Inhibitors topoisomerase

Toxicities associated with etoposide include dose-limiting myelosuppression (granulocytopenia and thrombocytopenia), mild to moderate nausea/vomiting, dermatologic reactions (alopecia, pruritic rash), and mucositis (which can be severe with high doses). Rapid infusion of high doses may be associated with fever, hypotension, bronchospasm, and metabolic acidosis. 

Topotecan and irinotecan both act by inhibiting topoisomerase I (topo I) enzymes, thereby inhibiting DNA replication. They are cell cycle-specific agents with most activity for cells in the S phase. Topotecan is used for treatment of refractory metastatic ovarian carcinoma and small cell lung cancer. It also may be useful in the treatment of head and neck cancer. Irinotecan is indicated for the treatment of metastatic carcinoma of the colon or rectum. 

Topotecan is associated with bone marrow suppression (dose-limiting neutropenia). Other side effects include mild to moderate nausea/vomiting, alopecia, and abdominal complaints. Irinotecan has been associated with both acute (within 24 hours) and delayed (3 to 11 days posttherapy) diarrhea. The diarrhea may be severe or prolonged and may lead to fluid and electrolyte imbalances. The early diarrhea may be mediated by cholinergic mechanisms and can sometimes be ameliorated by administration of atropine. 

Case Conclusion EH decides to proceed with the cisplatin/etoposick therapy as originally recommended. He tolerated 6 months of therapy with a complete response and minimal complications (m erate nausea/vamiting and alopecia). 

Prototype drugs Topotecan Irinotecan Etoposide (VP16) 

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Batcho indole synthesis is a useful tool for synthesis of naniral products. As oudined in Scheme 10.6, the Batcho indole synthesis is used for total synthesis of the slime mold alkaloid arcyriacyanin. Such indolocarbazole alkaloids represent a growing number of naniral products isolated from soil organism, slime molds, and marine sources. They are important as andnimor compounds and protein kinase C and topoisomerase inhibitors. 

Irinotecan Topoisomerase inhibitor that forms a complex with Dose-limiting... 

Risk factors for the development of AML include exposure to environmental toxins, Hispanic ethnicity, and genetics.6 Of greater concern is the increased prevalence of AML as a secondary malignancy, resulting from chemotherapy and radiation treatment for other cancers. Alkylating agents, such as ifosfamide and cyclophosphamide, and topoisomerase inhibitors, such as etoposide, are linked to an increased risk of myelodysplastic syndrome (MDS) and AML.8... 

Now that 80% or more of children survive their primary cancers, the incidence of secondary neoplasms may increase. Recognizing this potential, many treatment regimens for children are being modified appropriately to reduce exposure to alkylators, topoisomerase inhibitors, and radiation. Late effects clinics screen for secondary malignancies and other disease and treatment-related disabilities that accompany childhood cancer. Similar screening and educational opportunities are not currently established in adult survivors. 

Topoisomerase An enzyme that uncoils DNA during replication by cutting the DNA. Topoisomerase inhibitors prevent DNA from sealing the cut, which causes DNA strand breakage. 

Dervan PB, Poulin-Kerstien AT, Fechter EJ, Edelson BS (2005) Regulation of Gene Expression by Synthetic DNA-Binding Ligands. 253 1-31 Dias N, Vezin H, Lansiaux A, Badly C (2005) Topoisomerase Inhibitors of Marine Origin and Their Potential Use as Anticancer Agents. 253 89-108 DiMauro E, see Saladino R (2005) 259 29-68... 

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... 

In regard to the antineoplastic potentials of Rubiaceae, some evidence has already been presented that clearly demonstrates that anthraquinones inhibit the enzymatic activity of topoisomerase II. An example of antineoplastic anthraquinones that target topoisomerase II is mitoxantrone (Novatrone ), which is currently approved for clinical use in the United States (16). In the Pacific Rim, about 150 species of plants classified within the family Rubiaceae are medicinal, of which Prismatomeris albidiflora, Krtoxia valeriartoides, Damnacanthus indicus, and Morinda umbellata are known to produce anthraquinones. An interesting development from Rubiaceae would be to investigate its members for anthraquinones and assess them for topoisomerase inhibitors. The discovery of inhibitors of topoisomerase II of clinical antineoplastic value can be reasonably expected. 

Breast Cancer Resistance Protein (BCRP, also known as MXR or ABCP), first cloned from mitoxantrone and anthracycline-resistant breast and colon cancer cells [188, 189] is a half-transporter efflux pump believed to function as a homo-or hetero-dimer. Following its identification, BCRP-mediated drug resistance was observed for topoisomerase inhibitors including camptothecins [190, 191] and in-dolocarbazoles [192]. In normal tissues, BCRP was detected in placental syncytio-trophoblasts, hepatocyte canalicular membrane, apical intestinal epithelia and vascular endothelial cells [193]. These findings support the important role BCRP plays in modulating topotecan bioavailability, fetal exposure and hepatic elimination [194]. Considering that the substrates and tissue distributions for BCRP overlap somewhat with MDR1 and MRPs [195], additional studies will be required to define the relative contribution of each of these transporters in the overall and tis-... 

Sargent JM, Elgie AW, Williamson CJ, Hill BT. (2003) Ex vivo effects of the dual topoisomerase inhibitor tafluposide (FI 1782) on cells isolated from fresh tumor samples taken from patients with cancer. Anti-Cancer Drugs 14 467-473. 

An extensive database has demonstrated that many chemicals that are positive in this test also exhibit mutagenic activity in other tests. There are, however, examples of mutagenic substances, which are not detected by this test reasons for these shortcomings can be ascribed to the specific nature of the endpoint detected, differences in metabolic activation, or differences in bioavailability. On the other hand, factors which enhance the sensitivity of the bacterial reverse mutation test can lead to an overestimation of mutagenic activity. The bacterial reverse mutation test may not be appropriate for the evaluation of certain classes of chemicals for example, highly bactericidal compounds (e.g., certain antibiotics) and those which are thought (or known) to interfere specifically with the mammalian cell replication system (e.g., some topoisomerase inhibitors and some nucleoside analogues). In such cases, mammalian mutation tests may be more appropriate. 

Camptothecin Topoisomerase Inhibitors. The camptothecins (e.g., topotecan, 7.84, irinotecan, 7.85) are natural products that function as topoisomerase I enzyme inhibitors. 

There are many natural and biological macromolecules that possess anticancer activity. Cytokines, topoisomerase inhibitors, monoclonal antibodies, thymic hormones, cell growth inhibitors, and enzymes have been used [68], They have been recently reviewed [59,69] and their detailed description is beyond the scope of this article. The main problems connected with the administration of such natural macromolecules is their short intravascular half-life, immunogenicity, and sometimes poor solubility. Their modification with synthetic macromolecules can dramatically increase their therapeutic potential as described below. 

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