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At least 883 records · Page 49Linked to original sources
PubMed1987

Randomized phase III trial of single versus multiple chemotherapeutic treatment following surgery and during radiotherapy for patients with anaplastic gliomas.

In 81 patients with anaplastic supratentorial gliomas, single versus multiple chemotherapeutic agents were selected for treatment following surgery and during radiotherapy in a prospective randomized study. Time to treatment failure and survival were not significantly enhanced by multiple agent chemotherapy, as administered in this study.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Regulation of topoisomerase II expression during the VM-26 induced differentiation of IW32 murine erythroleukemia cells.

The effect of VM-26, a topoisomerase II targeting drug, on IW32 murine erythroleukemia cells was investigated. The VM-26 induced IW32 cells to differentiate at a non-toxic but cytostatic concentration (0.01 microgram/ml). More than 40% of the cells were induced to synthesize hemoglobin, and cells were arrested in G2/M phase of the cell cycle. Levels of beta-globin mRNA also increased significantly. Cells became committed to erythroid maturation after 16 h of continuous drug exposure. Replacement with fresh VM-26 after 48 h of drug treatment further increased the hemoglobin containing cells to greater than 80%. Unlike other drug induced erythroleukemia cell differentiation, c-myc mRNA expression was not affected by VM-26. Inhibition of topoisomerase II activity was observed during the first 12 h of VM-26 treatment; however, elevated enzyme activity was found thereafter. Northern blot analysis showed significant increase in the expression of topoisomerase IIalpha mRNA at 12 and 24 h after VM-26 addition. These findings indicate that VM-26 inhibited the activity of topoisomerase II and promoted the committed differentiation of IW32 cells along the erythroid pathway. In addition, a parallel increase in mRNA and activity levels of topoisomerase II in differentiated cells suggests that regulation of the enzyme expression occurred in the VM-26 induced erythroid maturation.

Animals↗
PubMed1988

Topoisomerase-II-mediated lesions in nascent DNA: comparison of the effects of epipodophyllotoxin derivatives, VM-26 and VP-16, and 9-anilinoacridine derivatives, m-AMSA and o-AMSA.

This study compares the effects of the epipodophyllotoxin derivatives, VM-26 and VP-16, and the 9-anilinoacridine derivatives, m-AMSA and o-AMSA, on nascent and mature DNA. Two types of lesion which are putatively mediated by topoisomerase II, DNA-protein crosslinks and DNA double-strand breaks, were analyzed in drug-treated nuclei from 3H/14C labelled L1210 cells. Potassium/dodecyl sulfate precipitation assay was used to assess DNA-protein crosslinks in mature and nascent (1 min old) DNA. Both epipodophyllotoxins and m-AMSA showed a strong preference for nascent DNA. DNA double-strand cleavage induced by VM-26 and m-AMSA also showed a preference for nascent DNA as indicated by neutral elution technique. Sedimentation on neutral sucrose gradients revealed that these drugs generated highly degraded fragments (under 30 S) in nascent DNA substantially faster than in mature DNA. Lesions in nascent DNA were diminished substantially by the omission of ATP or the addition of novobiocin. The ability to induce lesions in nascent DNA correlates with cytotoxic potency of the agents studied. The results suggest that replicating DNA may constitute a preferential target for antitopoisomerase II drugs.

Adenosine Triphosphate↗
PubMed1991

Netropsin and bis-netropsin analogs as inhibitors of the catalytic activity of mammalian DNA topoisomerase II and topoisomerase cleavable complexes.

This study examined the ability of netropsin and related minor groove binders to interfere with the actions of DNA topoisomerases II and I. We evaluated a series of netropsin dimers linked with flexible aliphatic chains of different lengths. These agents are potentially able to occupy longer stretches of DNA than the parental drug as a result of bidentate binding. Both netropsin and its dimers were found: (i) to inhibit the catalytic activity of isolated topoisomerase II and (ii) to interfere with the stabilization of the cleavable complexes of topoisomerase II and I in nuclei. Dimers with linkers consisting of 0-4 and 6-9 methylene groups (n) were far more inhibitory than netropsin against isolated enzyme and in the nuclear system. The compound with n = 5 was less active than netropsin in both assays while the dimer with n = 10 inhibited only the isolated enzyme. The comparison of dimers with fixed linker length (n = 2) but varying number of N-methylpyrrole residues (from 1 to 3) revealed that the inhibitory properties were enhanced with increasing number of N-methylpyrrole units. For dimers with varying linker length, drug ability to inhibit catalytic activity of isolated topoisomerase II was positively correlated with calf thymus DNA association constants. In contrast, no such correlation existed in nuclei. However, the inhibitory effects in the nuclear system were correlated with the association constants for poly(dAdT). The results indicate that bidentate binding can significantly enhance anti-topoisomerase activity of netropsin related dimeric minor groove binders. However, other factors such as the length of the linker, the number of pyrrole moieties and the nature of the target (isolated enzyme/DNA versus chromatin in nuclei) also contribute to these activities.

Animals↗
PubMed1992

Effects of analogs of the DNA minor groove binder Hoechst 33258 on topoisomerase II and I mediated activities.

By contrast with other DNA minor groove binders, Hoechst 33258 inhibited topoisomerase-mediated activity in intact cells. To determine whether specific structural alterations could modify the topoisomerase reactivity of this drug, a series of analogs of Hoechst 33258 (compound 1) was examined. When the relative DNA binding affinities (Ka) of these agents were determined, compound 1 had the highest Ka while agents with substitutions in either of the benzimidazole moieties showed reduced affinity. Whether these changes in DNA binding correlated with topoisomerase inhibitory potency was next examined. In isolated nuclei, 25 microM of agents 1, 5 and 7 reduced VM-26 induced cross-links by 64, 65 and 83%, compared with 15 to 25% reductions by agents 2, 3, 4 and 6, respectively. The structural modification common to the less active compounds was the substitution of an oxygen for nitrogen at either position 1 or 2. On the basis of these results, agents 1, 2, 3 and 7, representing a range of inhibitory potency, were chosen for further analyses. Cross-link induction by m-AMSA and camptothecin in isolated nuclei, as well as by VM-26 in intact cells, was inhibited to a greater extent by agents 1 and 7 than 2 or 3. Additionally, all four drugs inhibited relaxation of pBR 322 DNA induced by both topoisomerases, although topoisomerase I was 2 to 5-fold more sensitive than topoisomerase II. A linear correlation was observed between the logarithms of the Ka value of compounds 1, 2 and 3 and their IC25 values for both topoisomerases, suggesting a strong dependence on DNA binding affinity for enzyme inhibition. Nevertheless, agent 7, despite having less affinity for calf thymus DNA than 1, was the most potent topoisomerase inhibitor tested in intact cells and in isolated enzyme systems. Thus, retention of nitrogen at positions 1 and 2 as well as the addition of nitrogen at position 16 was associated with increased topoisomerase inhibitory potency.

Animals↗
PubMed1995

Transcriptional down-regulation of c-myc expression in the MCF-7 breast tumor cell line by the topoisomerase II inhibitor, VM-26.

In the MCF-7 human breast tumor cell line, the topoisomerase II inhibitor, VM-26, produces a concentration dependent reduction in expression of the oncogene c-myc which parallels growth inhibition. Down-regulation of c-myc expression was examined at transcriptional and post-transcriptional levels. VM-26, at 10 microM, produced a reduction in the transcription rate of both sense and antisense strands of c-myc as determined by nuclear run-off analysis. In contrast, in the presence of the RNA synthesis inhibitor, actinomycin D, VM-26 failed to alter the half-life of the c-myc message. The capacity of VM-26 to reduce c-myc expression was not abrogated in cells pretreated with the protein synthesis inhibitor, cycloheximide (despite superinduction of c-myc expression in both control and VM-26 treated cells); this observation suggests that de novo protein synthesis may not be required to mediate the effects of VM-26 on steady state c-myc transcript levels. An extended analysis of the time course of c-myc expression demonstrated that the decline of steady state c-myc mRNA levels induced by VM-26 was biphasic, 6 h after the initial reduction in c-myc expression to approx. 30% of control levels, c-myc levels rebounded to 70% of control; after 24 h, c-myc expression declined gradually and remained at depressed levels (40% of control) at 48 and 72 h. These observations suggest that the initial transient reduction in c-myc expression associated with inhibition of transcription may represent a component of an early signalling pathway leading to growth arrest in MCF-7 breast tumor cells exposed to VM-26.

Breast Neoplasms↗
PubMed1984

Combination chemotherapy with cisplatin and VM-26 in advanced transitional cell carcinoma of the bladder.

Forty-one evaluable patients with bidimensionally measurable metastases of transitional cell carcinoma of the bladder were treated with cisplatin 70 mg/m2 i.v. on day 1 and VM-26 100 mg/m2 i.v. on days 1 and 2, every 3 weeks. Response was evaluated after 2 treatment cycles. Complete response (CR) was achieved in 4 patients (10%) and partial response (PR) in 17 (41%). The median response duration was 6 months. In this group of previously untreated patients the combination of cisplatin and VM-26 did not appear to yield better response rates than would be expected from cisplatin alone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Comparison between VP 16 and VM 26 in Lewis lung carcinoma of the mouse.

The antitumoral activity and pharmacokinetics of VP 16 and VM 26 were comparatively investigated in Lewis lung carcinoma (3LL)-bearing mice. When the two drugs were given at equitoxic doses, in single or repeated treatment, the superior antitumoral activity of VM 26 was clear. Compared to VP 16, VM 26 had a different pattern of distribution, with a larger volume of distribution, a longer elimination half-life time and a lower clearance. The tissue to plasma AUC ratios indicated that VM 26 concentrated more in tumor and heart while VP 16 gave highest concentrations in liver and intestine. Flow cytometry studies showed that VM 26 was more potent than VP 16 in causing cell cycle perturbation of 3LL cells growing in primary culture. VM 26 displayed cytotoxic activity at a concentration in the medium one-tenth that of VP 16. The uptake of VM 26 by 3LL cells was 15 times that of VP 16.

Animals↗
PubMed1986

Combination chemotherapy with fluorouracil, adriamycin, cis-platinum and VM-26 in advanced transitional cell carcinoma of the urinary tract.

From October 1981 to October 1984, 42 consecutive patients with locally advanced unresectable or metastatic transitional cell carcinoma of the urinary tract were treated with cis-Platinum 50 mg/m2 i.v. and Adriamycin 50 mg/m2 i.v. day 1, and Fluorouracil 500 mg/m2 i.v. and VM26 100 mg/m2 days 1 and 8, every 3 weeks. In the 36 evaluable patients, 4 complete remissions and 15 partial remissions were noted (52.7% response rate). Of the 12 patients with previously untreated, locally advanced bladder carcinoma, 8 responded, with 3 pathologically confirmed complete remissions. Toxicity was moderate. Median survival was 44 weeks. This 4-drug combination had significant palliative activity in our patient population. Its role in the preoperative setting deserves further evaluation.

Adult↗
PubMed1986

Pharmacokinetics and efficacy of i.v. and i.p. VM26 chemotherapy in mice bearing Krebs II ascitic tumors.

The pharmacokinetics and the efficacy of VM26 are studied following i.p. or i.v. administration in mice bearing Krebs II ascitic tumors. The i.p. inoculation of 30.10(6) Krebs II cells in Swiss mice leads to the formation of ascites. The effects of VM26 were dependent upon the route of administration. A 2 mg/kg i.p. single dose induces an equivalent per cent increase of median survival time than a 20 mg/kg i.v. single dose. The survival advantage of i.p. VM26 was found to be related to the pharmacologic benefit of i.p. administration. If local toxicity does not prove to be a major problem, i.p. VM26 may constitute a safe and practical mode of therapy in patients with intraabdominal tumors.

Animals↗
PubMed1988

Ifosfamide in previously untreated disseminated neuroblastoma. Results of Study 3A of the European Neuroblastoma Study Group.

A prospective study of the effectiveness of ifosfamide as a single agent in the management of previously untreated patients with Evans stage IV neuroblastoma was undertaken. Eighteen children aged more than 1 year were treated with ifosfamide (IFX) 3 g/m2 daily for 2 days immediately after diagnosis and 3 weeks later. Treatment was continued with combination chemotherapy using vincristine, cyclophosphamide, cisplatinum and etoposide (OPEC) or a variant. Mesna (2-mercaptoethane sulphonate) was given to all patients during IFX treatment to prevent urotoxicity. Eight of the 18 patients (44%) responded to IFX. Nine had greater than 66% reduction in baseline tumor volume. Of 15 evaluable patients with raised pre-treatment urinary catecholamine excretion, six (40%) achieved greater than 50% reduction in pretreatment levels. Two of 10 patients evaluable for bone marrow response had complete clearance. Toxicity was mild in all patients. Upon completing 'first line' therapy, only four patients (22%) achieved a good partial remission (GPR) or complete response (CR). Median survival was 11 months. There was a lower rate of attaining GPR and shortened median survival in patients receiving phase II IFX before OPEC or variant, compared to patients with similar pre-treatment characteristics treated with OPEC from diagnosis in an earlier study.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Structure-bioactivation relationship of a series of podophyllotoxin derivatives.

With the aim of elucidating the structural requirements for O-demethylation of the antitumor agent VP-16-213 by cytochrome P-450, the binding of a series of podophyllotoxin derivatives to rat liver microsomal cytochrome P-450 was studied. The examined podophyllotoxin derivatives were: VP-16-213, VM-26, podophyllotoxin, 4'-demethylepipodophyllotoxin (the aglycone of VP-16-213 and VM-26) and 3,5-dimethoxy-4-hydroxytoluene (a model compound for the E-ring of VP-16-213). The binding to phenobarbital (Pb)-induced microsomes was more extensive than that to 3-methylcholanthrene (3-MC)-induced microsomes. Experiments on the binding to cytochrome P-450 in Pb-induced microsomes led to the following findings: (a) the presence of the polycyclic skeleton is necessary for binding; (b) the presence of the sugar moiety gives a further extension of binding, and changes in the sugar moiety affect binding; (c) binding increases on elevation of hydrophobicity; (d) the E-ring itself does not bind. For binding to cytochrome P-450 in 3-MC-induced microsomes conclusions (a) and (d) appeared to hold true. For the O-demethylation of the podophyllotoxin derivatives containing the dimethoxyphenol ring by Pb- and 3-MC-induced microsomes, the following order was observed: VM-26 greater than VP-16-213 greater than aglycone much greater than E-ring. A similar sequence was observed for the cytotoxicity against Chinese hamster ovary cells.

Animals↗
PubMed1996

Ultrafiltration and subsequent high performance liquid chromatography for in vivo determinations of the protein binding of etoposide.

Etoposide is extensively (approximately 94%) bound to plasma proteins and the free non-protein-bound levels have been shown to correlate more closely to toxicity than total drug concentrations. A rapid and easily performed method, compared to the time consuming equilibrium dialysis, to obtain the free fraction is needed. The aim of this study was to evaluate ultrafiltration and subsequent high performance liquid chromatography (HPLC) for the determination of protein binding of etoposide. Spiked plasma from healthy, drug-free volunteers was used to compare ultrafiltration, using Amicon Centrifree filters, with equilibrium dialysis at 37 degrees C. The variability (CV) of the ultrafiltration method was 6.1 and 13.5% (n = 6) at 37 degrees C and room temperature (RT), respectively. The relative size of the free fraction obtained by ultrafiltration at 37 degrees C and RT was 1.22 (P = 0.0005) and 0.37 (P = 0.0001), respectively, compared with equilibrium dialysis at 37 degrees C. The chromatographic separation of metabolites from the mother compound when free etoposide is analyzed is crucial. It is shown that a hydroxy-acid metabolite of etoposide is quite dominant in a protein-free plasma fraction. The free concentrations were determined throughout a dose interval of 24 h in a patient receiving etoposide 100 mg/m2 daily. Ultrafiltration and subsequent HPLC is considered convenient and suitable for in vivo pharmacokinetic investigations.

Antineoplastic Agents↗
PubMed1995

Comparative study of induction of endogenous DNA degradation in rat liver nuclei and intact thymocytes.

A common strongly ordered multi-step-pattern of endogenous DNA degradation was induced in rat liver nuclei and intact thymocytes, prepared in the presence of chelating agents and incubated in the presence of CaCl2 and/or MgCl2. It consisted of sequential generation of 0.3 Mbp, then 0.05 Mbp DNA fragments and finally of oligo- and mononucleosomal DNA. Oligonucleosomal DNA was generated when the genome had already been disintegrated into 0.05 Mbp DNA fragments. ZnCl2 completely inhibited advanced genome cleavage to oligo- and mononucleosomal DNA without affecting the initial generation of large DNA fragments. Therefore, the endonucleolytic activity which produce large DNA fragments is different from Ca2+/Mg2+ endonuclease. The similar pattern of DNA degradation was observed in thymocytes treated with dexamethasone and with the topoisomerase II inhibitor VM-26, the agents known to induce apoptosis. The effect of VM-26 strongly suggests the involvement of topoisomerase II in generation of large DNA fragments. Multi-level organization and regulation of the chromatin structure determine the stepwise process of genome degradation. Detachment of chromatin from the nuclear matrix attachment regions may be one of the possible mechanisms of switching off the genome function and triggering the multi-step process of endogenous chromatin degradation thus leading to cell death in terminal differentiation or stress-induced apoptosis.

Animals↗
PubMed1984

Sequential half-body irradiation (SHBI) and combination chemotherapy as salvage treatment for failed Ewing's sarcoma--a pilot study.

This study was undertaken to evaluate the toxicity of sequential half-body irradiation (SHBI) and combination chemotherapy (5-FU, VM-26 and BCNU) in patients who had failed primary aggressive therapy for their Ewing's sarcoma. A secondary goal was to evaluate the response of these previously treated patients to the combination of systemic radiation and multi-agent chemotherapy. The first patient in the study was treated with SHBI only and died 139 days following retreatment. Four subsequent patients successfully received the first cycle of combination chemotherapy. However, only one completed both upper and lower half-body irradiation while the remaining three patients, because of rapid progression of their disease, completed either the upper or the lower portion of their half-body irradiation (HBI). The time from retreatment to disease progression in these four patients ranged from 45 to 97 days (mean 79 days) and the time from retreatment to death ranged from 72 to 193 days (mean 126 days). The combination chemotherapy was tolerated well by all the patients, and the SHBI was accompanied by mild nausea and some vomiting within the first few hours following treatment. Failure to give the second half of the half-body irradiation and to complete further chemotherapy in three of the patients was a result of the progressive nature of the patients' disease and not to any limitations imposed by poor blood counts. Half-body irradiation provided good pain relief within 24 hours for all of the patients. Systemic radiation contributes to the palliative treatment of patients with failed Ewing's sarcoma, but appears to be relatively ineffective when the tumor burden is high.

Adolescent↗