Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Camptothecin (CPT), an alkaloid isolated from the stem wood and bark of Camptotheca acuminata native to China, was discovered in the early 60's after a systematic screening of natural products by the National Cancer Institute (NCI). This new anticancer agent displays an unique mechanism of action as it inhibits intranuclear enzyme topoisomerase 1, involved in DNA replication. CPT is poorly water soluble and causes severe and unpredictable toxicities such as haemorrhagic cystitis and diarrhea; for therefore reason, a number of analogues have been synthetized in a attempt to define the features of the molecule that are essential for cytotoxicity and to produce derivatives with increased solubility. Clinical trials of several soluble molecules are in progress in the different countries: irinotecan, topotecan, 9-AC. Encouraging results are observed against solid tumors. Irinotecan was recently commercialized in France. It is a prodrug; the active metabolite SN-38 showed a good activity in metastatic colorectal adenocarcinoma; the limiting toxicities are myelotoxicity and essentially late diarrhea. However, new studies are needed for state precisely the optimal schedule of administration and association with other chemotherapeutic agents.
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PMID:[Camptothecin and derivatives: a new class of antitumor agents]. 896 50

The purpose of this study was to develop and validate limited-sampling strategies for prediction of the area under the plasma-concentration time curves (AUCs) of the lactone and total (i. e., lactone plus carboxylate) forms of the novel topoisomerase-I inhibitor 9-amino-20(S)-camptothecin (9-AC). Complete pharmacokinetic curves for both drug species were obtained from 32 patients who received the drug orally in a clinical phase I setting at dose levels ranging from 0.25 to 1.10 mg/m2. The concentrations of the lactone and carboxylate forms of 9-AC in plasma were measured by HPLC. Using data from 20 randomly selected patients, forward-stepwise multivariate regression analysis was used to generate modeling strategies incorporating data from one, two, or three plasma samples. The simultaneous optimal prediction of both 9-AC lactone and 9-AC total AUCs was obtained with sample time points at 0.33, 3.0, and 11.0 h after drug dosing. Validation of the models on an independent data set comprising data of the remaining 12 patients demonstrated that 9-AC lactone and 9-AC total AUCs could be predicted sufficiently unbiased and precise using one and two time points: [AUC (ng. h/ml) = 7.103*C3 + 4.333] for 9-AC lactone and [AUC (ng. h/ml) = 9.612*C3 + 13.77*C11 - 44.11] for 9-AC total, where C3 and C11 represent the 9-AC plasma concentrations in ng/ml at 3 and 11 h after drug dosing. Application of the proposed models will be valuable in the determination of 9-AC population pharmacokinetics and permits treatment optimization for patients on the basis of individual pharmacokinetic characteristics through restricted drug monitoring in clinical routines.
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PMID:Prediction of the systemic exposure to oral 9-amino-20(S)-camptothecin using single-sample analysis. 1038 26

The renewed interest in topoisomerase 1 inhibitors, based on new insights on the mechanism of action and the development of semi-synthetic derivates of camptothecin with a more favourable toxicity profile, has led to extensive preclinical and clinical research. Significant levels of anti-tumor activity in human tumor xenografts were seen especially with prolonged duration of exposure. Since oral drug delivery is a more convenient method for prolonged drug administration, and preferred by patients, further development of oral formulations seems attractive. Common concerns in the development of oral formulations are their sometimes low oral bioavailability and the frequently large intra- and interpatient variation in systemic exposure. Efforts to improve absorption and minimize intestinal metabolism/efflux of the oral chemotherapeutic agent using new formulas might lead to better bioavailability. Pharmacokinetic and pharmacodynamic evaluations have enabled guidance in recommendations of schedules. Given the interpatient variation in exposure it is interesting to note that flat dosing of topotecan resulted in the same systemic exposure compared with the more complex dosing per body surface area. In order to diminish the interpatient variation in exposure to 9-AC a limited sampling model for oral 9-AC was developed, enabling prediction of the systemic exposure for 9-AC and optimizing treatment for any given patient. Drug sequencing plays a key role in the combination topotecan/cisplatin and might be important for combination with other classes of drugs. Therefore, forthcoming phase 1 trials on combination therapy with oral topoisomerase 1 inhibitors should include studies on sequence dependence and pharmacokinetic analyses to evaluate any mutual interaction.
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PMID:Oral topoisomerase 1 inhibitors in adult patients: present and future. 1075 6