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Radioimmunoassay for etoposide and teniposide.

A radioimmunoassay for VP-16 or VM-26 was developed by using tritiated ligand and antisera produced from rabbits immunized with succinyl-VP-16 bovine serum albumin conjugates. Separate determinations of VP-16 and its hydroxy acid, a metabolite which cross-reacted with the VP-16 antisera, could be accomplished by extracting samples with chloroform in which the metabolite was insoluble. The assay was reproducible and sensitive. Extracted standard curves were linear from 0.025 to 5 micrograms for VP-16 and 0.1 to 10 micrograms for the hydroxy acid per 0.5 ml assay mixture. Fifty percent inhibition of binding was achieved at 0.066 and 0.55 microgram for VP-16 or VM-26 and the metabolite, respectively. Preliminary disposition studies in mice and dog, and human urinary excretion support the application of the assay in pharmacologic studies.

Animals↗

Teniposide (VM26): an effective treatment for brain metastases of small cell carcinoma of the lung.

Despite good results of chemotherapy in small cell lung cancer (SCLC), occurrence of brain metastases is frequent and unaffected by commonly employed antineoplastic drugs, mainly because they do not cross the blood-brain barrier. We treated eight patients with SCLC and cerebral metastases with VM26 at 120 mg/m2 given on days 1, 3 and 5 and repeated every 3 weeks. Two patients achieved complete response and one had partial response. Mean response duration was 8.2 months and survival was more than 9 months in responding patients. Toxicity was manageable. VM26 is an active drug in SCLC with brain metastases.

Aged↗

Local base sequence preferences for DNA cleavage by mammalian topoisomerase II in the presence of amsacrine or teniposide.

Several classes of antitumor drugs are known to stabilize topoisomerase complexes in which the enzyme is covalently bound to a terminus of a DNA strand break. The DNA cleavage sites generally are different for each class of drugs. We have determined the DNA sequence locations of a large number of drug-stimulated cleavage sites of topoisomerase II, and find that the results provide a clue to the possible structure of the complexes and the origin of the drug-specific differences. Cleavage enhancements by VM-26 and amsacrine (m-AMSA), which are representative of different classes of topoisomerase II inhibitors, have strong dependence on bases directly at the sites of cleavage. The preferred bases were C at the 3' terminus for VM-26 and A at the 5' terminus for m-AMSA. Also, a region of dyad symmetry of 12 to 16 base pairs was detected about the enzyme cleavage positions. These results are consistent with those obtained with doxorubicin, although in the case of doxorubicin, cleavage requires the presence of an A at the 3' terminus of at least one the pair of breaks that constitute a double-strand cleavage (Capranico et al., Nucleic Acids Res., 1990, 18: 6611). These findings suggest that topoisomerase II inhibitors may stack with one or the other base pair flanking the enzyme cleavage sites.

Amsacrine↗

[Teniposide inducing apoptosis and G2/M phase arrest of Tca8113 cells].

PURPOSE: The present study is designed to identify quantitatively the in vitro effect of VM-26 against oral squamous cell carcinoma Tca8113 and to explore the underlying mechanism. METHODS: Human tongue squamous cell carcinoma cell line Tca8113 was used as subject. Cells were incubated with VM-26 of various concentrations for a variety of time spans. Cisplatin (CDDP) was employed as a control agent. MTT assay was used to assess the inhibition of cell growth by VM-26. Flow cytometer (FCM), transmission electron microscope (TEM) and fluorescence staining were employed for determining the apoptotic rate of cells induced by VM-26. Cell cycle distribution of Tca8113 cells incubated with VM-26 was examined through flow cytometer assay. SAS 6.12 was used for one-way ANOVA. RESULTS: The IC50 of VM-26 against Tca8113 cells was 0.35microg/ml and that of CDDP was 1.1microg/ml. The changes in morphology and ultrastructure of Tca8113 cells were observed using fluorescence microscope and TEM, and apoptotic morphological feature could be found in the nucleus. Apoptotic rate of Tca8113 cells incubated with VM-26 of 5.0microg/ml for 72 hours was 81.01% and cell cycle appeared was arrested at S phase. However, exposed to VM-26 of 0.15microg/ml for 72 hours, Tca8113 cells in the G2/M phase increased from 12.75% to 98.71%, while the apoptotic rate of these cells was 17.38% and far below than that of cells treated with VM-26 of 5.0microg/ml. CONCLUSION: VM-26 could significantly induce apoptosis of oral squamous cell carcinoma cells and inhibit cell growth. There may be another pathway to induce apoptosis of oral squamous cell carcinoma cells except for G2/M phase arrest. Supported by National Natural Science Foundation of China (30300388, 30171014, 30330580) and Research Grant (No.036505013, 034107002) of Science and Technology Committee of Shanghai Municipality.

Antineoplastic Agents↗

[Efficacy of lomustine, teniposide, doxorubicin, bleomycin and prednisone (LTABP) or adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) in the treatment of malignant lymphogranulomatosis resistant to MOPP].

LTABP regimen was applied to 18 patients in IIB and IV stage of malignant lymphogranulomatosis resistant to MOPP. The obtained results were compared with historical control group of 18 patients with similar stage of the disease treated according to ABVD regimen. In both regimens courses were repeated every 28 days or more rarely, when leucopenia and thrombocytopenia prolonged. Only patients who had received at least 3 courses were analysed. In the LTABP group the complete remission was obtained in 10 cases (55%) while partial remission in 6 (33%). In the group treated with ABVD complete remission was obtained in 4 cases (22%) and partial in 9 cases (50%). In the LTABP group 11 patients are still alive and remain in complete remission, while in ABVD group--4 patients. The most frequent side effects in both groups included leucopenia, thrombocytopenia and symptoms of gastrointestinal intolerance. The LTABP regiment allows to obtain higher percentage of the complete remission than ABVD.

Adolescent↗