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PubMed2004

Pharmacokinetic studies in children with cancer.

We reviewed the current status of our knowledge of pharmacokinetics and pharmacodynamics of some anti-neoplastic drugs, used in the treatment of childhood cancer. Extrapolation of data from pharmacokinetic studies in adults to the paediatric population is often not feasible. Specific studies in children are needed. Of all reviewed anti-neoplastic drugs methotrexate appears to be most extensively studied. Methotrexate pharmacokinetics is correlated with toxicity and response to therapy, and it has been shown that individualized adaptive dosing of methotrexate is correlated with a better response to therapy without increasing toxicity in children with ALL and osteosarcoma. Of most of the other reviewed anti-neoplastic drugs it is demonstrated that pharmacokinetics is correlated with toxicity, and of some drugs a relationship of pharmacokinetics with response to therapy is demonstrated as well. In case of cytarabine, etoposide, and teniposide, individualized dosing also appears to be feasible. However, there is no evidence that this strategy improves response to therapy. Specifically data on pharmacokinetic and pharmacodynamic correlations and effect of pharmacokinetically guided, individualized dosing are important for the design of optimal cancer chemotherapy for individual patients. Unfortunately for a considerable number of anti-neoplastic drugs these specific data are lacking in children and future research is needed.

Antineoplastic Agents↗

PubMed2006

Bioconversion of deoxypodophyllotoxin into epipodophyllotoxin in E. coli using human cytochrome P450 3A4.

Biotransformation of deoxypodophyllotoxin to epipodophyllotoxin by three major human hepatic enzymes, CYP1A2, CYP2C9 and CYP3A4, heterologously expressed in E. coli DH5alpha, was investigated. It was shown that CYP3A4 catalysed the hydroxylation of deoxypodophyllotoxin into epipodophyllotoxin in yields up to 90%. The structure of the metabolite was determined using HPLC-MS and HPLC-SPE-NMR techniques. There was no detectable production of epipodophyllotoxin or podophyllotoxin by CYP1A2 and CYP2C9 enzymes. The CYP3A4 enzyme shows a distinctly different reactivity to deoxypodophyllotoxin compared to the semi-synthetic derivatives etoposide and teniposide, which are degraded by 3-O-demethylation. These findings demonstrate a novel system for the production of 2,7'-cyclolignans, starting from the easily accessible deoxypodophyllotoxin.

Biotransformation↗

PubMed2004

Poly(N-vinylpyrrolidone)-block-poly(D,L-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs: in vitro and in vivo evaluation.

The majority of novel anticancer drugs developed to date are intended for parenteral administration. Paradoxically, most of these drugs are water-insoluble, delaying their clinical development. A common approach to confering water solubility to drugs is to use amphiphilic, solubilizing agents, such as polyethoxylated castor oil (e.g., Cremophor EL, CrmEL). However, these vehicles are themselves associated with a number of pharmacokinetic and pharmaceutical concerns. The present work is aimed at evaluating a novel polymeric solubilizer for anticancer drugs, i.e., poly(N-vinylpyrrolidone)-block-poly(D,L-lactide) (PVP-b-PDLLA). This copolymer self-assembles in water to yield polymeric micelles (PM) that efficiently solubilize anticancer drugs, such as paclitaxel (PTX), docetaxel (DCTX), teniposide (TEN) and etoposide (ETO). A PM-PTX formulation was evaluated, both, in vitro on three different cancer cell lines and in vivo for its safety, pharmacokinetics, biodistribution and antitumor activity. In vitro, cytotoxicity studies revealed that the drug-loaded PM formulation was equipotent to the commercial PTX formulation (Taxol). In the absence of drug, PVP-b-PDLLA with 37% DLLA content was less cytotoxic than CrmEL. In vivo, acute toxicity was assessed in mice after a single injection of escalating dose levels of formulated PTX. PM-PTX was well tolerated and the maximum tolerated dose (MTD) was not reached even at 100 mg/kg, whereas the MTD of Taxol was established at 20 mg/kg. At 60 mg/kg, PM-PTX demonstrated greater in vivo antitumor activity than Taxol injected at its MTD. Finally, it was shown in mice and rabbits that the areas under the plasma concentration-time curves were inversely related to PM drug loading.

Animals↗

PubMed2005

Chemotherapy for retinoblastoma.

Retinoblastoma is the most common eye cancer in children. Pilot studies of chemotherapy for intraocular retinoblastoma have been reported by several groups, using different combinations, dosages, schedules, and durations of carboplatin, etoposide, or teniposide, with or without vincristine, and with or without cyclosporine to counteract multidrug resistance. All studies of chemotherapy for intraocular retinoblastoma have included consolidation by focal therapy, with or without radiation. Chemotherapy alone reduces tumor size but does not cure retinoblastoma. Focal therapy, consisting of photocoagulation, thermotherapy, cryotherapy, or brachytherapy, is necessary to consolidate chemotherapy response.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Diverse biomodulatory effects of glucomannan from Candida utilis.

Using four experimental model systems, it was demonstrated that glucomannan (GM) isolated from the cell wall of the industrial yeast Candida utilis revealed a broad range of protective activities. This effect depended on the nature and mode of action of the counteracting genotoxic compound as well as on the experimental model system used. In the Saccharomyces bioprotectivity assay, GM increased resistance towards ofloxacin-induced toxicity in the wild type and recombination repair-deficient yeast strains significantly enhancing survival of the cells. In the chromosomal aberration assay, GM exerted anticlastogenic effect against maleic hydrazide induced clastogenicity in Vicia faba L. In the DNA-topology assay, GM protected plasmid DNA from the breaks induced by Fe(2+) ions, but enhanced damage induced by bleomycin and hydrogen peroxide. In the cell-revitalization assay, it enhanced cytotoxic/cytostatic effect of teniposide applied to mouse leukemia cells. Thus, depending on the experimental model, GM acted as antimutagen, anticlastogen, DNA breaks inhibitor or inducer, and as cytotoxic/cytostatic effect enhancer. Several possible mechanisms of bioprotective action underlying the observed activities are suggested including iron chelation and free radical scavenging. The results imply that GM is a polysaccharide with marked biological activities and suggest its potential biomedical application, especially in combination with other bioactive compounds.

Animals↗

PubMed2000

Catalytic inhibition of DNA topoisomerase II by N-benzyladriamycin (AD 288).

N-Benzyladriamycin (AD 288) is a highly lipophilic, semi-synthetic congener of doxorubicin (DOX). Unlike DOX, which stimulates double-stranded DNA scission by stabilizing topoisomerase II/DNA cleavable complexes, AD 288 is a catalytic inhibitor of topoisomerase II, capable of preventing topoisomerase II activity on DNA. The concentration of AD 288 required to inhibit the topoisomerase II-catalyzed decatenation of linked networks of kinetoplast DNA was comparable to that for DOX. However, AD 288 did not stabilize cleavable complex formation or stimulate topoisomerase II-mediated DNA cleavage. In addition, AD 288 inhibited the formation of cleavable complexes by etoposide in a concentration-dependent manner. Human CCRF-CEM cells and murine J774. 2 cells exhibiting resistance against DOX, teniposide, or 3'-hydroxy-3'-deaminodoxorubicin through reduced topoisomerase II activity remained sensitive to AD 288. These studies suggest that AD 288 inhibits topoisomerase II activity by preventing the initial non-covalent binding of topoisomerase II to DNA. Since AD 288 is a potent DNA intercalator, catalytic inhibition is achieved by prohibiting access of the enzyme to DNA binding sites. These results also demonstrate that specific substitutions on the aminosugar of DOX can alter the mechanism of topoisomerase II inhibition.

Antineoplastic Agents, Phytogenic↗

PubMed2003

Inhibition of DNA topoisomerases I and II, and growth inhibition of human cancer cell lines by a marine microalgal polysaccharide.

We have previously reported purification of an extracellular polysaccharide GA3P, D-galactan sulfate associated with L-(+)-lactic acid, produced by a toxic marine microalga Dinoflagellate Gymnodinium sp. A(3) (GA3), and induction thereby of apoptosis on human myeloid leukemia K562 cells. In the present report, we show that the GA3P is a potent inhibitor of DNA topoisomerase (topo) I and topo II, irrespective of the presence or absence of the lactate group. Dextran sulfate also showed similar level of inhibition of topo I and topo II. We also demonstrated that, unlike camptothecin (CPT) or teniposide (VM-26), the inhibition of topo I or topo II by the polysaccharide does not involve accumulation of DNA-topo I/II cleavable complexes, clearly showing that they are not topo poisons but catalytic inhibitors with dual activity. Furthermore, the polysaccharide, when added to the reaction mixture with CPT or VM-26, inhibited stabilization of cleavable complex induced by the latter compounds. In addition, when added to the reaction mixture after the formation of the cleavable complexes by topo poisons, CPT for topo I and VM-26 for topo II, either GA3P or dextran sulfate diminished the amount of the complexes already accumulated, i.e. reversal of the reaction. These results suggest that the polysaccharides bind to the enzymes with high affinities, and that, as for topo I/II inhibition, the GA3P shares a common mechanism with dextran sulfate. As examined in vitro with a human cancer cell line panel, GA3P exhibited significant cytotoxicity against a variety of cancer cells. These findings show that the polysaccharide GA3P would prove to be a potential anticancer chemotherapeutic agent with dual activity of topo I and topo II catalytic inhibition.

Antineoplastic Agents↗

PubMed1997

Plant-derived anticancer agents.

Natural product drugs play a dominant role in pharmaceutical care. This is especially obvious in the case of antitumor drugs, as exemplified by paclitaxel (Taxol), vincristine (Oncovin), vinorelbine (Navelbine), teniposide (Vumon), and various water-soluble analogs of camptothecin (e.g., Hycamtin). The most efficient method of discovering drugs such as these (i.e. novel chemical prototypes that may function through unique mechanisms of action) is bioactivity-guided fractionation, and it is certain that additional natural product drugs, some of which should be useful for the treatment of humans, remain to be discovered. For the commercial procurement of structurally complex natural product drugs, isolation from plant material may be most practical. With the advent of combinatorial chemistry and high throughput screening, however, even greater progress may now be expected with natural product leads. While systemic drug therapy, to an appreciable extent based on natural products, has been the mainstay of pharmaceutical care, the logic of disease prevention is overwhelming. Bearing in mind the pandemic nature of cancer, a proposal is put forth to create a cancer chemoprevention drug formulation for utilization on a widespread basis by the general population. Cancer chemopreventive agents, many of which are natural products, are capable of preventing or inhibiting the process of carcinogenesis. As with other pharmaceutical agents useful for disease prevention, a pharmacoeconomic analysis of a cancer chemopreventive formulation would need to be considered, and the composition of the formulation should improve over time. Nonetheless, implementation should commence immediately.

Anticarcinogenic Agents↗

PubMed1998

Potentiation of treosulfan toxicity by the glutathione-depleting agent buthionine sulfoximine in human malignant glioma cells: the role of bcl-2.

Median survival of human malignant glioma patients is less than one year even with cytoreductive surgery and postoperative radiotherapy. Adjuvant chemotherapy has been rather ineffective. Here, we studied the potentiation by L-buthionine-[S,R]-sulfoximine (BSO), a glutathione-depleting agent, of anticancer drug actions on two human malignant glioma cell lines, LN-229 and T98G. LN-229 has wild-type p53 status, T98G is mutant for p53. Glutathione levels were depleted by BSO with similar kinetics in both cell lines. Only LN-229 cells were growth-inhibited by BSO. BSO had minor effects on the toxicity of doxorubicin, ACNU (1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosou rea, nimustine) and vincristine. BSO failed to alter teniposide or cytarabine toxicity. BSO induced prominent sensitization to the alkylating agent, treosulfan, in both cell lines, as assessed by viability assays, in situ DNA end labeling and quantitative DNA fragmentation. Treosulfan is thought to mediate toxicity via formation of reactive epoxides. In the absence of BSO, treosulfan had little acute cytotoxic and moderate antiproliferative effects. Synergistic glioma cell cytotoxicity induced by treosulfan and BSO was not associated with reactive oxygen species formation. Ectopic expression of bcl-2 did not alter basal glutathione levels but attenuated glutathione depletion induced by BSO. Bcl-2 provided only moderate protection from synergistic induction of glioma cell death by treosulfan and BSO. Glutathione depletion may play a role in BSO-mediated chemosensitization, but other mechanisms are probably involved as well. BSO may be a useful agent for glioma cell sensitization to specific chemotherapeutic drugs such as treosulfan.

Antineoplastic Agents, Alkylating↗

PubMed2000

Poly(ADP-ribose) polymerase-independent potentiation of nitrosourea cytotoxicity by 3-aminobenzamide in human malignant glioma cells.

Poly(ADP-ribose) polymerase is a zinc-finger DNA-binding protein that detects specifically DNA strand breaks generated by genotoxic agents and is thought to be involved in DNA repair. Here, we examined the effects of 3-aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, on the chemosensitivity of human malignant glioma cells. 3-Aminobenzamide selectively potentiated the cytotoxicity of the nitrosoureas, nimustine, carmustine and lomustine in 10 of 12 human malignant glioma cell lines. In contrast, 3-aminobenzamide did not modulate the cytotoxic effects of doxorubicine, teniposide, vincristine, camptothecin or cytarabine. The nitrosoureas did not induce poly(ADP-ribose) polymerase activity in the glioma cells. Ectopic expression of truncated poly(ADP-ribose) polymerase containing the poly(ADP-ribose) polymerase DNA-binding domain, which acts as a dominant-negative mutant, in LN-18 or LN-229 cells did not alter the 3-aminobenzamide effect on nitrosourea-mediated cytotoxicity. Thus, 3-aminobenzamide may target another nicotinamide adenine dinucleotide (NAD)-requiring enzyme, but not poly(ADP-ribose) polymerase, when enhancing nitrosourea cytotoxicity in human malignant glioma cells. Carmustine cytotoxicity was associated with a G2/M arrest. Coexposure to carmustine and 3-aminobenzamide overcame this G2/M arrest in T98G cells, which are sensitized to carmustine by 3-aminobenzamide, but not in U251MG cells, which are refractory to 3-aminobenzamide-mediated sensitization to carmustine. Thus, 3-aminobenzamide-mediated sensitization to carmustine cytotoxicity may result from interference with the stable G2/M arrest response to carmustine in human glioma cells.

Benzamides↗

PubMed2001

Cytotoxic cyclolignans related to podophyllotoxin.

The cyclolignan family of natural products includes compounds with important antineoplastic and antiviral properties such as podophyllotoxin and two of their semisynthetic derivatives, etoposide and teniposide. The latter are included in a wide variety of cancer chemotherapy protocols. Due to these biological activities, cyclolignans have been the objective of numerous studies focused to prepare better and safer anticancer drugs. Several cyclolignans related to podophyllotoxin have been prepared and evaluated for their cytotoxic activities on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28); some of them have antiviral and immunosuppressive activities.

Aldehydes↗

PubMed1997

Multiple lymphomatous polyposis of the gastrointestinal tract: prospective clinicopathologic study of 31 cases. Groupe D'étude des Lymphomes Digestifs.

BACKGROUND & AIMS: Multiple lymphomatous polyposis (MLP) is an uncommon type of gastrointestinal lymphoma. The aim of this study was to analyze the clinicopathologic features and outcome of a large series of patients. METHODS: From 1984 to 1995, 31 patients were enrolled prospectively. Exhaustive staging and immunohistochemical analysis were performed. The first 10 patients were treated with cyclophosphamide-vincristine-prednisolone (COP) and the subsequent 21 with doxorubicin-teniposide-cyclophosphamide-prednisolone (AVmCP). Eleven patients were treated with high-dose radiochemotherapy and stem cell autotransplantation because of partial response or relapse. RESULTS: Advanced age and multiple polyps involving several gastrointestinal segments characterized initial clinical presentation. The typical tumor cell phenotype (pan-B+, CD5+, and CD10-) along with Bcl-1 rearrangement indicated that MLP is the gastrointestinal counterpart of mantle cell lymphoma. After COP treatment, only 3 patients achieved partial remissions, whereas 80% of patients after AVmCP treatment achieved complete or good partial remission. High-dose radiochemotherapy changed partial into complete remission in 80% of cases. None of the initial 10 patients survived for 3 years, but the expected 5-year survival rate was 59% in patients receiving the anthracycline-containing regimen (P < 0.0001). CONCLUSIONS: MLP is a distinct entity among gastrointestinal lymphomas. An anthracycline-containing multidrug regimen and high-dose radiochemotherapy supported by autotransplantation seem to improve its poor prognosis.

Adult↗

PubMed2000

Podophyllotoxin.

Podophyllin, an ethanolic extract of Podophyllum peltatum L. or P. emodi Wall (syn. P. hexandnum Royle), is a good source of the aryltetralin-type lignan, podophyllotoxin. The latter compound, as well as its congeners and derivatives exhibit pronounced biological activity mainly as strong antiviral agents and as antineoplastic drugs. The podophyllotoxin derivatives etoposide, etopophos (etoposide phosphate), and teniposide are thus successfully utilized in the treatment of a variety of malignant conditions. Continued research on the Podophyllum lignans is currently focused on structure optimization to generate derivatives with superior pharmacological profiles and broader therapeutic scope, and the development of alternative and renewable sources of podophyllotoxin.

Podophyllotoxin↗

PubMed2000

Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia.

BACKGROUND: Many antileukaemic agents or their metabolites are inactivated by liver enzymes. Most anticonvulsant drugs induce drug-metabolising enzymes and thereby increase the clearance of anticancer agents. We investigated whether anticonvulsants compromise the efficacy of cancer chemotherapy. METHODS: We identified whom of 716 children treated consecutively for acute lymphoblastic leukaemia at a single academic hospital in the USA between 1984 and 1994 received treatment for 30 days or longer with anticonvulsants (phenytoin, phenobarbital, carbamazepine, or a combination) at the same time as antileukaemic therapy. Cox's proportional-hazards models were used to assess the prognostic significance of anticonvulsants on event-free survival and risk of haematological and central-nervous-system (CNS) relapse, with stratification for treatment protocol. FINDINGS: 40 (5.6%) of 716 patients received anticonvulsants. Use of these drugs was associated with age over 10 years (p=0.003), non-hyperdiploid leukaemia (p=0.031), and T-cell immunophenotype (p=0.022). After adjustment for age and ploidy, anticonvulsant therapy was significantly related to worse event-free survival (hazard ratio 2.67 [95% CI 1.50-4.76]; p=0.0009), haematological relapse (3.40 [1.69-6.88]; p=0.0006), and CNS relapse (2.90 [1.01-8.28]; p=0.047) among the 566 patients with B-lineage leukaemia. No such associations were seen among the 114 patients with T-cell leukaemia (p=0.61, 0.35, and 0.53, respectively). Faster clearance of teniposide (p=0.0001) and methotrexate (p=0.051), but not cytarabine (p=0.26) was found among patients receiving anticonvulsants. INTERPRETATION: Long-term anticonvulsant therapy increases the systemic clearance of several antileukaemic agents and is associated with lower efficacy of chemotherapy. Alternatives to enzyme-inducing anticonvulsants should be prescribed for patients receiving chemotherapy for acute lymphoblastic leukaemia.

Anticonvulsants↗

PubMed1998

Interferon-alpha enhances CD95L-induced apoptosis of human malignant glioma cells.

CD95 ligand (CD95L)-induced apoptosis is a novel immunotherapeutic approach to malignant glioma. Here, we report that interferon-alpha (IFN-alpha) sensitizes LN-229 and T98G human malignant glioma cells to CD95L-induced apoptosis. In contrast to the effects of IFN-gamma and TNF-alpha which sensitize glioma cells to CD95 antibody-induced apoptosis in part by enhancing CD95 expression, IFN-alpha has no effect on CD95 expression at the cell surface of LN-229 and T98G cells. To confirm that changes in CD95 expression are not required for the effects of IFN-alpha, we show that IFN-alpha enhances CD95L-induced apoptosis even in CD95-transfected LN-308 glioma cells. These LN-308 cells have little endogenous CD95 expression but express high levels of CD95 from a stably integrated CD95 expression plasmid. The sensitizing effects of IFN-alpha appear to be independent of cell cycle effects of IFN-alpha and are unaffected by ectopic expression of the bcl-2 proto-oncogene. IFN-alpha enhances CD95L-induced activation of caspase-3, a critical mediator of CD95L-induced cell death. IFN-alpha also increases the cytotoxic effects of BCNU, teniposide and cytarabine in both cell lines, and of vincristine in LN-229 cells. Doxorubicin and 5-fluorouracil toxicity are unaffected by IFN-alpha. IFN-alpha may be a useful adjunct to novel strategies of immunochemotherapy for malignant gliomas that target CD95-mediated apoptosis.

Antineoplastic Agents, Alkylating↗

PubMed1998

Clinical applications of anticancer drugs targeted to topoisomerase II.

Agents which 'poison' the enzyme topoisomerase II, have proven to be useful drugs for cancer treatment. Six antineoplastic drugs, which target topoisomerase II (doxorubicin, daunorubicin, idarubicin, mitoxantrone, etoposide and teniposide) are currently approved for clinical use in the United States. In this paper, the strategies and goals of cancer chemotherapy are summarized for the non-clinician. The use, pharmacology and toxicity of each of the six currently approved topoisomerase II inhibiting agents are reviewed.

Antibiotics, Antineoplastic↗

PubMed2001

Chemotherapy as treatment of primary and recurrent small cell lung cancer.

Chemotherapy is the treatment of choice in metastatic stage of small-cell lung cancer (SCLC). Radiation therapy, surgery and other forms of therapy are only included in special treatment situations, particularly for different local problems. A wide range of chemotherapeutic agents have proven to be effective in SCLC, including carboplatin, cisplatin, cyclophosphamide, doxorubicin, epirubicin, etoposide, ifosfamide, teniposide and vincristine. However, treatment results could not be improved over the last 10 years and the median survival of patients with metastatic disease is limited to 7-10 months. New agents like docetaxel, gemcitabine, irinotecan, paclitaxel, topotecan and vinorelbine have shown promising results in phase-II investigations. Yet, no evidence is provided from randomized trials to employ these drugs in first line treatment. Clearly, polychemotherapy is superior to single agent treatment. Compared to the combination of cisplatin and etoposide, no other combination has clearly shown improved results in large phase-III randomised trials, yet. The combination of cisplatin and irinotecan has also shown promising results in a single randomised trial with the need to be confirmed in larger settings. Neither extending the initial treatment beyond the median number of six cycles, nor maintenance treatment have-so far-resulted in any increase in survival results for patients with metastasised SCLC. Nor has dose-intensification, which causes significantly higher toxicities in patients, shown a clear impact on the overall survival of these patients. Brain metastases represent a high frequent complication associated with SCLC. In these cases, the combination of chemotherapy and whole brain radiation therapy is advocated. Second-line treatment should always be considered in patients with relapse or failure to first-line therapy. In addition to a rechallenging with the prior drug combination or selecting a different potentially non-cross resistant one, monotherapy with topotecan proved to be effective as well. In summary, up to now, no standard chemotherapy combination exists for metastatic SCLC. The individual therapy strategy can only be selected by considering the clinically relevant conditions of the patient.

Antineoplastic Agents↗

PubMed2002

Effect of the DNA topoisomerase II inhibitor VP-16 on illegitimate recombination in yeast chromosomes.

Etoposide and teniposide, derivatives of podophyllotoxin, are inhibitors of DNA topoisomerase II and are potent anticancer agents. An adverse effect linked to the use of these drugs is the development of acute myeloid leukemia, a disorder usually associated with chromosomal translocation. To examine podophyllotoxin-induced DNA rearrangement, we developed an assay system to measure illegitimate recombination in Saccharomyces cerevisiae chromosomes. This approach uses juxtaposed CAN1-CYH2 negative selection markers that are introduced into the LEU2 locus, which is located on chromosome III, in a yeast strain carrying the mutated can1 and cyh2 genes. Upon formation of a deletion over the active CAN1-CYH2 genes, a cell becomes resistant to both canavanine and cycloheximide. To introduce drugs into the cell, we used a yeast strain carrying an ISE2 mutation, thereby making the cell drug-permeable. Here we show that treatment of cells with etoposide (VP-16) increases the rate of illegitimate recombination in yeast, indicating that VP-16 stimulates DNA topoisomerase-mediated illegitimate recombination. Structural analysis of the resulting recombinants indicate that most are formed by deletion mutations on chromosome III, which take place between short homologous regions of DNA. We propose a model for illegitimate recombination, in which VP-16 facilitates formation of a cleavable complex between DNA topoisomerase II and DNA, thus promoting DNA double-strand breakage with the resulting DNA ends joined by a non-homologous mechanism.

3-Isopropylmalate Dehydrogenase↗