoside transporter is discussed.

Amino Acids↗