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PubMed1998

Chemotherapy with cisplatin and teniposide for cerebral metastases in non-small cell lung cancer.

Twenty-three patients with brain metastases from non-small cell lung cancer (NSCLC) (median age 62 years, Karnofsky PS 50-100) were treated with cisplatin (100 mg/m2, day 1) and teniposide (80 mg/m2, days 1, 3 and 5) every 3 weeks. Response was evaluated by contrast-enhanced brain CT every two to three cycles of treatment. The objective response rate of brain metastases was 35% (8/23); three patients achieved complete response (CR) and five partial response (PR). The median response duration was 24 weeks for CR patients and 32 weeks for PR patients. The median survival was 21 weeks overall and 45 weeks for responding patients. Grade 3/4 leukocytopenia and thrombocytopenia were seen in 28 and 9%, respectively. Two patients died from infections while in neutropenia. Cisplatin and teniposide seems an active regimen against brain metastases in NSCLC. These data may indicate the need for reconsideration of the role of chemotherapy for brain metastases of NSCLC.

Aged↗
PubMed1999

Effect of teniposide (VM-26) on the cell survival, micronuclei-induction and lactate dehydrogenase activity on V79 cells.

The genotoxic effect of 0, 1, 5, 10, 25, 50 and 100 nM teniposide (VM-26) treatment was studied on cultured V79 cells. Treatment of V79 cells with different concentrations of teniposide resulted in a concentration-dependent decline in the cell survival and growth kinetics. VM-26 treatment also caused alteration in the cell proliferation kinetics as evidenced by the increase in the frequency of mononucleate cells, with a consequent decline in the frequency of binucleate cells in a concentration-dependent manner at all the post-treatment time periods. Exposure of V79 cells to different concentrations of VM-26 resulted in a concentration related elevation in the frequency of micronucleated binucleate (MN) cells. The frequency of MN was significantly higher in VM-26 treated cells than that of non-drug treated cells at all the post-treatment time periods. A peak frequency of MN was observed at 16 h post-treatment that declined thereafter. The release of lactate dehydrogenase increased with the increase in drug concentration and a maximum LDH release was observed at 0.5 h post-treatment after exposure to 10-100 nM VM-26. While a peak value was observed at 1 and 2 h for 5 and 1 nM VM-26, respectively. The biological response was evaluated by determining the relationship between micronuclei and cell survival. The cell survival declined with increasing MN frequency, resulting in a close but an inverse relationship between the cell survival and micronuclei-induction. The dose effect relationships for micronuclei induction, LDH release and biological response was linear quadratic.

Animals↗
PubMed1999

Correlation between cell survival, micronuclei-induction, and LDH activity in V79 cells treated with teniposide (VM-26) before exposure to different doses of gamma radiation.

The influence of teniposide (VM-26) treatment was studied on the radiation-induced alterations in cell survival, micronuclei (MN) formation and lactate dehydrogenase (LDH) release in V79 cells. Treatment of V79 cells with 10 nM teniposide before exposure to different doses of gamma radiation resulted in a significant decline in the cell survival when compared with the PBS + irradiation group. The decline in cell survival was dose related. The cell proliferation indices also declined in a dose-dependent manner in both PBS + irradiation and VM-26 + irradiation groups. The decline was higher in the VM-26 + irradiation group in comparison with the PBS + irradiation group. In contrast, the frequency of micronuclei increased in a dose-related manner in both PBS + irradiation and VM-26 + irradiation groups. However, the frequency of micronuclei was significantly greater in the latter group when compared with the former group at all the post-irradiation time periods studied. The LDH contents increased in a dose-dependent manner in both PBS + irradiation and VM-26 + irradiation groups at all the post-irradiation time periods evaluated. This elevation in LDH contents was significantly greater in the VM-26 + irradiation group in comparison with the PBS + irradiation group.

Animals↗
PubMed1989

Automated reversed-phase chromatographic analysis of etoposide and teniposide in plasma by using on-line surfactant-mediated sample clean-up and column-switching.

An automated high-performance liquid chromatographic method for the plasma assay of two neutral drugs, etoposide and teniposide, involving direct plasma injection is presented. The problematic nature of protein precipitation has been circumvented by adding the anionic surfactant sodium dodecyl sulphate to the plasma at a final concentration of 38 mM. Plasma samples are loaded on to a clean-up column with an aqueous mobile phase with which the analyte(s) is (are) retained, whereas the solubilized plasma proteins are flushed to waste. Next, the retained compounds are eluted from the clean-up column on to the analytical column by using the chromatographic mobile phase with a higher elution capacity. The column-switching technique is used to achieve an automated assay. At least 10 ml of plasma, representing 100 repeated injections of 100 microliters or five repeated injections of 2 ml, can pass through the clean-up column without increasing the back-pressure. The recovery increased considerably from 10-30% to 90-95% on adding surfactant to the plasma samples prior to the analysis. The relative standard deviation of the proposed clean-up procedure is 3.5% (n = 6) for both drugs measured at the 2 micrograms/ml level without using an internal standard. The limit of determination with 100-microliters injections is 0.10-0.15 microgram/ml for ultraviolet detection and is seven times lower with electrochemical detection. Teniposide was determined in patients' plasma and the results agreed well with those obtained by the conventional procedure involving manual liquid-liquid extraction prior to chromatographic analysis.

Chromatography, High Pressure Liquid↗
PubMed1995

Quality versus quantity of life in the treatment of patients with advanced small-cell lung cancer? A randomized phase III comparison of weekly carboplatin and teniposide versus cisplatin, adriamycin, etoposide alternating with cyclophosphamide, methotrexate, vincristine and lomustine. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: Based on a promising pilot study with weekly carboplatin and teniposide (CBDCA/VM) the Swiss Group for Clinical Cancer Research (SAKK) performed a randomised phase III trial in patients with extensive-disease small-cell lung cancer aimed at the development of an effective palliative treatment with low subjective toxicity. PATIENTS AND METHODS: From September 1989 to September 1991 patients were randomised to a weekly regimen of CBDCA/VM or to our 'standard chemotherapy' of cisplatin, adriamycin and etoposide alternating with cyclophosphamide, methotrexate, vincristine and lomustine (PAV-CyMOC). RESULTS: The trial was closed before the planned accrual of 140 evaluable patients due to a significant survival difference shown by an interim analysis. Of the 61 patients 59 were eligible and included in the final analysis. The results achieved with the PAV-CyMOC regimen were significantly better than those observed in patients treated with weekly CBDCA/VM (remission rate of 65% vs. 29%; p = 0.006). The median survival of patients treated with the PAV-CyMOC combination was significantly longer than that of patients receiving weekly CBDCA/VM (260 days vs. 147 days; p = 0.0035). The 1-year survival rate was 30% in the PAV-CyMOC arm compared to 4% in the CBDCA/VM-treated patients. As expected, side effects including myelosuppression, alopecia and mucositis were significantly more pronounced in patients treated with the PAV-CyMOC regimen. No significant difference was found in patient-rated tumor symptoms and general quality-of-life categories. CONCLUSION: Contrary to our initial expectation that we would achieve similar therapeutic results with less subjective toxicity, in this randomised prospective trial the results achieved by weekly carboplatin and teniposide were significantly inferior in terms of remission rate and survival to those of our 'standard regimen' of cisplatin, adriamycin and etoposide alternating with cyclophosphamide, methotrexate, vincristine and lomustine. The weekly regimen was less toxic than the standard chemotherapy. Whether patients are willing to accept a significant trade-off between quantity and quality of life remains to be evaluated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Teniposide (VM-26) in patients with non-squamous-cell carcinoma of the cervix. A phase II trial of the Gynecologic Oncology Group.

Twenty-three evaluable patients with non-squamous-cell carcinoma of the cervix were treated with teniposide 100 mg/m2 per week administered as a 30-60 min infusion. Escalations of 20 mg/m2 per week to a maximum dose of 160 mg/m2 were performed in patients without toxicity. Thirteen of the 23 patients had no prior chemotherapy. One patient had a partial response (95% confidence intervals for response less than or equal to 19%). Toxicity was minimal. Seven patients had white blood cell counts of less than 2,000/mm3 but only one had less than 1,000/mm3. No patients had platelet counts less than 50,000/mm3, and no bleeding or septic episodes were noted. Two patients had mild nausea and seven had mild nausea and vomiting. Teniposide displays no major activity in patients with non-squamous-cell cervical cancer.

Adult↗
PubMed1991

Teniposide (VM-26) in patients with advanced endometrial carcinoma. A phase II trial of the Gynecologic Oncology Group.

Twenty-two evaluable patients with advanced endometrial cancer were treated with teniposide 100 mg/m2/week administered as a 30-60-minute infusion. Escalations of 20 mg/m2/week to a maximum dose of 160 mg/m2 were performed in patients without toxicity. Seventeen of the 22 patients had prior chemotherapy. Two patients had a partial response (95% upper confidence bound for response: 25.9%). Toxicity was minimal. Four patients had white blood cell counts of less than 2,000/mm3 but only two with less than 1,000/mm3. Only one patient had a platelet count between 25,000 and 50,000, and no bleeding or septic episodes were noted. Four patients had mild nausea, and eight mild nausea and vomiting. Teniposide displays no major activity in patients with advanced endometrial cancer who have had prior chemotherapy.

Adenocarcinoma↗
PubMed1986

Hypersensitivity reactions to teniposide (VM-26): an analysis.

An analysis of hypersensitivity reactions to teniposide was approached using three methods: investigator survey, adverse drug reaction analysis, and literature search. By the survey method, hypersensitivity incidence was 6.5% with the majority of the reactions (82%) occurring in brain tumor or neuroblastoma patients. By the second method, 43 cases of hypersensitivity that were reported to the National Cancer Institute (NCI) between January 1983 and October 1985 were analyzed in detail. Reaction onset was unpredictable according to the number of drug doses. The majority of the patients (65%) experiencing the reaction had neuroblastoma or brain tumors, and these patients also tended to react earlier in the course of drug administration than those with hematologic malignancies. Clinical presentation was not correlated with the patient's diagnosis. All patients recovered. However, only six of 13 were successfully rechallenged with the drug. The third approach, the literature search, provided information on 82 hypersensitivity reactions among 2,250 patients (3.6% incidence). Forty-five percent of these reactions were linked to neuroblastoma or brain tumor patients. The analysis of hypersensitivity to teniposide by these three methods provides insight into the true incidence of hypersensitivity reactions in the general patient population. The frequency of the reactions is substantially higher in patients with neuroblastoma and brain tumors. This population should be considered for future trials of aggressive prophylactic therapy.

Adolescent↗
PubMed1994

Leukemia risk following Hodgkin's disease: relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage.

PURPOSE: The development of leukemia is one of the most serious long-term complications of modern treatment for Hodgkin's disease (HD). This study was undertaken to examine the relation between risk of leukemia and various treatment factors (including cumulative dose of cytostatic drugs and interaction with radiotherapy [RT]), while also assessing the effect of treatment-induced bone marrow damage. PATIENTS AND METHODS: We conducted a case-control study in a cohort of 1,939 patients treated for HD between 1966 and 1986 in the Netherlands. Detailed information from the medical records was obtained for 44 cases of leukemia and 124 matched controls, in whom leukemia had not developed. RESULTS: The cumulative dose of mechlorethamine was the most important factor in determining leukemia risk. As compared with patients who received RT alone, patients treated with six or fewer cycles of combinations including nitrogen mustard (mechlorethamine) and procarbazine had an eightfold increased risk of developing leukemia (P = .08), while patients who received more than six of such cycles had a greater than 40-fold excess risk (P < .001). Treatment with lomustine or a combination of teniposide and cyclophosphamide also significantly increased the risk of leukemia. Patients who had received chemotherapy (CT) during two or more time periods had a nearly 40-fold increased risk of leukemia as compared with patients treated only once. The extent of RT did not further increase leukemia risk among patients who also received CT. A significantly increased risk of leukemia was found among patients with low platelet counts, both in response to initial therapy and during follow-up. Patients who experienced 2 or more half-year periods with platelet counts less than 75 x 10(6)/mL had an approximately fivefold risk of developing leukemia, and a similar risk increase was found for patients who responded to initial treatment with a > or = 70% decrease of platelet counts (as compared with patients who had a < or = 50% decrease). CONCLUSION: In addition to mechlorethamine, lomustine and teniposide combinations were also linked to an elevated risk of developing leukemia. Since the number of CT episodes was found to be a strong determinant of leukemia risk, it is important that new therapies for HD continue to yield high initial cure rates. Further studies are warranted to investigate whether patients at high risk for developing leukemia may be identified from the response of their platelets to initial therapy for HD.

Adult↗
PubMed2004

Vincristine, cisplatin, teniposide, and cyclophosphamide combination in the treatment of recurrent or metastatic adrenocortical cancer.

The efficacy and tolerability of a combination of vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) in 11 patients (median age, 45 yr) with recurrent and/or metastatic adrenocortical cancer (ACC) (seven functional and four nonfunctional) were evaluated. All patients received this regimen after the failure of streptozocin and o,p'-DDD (SO) combination therapy. The regimen comprised cyclophosphamide, 600 mg/m2, and vincristine, 1.5 mg/m2, maximum dose 2.0 mg (d 1); cisplatin, 100 mg/m2 (d 2) and teniposide, 150 mg/m2 (d 4). Cycles were repeated every 4 wk. One to eight cycles (median, six cycles) of OPEC were administered to each patient. The median duration of treatment was 6 mo. The overall 2-yr survival rate was 82% and the median survival since diagnosis was 44 mo while it was 21 mo since start of OPEC therapy. Responses were obtained in nine patients: partial response in two patients, and stable disease in seven patients. The median duration of response was 6.75 mo. A total of 60 cycles of chemotherapy were given to all patients; grade 1-2 toxicity occurred in 57 cycles, while grade 3 toxicity was observed only in two cycles, according to NCI's Common Toxicity Criteria. We conclude that the OPEC regimen may be considered in recurrent or metastatic ACC as a second-line medical treatment. However, the combination is accompanied by considerable side effects and dose modifications are necessary in order to be able to recommend the treatment. This regimen needs further evaluation compared with SO therapy preferably in a randomized multicenter trial.

Adrenal Cortex Neoplasms↗
PubMed1997

[Teniposide, cyclophosphamide and dexamethasone combination treatment for stage III multiple myeloma: a report of 21 cases].

OBJECTIVE: To evaluate the efficacy and toxicites of combination chemotherapy of teniposide, cyclophosphamide, and dexamethasone (VCD) for stage III multiple myeloma (MM). METHODS: Twenty-one patients with stage III MM were treated with VCD regimen. Among 21 evaluable patients, 16 were in stage IIIA; 5 in stage IIIB. Teniposide was given 30 mg/m2 by intravenous(i.v.) infusion on days 1-3; cyclophosphamide 200 mg/m2 i.v. on day 1, 3, 5; dexamethasone 10-20 mg daily p.o. on days 1-7. The treatment was recycled every 28 days. RESULTS: The overall response rate was 76%(16/21), including partial response 38%(8/21); improvement 38%(8/21) and failure 24%(5/21). The survival time was 3-31 months; medium survival time (MST) 13 months; MST of MM patients in stage IIIA, IIIB were 11, 12 months, respectively. The medium duration of response was 5 months; the medium cycle for initial response was 2. Among 21 cases, leukopenia and thrombocytopenia were detected respectively in 10%, 54%, 31%, 5% and 67%, 17%, 13%, 3% according to WHO grade 0, I, II, III criteria. The gastrointestinal reaction was mild. No cardiovascular, renal and hepatic toxicites were observed. CONCLUSION: VCD regimen is an effective treatment for stage III multiple myeloma.

Adult↗
PubMed2002

[Teniposide and cisplatin compared with etoposide and cisplatin for treatment of small cell lung cancer].

BACKGROUND & OBJECTIVE: EP regimen[etoposide (VP-16) + cisplatin (DDP)] is a standard regimen for treatment of small cell lung cancer (SCLC), but the cure rate is still low. Teniposide (VM-26) is highly active single agent for SCLC as VP-16, and penetratable through blood-brain barrier. This clinical trial was designed to compare the efficacy and toxicity of teniposide plus cisplatin (VM-26 + DDP) regimen and EP regimen in treatment of SCLC, and the possible role of VM-26 on prevention of brain metastasis of SCLC. METHODS: A total of 70 previously untreated SCLC patients without brain metastasis were included; 34 patients received VM-26 + DDP and 36 patients received EP. The characteristics of patients were comparable according to chi 2 test. RESULTS: The overall response rate-was 76.5% for VM-26 + DDP group with 12 complete response (CR) and 14 partial response (PR), and 69.4% in the EP group with 12 CR and 13 PR (P = 0.595). The median duration of survival was 10.4 months for VM-26 + DDP group versus 9.8 months for EP group (P > 0.05). The 1, 2, and 5-year survival rates were 35.3%, 14.7%, 8.8% in the VM-26 + DDP group; and 38.9%, 13.9%, 8.3% in the EP group (P > 0.05, without statistical difference). The rate of brain metastasis was 5.9% for VM-26 + DDP group and 19.4% for EP group (P = 0.027, with statistical difference). The main toxicity was mylosuppression (I-II); there was no significant difference between the two groups (P > 0.05). CONCLUSION: VM-26 + DDP is a highly active regimen for treatment of SCLC; there is no difference in the effectiveness and toxicity versus EP regimen; VM-26 is possibly effective in prevention of brain metastasis in SCLC patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Treatment of brain metastases of small cell lung cancer with teniposide.

Over 50% of patients with small cell lung cancer (SCLC) will develop symptomatic brain metastases during the course of their disease. Results of whole brain radiotherapy, the standard treatment, are rather poor and relapses are frequent. Thus, new modes of therapy are urgently needed for these patients. In this study, the efficacy of teniposide was evaluated at a dose of 150 mg/m2 intravenously on days 1, 3, and 5 at 3-week intervals. In 11 of 26 evaluable patients an intracranial response was observed. Median response duration was 23 weeks (range, 9 to 50). Toxicity was acceptable, with grades 3/4 leukocytopenia and thrombocytopenia reported in 37% and 16%, respectively, of 123 courses. Therefore, teniposide is an effective agent against brain metastases of SCLC and is suitable for palliation of these patients.

Aged↗
PubMed1992

The European Organization for Research and Treatment of Cancer experience with teniposide: preliminary results of a randomized study in non-small cell lung cancer.

Chemotherapy for non-small cell lung cancer (NSCLC) is unsatisfactory, and the search for new active drugs has been relatively unsuccessful. Most polychemotherapy regimens in NSCLC include cisplatin with a vinca alkaloid or etoposide. Among the new agents tested in recent years, teniposide produced a 17% response rate in 42 evaluable patients, with a 21% response rate in untreated patients. The Lung Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer has started a randomized trial comparing two different schedules of teniposide administration with and without cisplatin. This paper reports the preliminary findings for the initial 80 patients in this randomized study.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

[Chemotherapy with higher or lower dose of teniposide combined with cisplatin and pingyangmycin for oral squamous cell carcinoma].

OBJECTIVE: To compare the clinical efficacy and toxicity of teniposide (VM26) of higher dose with those of lower dose, both combined with cisplatin (CDDP) and pingyangmycin (PYM), in the treatment of patients with squamous cell carcinoma of oral and maxillofacial region (SCCOMR). METHODS: Sixty-five patients with SCCOMR entered into this study prospectively. Thirty-three patients were treated with higher dose of VM26 (total dose was 320 mg) combined with CDDP and PYM (PTP1), the other thirty-two patients were treated with lower dose (total dose was 158 mg) of VM26 combined with CDDP and PYM (PTP2). RESULTS: Thirty-three patients received a total of 38 cycles of PTP1. The overall response rate was 81.82% (27/33). Thirty-two patients received a total of 36 cycles of PTP2 and showed overall response rate by 81.25% (26/32). There was no significant difference between PTP1 and PTP2 groups in response rate (P > 0.05). But the blood toxicity was more severe in PTP1 group than in PTP2 group (P < 0.01). Bone marrow depression rate (1-4 stage) was 48.48% in PTP1 group versus 25.00% in the other group. CONCLUSIONS: A high response rate of 81.25% and relatively slighter adverse events could be obtained for lower dose of VM26 combined with CDDP and PYM (PTP2). So, the chemotherapy schedule, PTP2, a novel teniposide based regimen in SCCOMR could be employed and spread in clinical practice.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

[A high performance liquid chromatographic method for the determination of teniposide in brain tissue using electro-chemical detection].

A reversed-phase HPLC method for the determination of teniposide in brain tissue is described. Teniposide can be separated on a Hypersil ODS column with a mobile phase of methyl alcohol-water-acetic acid (56:41:3, V/V) and flow rate of 0.8 mL/min (10 MPa). Column temperature was 35 degrees C and operating potentials for electrochemical detection was 0.70 V. To 50 mg brain tissue were 1 mL 50% ammonium sulfate and 4 mL ethyl acetate. The sample was vortexed for 5 min and ultrasonically agitated for 15 min, then centrifuged at 3000 r/min for 15 min. The upper (organic) layer was collected and the lower layer reextracted with 4 mL of ethyl acetate by vigorously vortexing, then centrifuged at 3000 r/min for 15 min. The organic layer was combined with the previously collected ethyl acetate layer. This organic extract was dried under a gentle nitrogen stream, and the residue was reconstituted with 1 mL internal standard of guaifenesinum before HPLC analysis. The linear range was 0.1-10.0 mg/L, and the detection limit 0.1 mg/L. Intra-day and inter-day RSD for assaying brain tissue sample were 0.87% and 1.41%, respectively. The average recovery was 92.87% with coefficient of variation of 2.35%.

Brain Chemistry↗
PubMed1992

Cell cycle-related expression of p120 nucleolar antigen in normal human lymphocytes and in cells of HL-60 and MOLT-4 leukemic lines: effects of methotrexate, camptothecin, and teniposide.

Expression of the proliferation-associated nucleolar antigen p120 was studied by flow cytometry in human quiescent and phytohemagglutinin-stimulated lymphocytes, as well as in human lymphocytic (MOLT-4) and promyelocytic (HL-60) cell lines. Bivariate analysis of p120 and DNA content made it possible to correlate p120 expression with cell position in the cycle. Proliferating lymphocytes and MOLT-4 and HL-60 cells had a similar pattern of p120 expression. Populations of G1 cells, in all three cell types, were very heterogenous with respect to p120, and a threshold in G1 was observed. The cells with a p120 level below the threshold value did not enter S phase. An increase in p120 was observed during progression through S phase, and the antigen was maximally expressed in G2 cells. The p120/DNA content ratio, however, was highest in late G1 cells (G1B) and was declining during S and G2. The data thus suggest that p120 may be degraded during mitosis and that the postmitotic cells inherit little, if any, of this protein; the antigen then accumulates predominantly during G1, and must reach a threshold level to enable the cells to enter S phase. Antigen p120 could not be detected in noncycling lymphocytes nor in HL-60 cells induced to myeloid differentiation by growth in the presence of dimethyl sulfoxide. Treatment of MOLT-4 cells with pharmacological concentrations of methotrexate, camptothecin, or teniposide induced cell arrest in S or G2; expression of p120 in the arrested cells was unchanged from that of untreated MOLT-4 controls at the same phase of the cycle. The level of p120 was minimal in MOLT-4 or HL-60 cells arrested in M phase by vinblastine, but vinblastine had no effect on p120 fluorescence of interphase cells. Camptothecin or teniposide induced apoptosis selectively in S phase of HL-60 cells; apoptotic cells from camptothecin-treated cultures, however, despite the marked nucleolysis, still expressed p120. The data on the drug-treated cells indicate that the p120 level in tumors of patients may be used as a marker of tumor/malignancy even in clinical samples obtained during treatment.

Antigens, Neoplasm↗
PubMed1989

Altered formation of DNA in human cells treated with inhibitors of DNA topoisomerase II (etoposide and teniposide).

We have investigated the importance of DNA topoisomerase II for the formation of mammalian DNA replication intermediates. Treatment with the DNA topoisomerase II inhibitor etoposide (teniposide) prevents the formation of large intermediates, such as 10-kilobase DNA, but allows the formation of small intermediates, i.e., Okazaki fragments. In untreated cells, there is a distinct stage in which the 10-kilobase DNA intermediates are joined before the appearance of mature chromatin. We find that pretreatment with etoposide (teniposide) prevents the appearance of this stage. When the protocol is reversed and the cells contain labeled 10-kilobase DNA before exposure to the drugs, one can detect the stage.

DNA Replication↗