Topoisomerase model

The most important aspect of coralyne is its ability to inhibit DNA relaxation in a fashion significantly similar to the most potent antitumour alkaloid camptothecin, which is known to exert this property [242], Presumably, the most notable biological action of these alkaloids appears to be topoisomerase inhibition [238-242], which has direct relevance to their DNA intercalating property. In this context. Pilch et al. [167] described a mixed binding mode model (Fig. 16) in which the protoberberine structure constitutes portions that can intercalate or bind to the minor groove of DNA. Wang et al. [240] demonstrated that coralyne (Ci) and several of its derivatives (Ce to Ch) (Scheme 5), including the partial saturated... 

Etoposide causes multiple DNA double-strand breaks by inhibiting topoisomerase II. The pharmacokinetics of etoposide are described by a two-compartment model, with an a half-life of 0.5 to 1 hour and a (5 half-life of 3.4 to 8.3 hours. Approximately 30% of the dose is excreted unchanged by the kidney.16 Etoposide has shown activity in the treatment of several types of lymphoma, testicular and lung cancer, retinoblastoma, and carcinoma of unknown primary. The intravenous preparation has limited stability, so final concentrations should be 0.4 mg/mL. Intravenous administration needs to be slow to prevent hypotension. Oral bioavailability is approximately 50%, so oral dosages are approximate two times those of intravenous doses however, relatively low oral daily dosages are used for 1 to 2 weeks. Side effects include mucositis, myelosuppression, alopecia, phlebitis, hypersensitivity reactions, and secondary leukemias. 

Teniposide, a topoisomerase II inhibitor, is administered as an infusion over 30 to 60 minutes to prevent hypotension. The pharmacokinetics are described by a three-compartment model, with an a half-life of 0.75 hours, a (5 half-life of 4 hours, and a terminal half-life of 20 hours. Considerable variability in clearance of teniposide in children has been reported.17 Teniposide has shown activity in the treatment of acute lymphocytic leukemia, neuroblastoma, and non-Hodgkin s lymphoma. Side effects include myelosuppression, nausea, vomiting, mucositis, and venous irritation. Hypersensitivity reactions may be life-threatening. 

Topotecan inhibits topoisomerase I to cause single-strand breaks in DNA. The pharmacokinetics of topotecan can be described by a two-compartment model, with a terminal half-life of 80 to 180 minutes, with renal clearance accounting for approximately 70% of the clearance.19 Topotecan has shown clinical activity in the treatment of ovarian and lung cancer, myelodysplastic syndromes, and acute myelogenous leukemia. The intravenous infusion may be daily for 5 days or once weekly. Side effects include myelosuppression, mucositis, and diarrhea. 

Daunorubicin is an anthracycline that is sometimes referred to as an antitumor antibiotic. Daunorubicin inserts between base pairs of DNA to cause structural changes in DNA however, the primary mechanism of cytotoxicity is the inhibition of topoisomerase II. The pharmacokinetics are best described by a two-compartment model, with a terminal half-life of about 20 hours. The predominant route of elimination of daunorubicin and hydroxylated metabolites is hepatobiliary... 

Epirubicin inhibits both DNA and RNA polymerases and thus inhibits nucleic acid synthesis and topoisomerase II enzymes. Epirubicin pharmacokinetics are best described by a three-compartment model, with an a half-life of 4 to 5 minutes, a... 

Idarubicin inhibits both DNA and RNA polymerase, as well as topoisomerase II. The pharmacokinetics of idarubicin can best be described by a three-compartment model, with an a half-life of 13 minutes, a (3 half-life of 2.4 hours, and a terminal half-life of 16 hours.22 Idarubicin is metabolized to an active metabolite, idarubicinol, which has a half-life of 41 to 69 hours. Idarubicin and idarubicinol are eliminated by the liver and through the bile. Idarubicin has shown clinical activity in the treatment of acute leukemias, chronic myelogenous leukemia, and myelodysplastic syndromes. Idarubicin causes cardiomyopathy at cumulative doses of greater than 150 mg/m2 and produces cumulative cardiotoxic effects with other anthracyclines. Idarubicin is a vesicant and causes red-orange urine, mucositis, mild to moderate nausea and vomiting, and bone marrow suppression. 

This royal-blue-colored drug is an anthracenedione that inhibits DNA topoisomerase II. The pharmacokinetics of mitoxantrone may best be described by a three-compartment model, with an a half-life of 3 to 10 minutes, a 3 half life of 0.3 to 3 hours, and a median terminal half-life of 12 days. Biliary elimination appears to be the primary route of elimination, with less than 10% of the drug eliminated by the kidney.23 Mitoxantrone has shown clinical activity in the treatment of acute leukemias, breast and prostate cancer, and non-Hodgkin s lymphomas. Myelosuppression, mucositis, nausea and vomiting, and cardiac toxicity are side effects of this drug. The total cumulative dose limit is 160 mg/m2 for patients who have not received prior anthracycline or mediastinal radiation. Patients who have received prior doxorubicin or daunorubicin therapy should not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn a blue-green color. 

Taxonomically close to the Annonaceae, the Lauraceae family abounds with apor-phinoid alkaloids. A remarkable advance in the search for topoisomerase inhibitors from Lauraceae has been provided by Woo et al. (6). Using DNA-unwinding assay and structural modeling, they showed that dicentrine can attain a relatively planar conformation and molecular bulk which allow it to occupy the active site of topoisomerase II which becomes inactive. The requirement of a suboptimal conformation to achieve DNA binding appears to make dicentrine less potent against topoisomerase II than the... 

TNF-a converting enzyme, 38,153 toll-like receptor (TLR) signaling, 45, 191 topical microbicides, 40, 277 topoisomerase, 21, 247 44, 379 toxicity, mathematical models, 18, 303 toxicity reversal, 15, 233... 

Representatives of another important class of plant-derived semisynthetic compounds are the camptothecin (27) derivatives, irinotecan (28) and topotecan (29). Camptothecin (27) was originally discovered as an antileukemic agent in a mouse model when isolated from Camptotheca acuminata Decne. Compounds (28) and (29) are both employed in cancer chemotherapy. These substances are important mechanistically because of their activity against the enzyme, topoisomerase I. These compounds were designed to address efficacy and toxicity concerns with the parent compound, camptothecin, and its sodium salt. ... 

Irinotecan, an antineoplastic-prodrug, is widely used for the treatment of colorectal, lung and other cancers, and is one of model pharmaceuticals for personalized medicine. The active metabolite, SN-38, is a topoisomerase I inhibitor generated by hydrolysis of irinotecan by carboxylesterases. SN-38 is subsequently glucuronidated... 

HGURE 24-35 Model for the effect of condensins on DNA super-coiling. Binding of condensins to a closed-circular DNA in the presence of topoisomerase I leads to the production of positive supercoils (+). Wrapping of the DNA about the condensin introduces positive supercoils because it wraps in the opposite sense to a solenoidal supercoil (see Fig. 24-24).The compensating negative supercoils (—) that appear elsewhere in the DNA are then relaxed by topoisomerase I. In the chromosome, it is the wrapping of the DNA about condensin that may contribute to DNA condensation. 

Figure 27-5 (A, B) Two possible models of the 30-nm chromatin fiber.55 (A) Thoma et al.85 (B) Woodcock et al.6i 87 The fully compacted structure is seen at the top of each figure. The bottom parts of the figures illustrate proposed intermediate steps in the ionic strength-induced compaction. (C) Possible organization of the DNA within a metaphase chromosome. Six nucleosomes form each turn of a solenoid in the 30-nm filament as in (A). The 30-nm filament forms 30 kb-loop domains of DNA and some of these attach at the base to the nuclear matrix that contains topoisomerase II. About ten of the loops form a helical radial array of 250-nm diameter around the core of the chromosome. Further winding of this helix into a tight coil 700 nm in diameter, as at the top in (C), forms a metaphase chromatid. From Manuelidis91.

The BCRP is an ABC transporter similar to P-gp whose expression results in resistance to anticancer therapeutics and may limit intestinal absorption of drugs. However, there have been limited studies to elucidate the selectivities of dmgs for P-gp and BCRP (Brooks et al. 2004). We used a published dataset of seven topoisomerase inhibitors (Maliepaard et al. 2001) to construct a HipHop model for BCRP. We then mapped the potent tyrosine kinase inhibitor Gleevec to this pharmacophore as this compound has been suggested experimentally in conflicting studies as both a substrate and inhibitor of BCRP (Burger et al. 2004 Houghton et al. 2004). 

Finally, replication-competent viral vector systems have been combined with standard cancer therapy in animal models, resulting in synergistic effects. This has, for example, been shown for ONYX-015 plus cisplatin or ionizing radiation [108,112] and for an AdElB 55k-deleted virus expressing HSV-tk (plus ganciclovir) in combination with the topoisomerase inhibitor topotecan [114]. 

Camptothecin acts by forming a reversible ternary complex ( cleavable complex ) with DNA and topoisomerase I, preventing the re-ligation of the DNA strand cut by topoisomerase to allow relaxation, and thus inducing apoptosis [14]. The X-ray structure of crystals of such a complex of a 22-base DNA fragment with topoisomerase I and topotecan has been reported [15], and molecular models of the interaction have been proposed [16-18]. This kind of information should be of help in... 

A series of 2,7- and 3,6-bis-cationic carbazoles, for example, 49, shows activity against a rat model of Pneumocystis carinii pneumonia (PCP), and some are more potent and less toxic than the standard anti-PCP drug pentamidine <1997EJM781>. While no quantitative correlation was seen between anti-PCP activity, topoisomerase inhibition, and DNA binding, a minimal level of DNA binding was found to be necessary for antimicrobial activity. 

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