Modulation of camptothecin analogs in the treatment of cancer: a review

Kehrer, Diederik F.S.; Soepenberg, Otto; Loos, Walter J.; Verweij, Jaap; Sparreboom, Alex

doi:10.1097/00001813-200102000-00002

Cited by 108 publications

(60 citation statements)

References 107 publications

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“…Regarding administration regimens of CPT-11 used in cancer patients, it is particularly noteworthy that different schedules are being used in Europe (350 mg m 72 once every 3 weeks), the USA (125 mg m 72 weekly for 4 or 6 weeks) and Japan (100 mg m 72 every week, Kehrer et al, 2001b). Furthermore, there is a current trend for the use of protracted intravenous or oral dosing regimens of CPT-11 using daily drug administration (Kehrer et al, 2001b), based on earlier clinical experience with camptothecin analogues with relatively short terminal disposition half-lives, such as topotecan. However, the unique pharmacokinetic behaviour of SN-38, coupled to our current pharmacodynamic observations, suggests that a single administration of CPT-11 repeated every third week is the preferred regimen, and that increased frequency of administration may result in drug accumulation.…”

Section: Discussionmentioning

confidence: 99%

Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38

et al. 2002

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We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500 h, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC 500 h ) was significantly related to this AOC (P50.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC 500 h using only two timed samples: AUC 500 h =(6.5886C 2.5 h )+(146.46C 49.5 h )+15.53, where C 2.5 h and C 49.5 h are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively. Irinotecan (CPT-11) belongs to the family of camptothecins, and is a member of the class of topoisomerase I inhibitors. A broad spectrum of anti-tumour activity was seen in preclinical models as well as in patients, with responses observed in various disease types, including colorectal, lung, cervical, and ovarian cancers (Mathijssen et al, 2001;Vanhoefer et al, 2001). CPT-11 is a prodrug that requires activation to the active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), which is approximately 100-to 1000-fold more active than the parent drug (Hertzberg et al, 1989). A host of enzymes, including carboxylesterases to form SN-38 (Humerickhouse et al, 2000), UDP glucuronosyltransferases mediating SN-38 glucuronidation to form the b-glucuronic acid conjugate, SN-38G, (Iyer et al, 1998), intestinal and endogenous b-glucuronidases causing deconjugation of SN-38G (Sparreboom et al, 1998; Slatter et al, 2000), as well as cytochrome P-450 isoforms (Haaz et al, 1999;Santos et al, 2000) to form APC and NPC are involved in CPT-11 metabolism. In addition, several drug-transporting proteins, notably a canalicular multispecific organic anion transporter (cMOAT) located on the bile canalicular membrane (Chu et al, 1998), and P-glycoprotein (Chu et al, 1999), can influence CPT-11 elimination through hepatobiliary secretion and intestinal (re-)absorption.As a result of these (and probably also other presently unknown) mechanisms, CPT-11 and its metabolites are subject to large interindividual kinetic variability (Mathijssen et al, 2002a), and show relatively long disposition half-lives. We have recently shown that by applying an extended sampling-time period of 500 h, the circulation time of SN-38 in cancer patients was found to be substantially longer than held previously (Kehrer et al, 2000). We hypothesised that, because of the poorly defined relationships between pharmacokinetic parameters and pharmacodynamic outcome of CPT-11 treatment (Mathijssen et al, 2001), ...

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Section: Discussionmentioning

confidence: 99%

Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38

et al. 2002

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“…Here we extended the study to a B ring-substituted analog. According to the topoisomerase I-DNA-camptothecin ternary complex models (16,17) and structure-activity relationships studies (18), there is a space for substitutions at positions 7 and 10 on the B and A ring of the quinoline moiety of CPT, respectively, without decrease in activity. Therefore, we synthesized conjugates of the 16-and 18-mer TFO linked to 7-(2-aminoethyl)camptothecin via an hexyl linker (structure in Fig.…”

Section: Effect Of the Triplex Size And Length Of The Linker Arm-mentioning

confidence: 99%

Design and Optimization of Camptothecin Conjugates of Triple Helix-forming Oligonucleotides for Sequence-specific DNA Cleavage by Topoisomerase I

Arimondo¹,

Boutorine²,

Baldeyrou³

et al. 2002

Journal of Biological Chemistry

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To achieve a sequence-specific DNA cleavage by topoisomerase I, derivatives of the antitumor drug camptothecin have been covalently linked to triple helix-forming oligonucleotides that bind in a sequence-specific manner to the major groove of double-helical DNA. Triplex formation at the target sequence positions the drug selectively at the triplex site, thereby stimulating topoisomerase I-mediated DNA cleavage at this site. In a continuous effort to optimize this strategy, a broad set of conjugates consisting of (i) 16 -20-base-long oligonucleotides, (ii) alkyl linkers of variable length, and (iii) camptothecin derivatives substituted on the A or B quinoline ring were designed and synthesized. Analysis of the cleavage sites at nucleotide resolution reveals that the specificity and efficacy of cleavage depends markedly on the length of both the triple-helical structure and the linker between the oligonucleotide and the poison. The optimized hybrid molecules induced strong and highly specific cleavage at a site adjacent to the triplex. Furthermore, the drug-stabilized DNA-topoisomerase I cleavage complexes were shown to be more resistant to salt-induced reversal than the complexes induced by camptothecin alone. Such rationally designed camptothecin conjugates could provide useful antitumor drugs directed selectively against genes bearing the targeted triplex binding site. In addition, they represent a powerful tool to probe the molecular interactions in the DNA-topoisomerase I complex.The reaction between double-stranded DNA and topoisomerase I produces a covalent 3Ј-phosphorotyrosyl adduct, usually referred to as the cleavage complex (1, 2). Under physiological conditions, the covalent intermediate is barely detectable, because a fast religation step occurs after relaxation of the DNA constraints. A number of drugs, such as the antitumor alkaloid camptothecin (CPT), 1 can convert topoisomerase I into a cell poison by blocking the religation step, thereby enhancing the formation of persistent DNA breaks responsible for cell death (1, 3, 4). However, topoisomerase I poisons display a weak sequence specificity. Mainly one or two nucleotides on the 3Ј and 5Ј-side of the cleavage site (essentially thymine-guanine steps in the case of CPT) represent the only recognition elements. As a result, drugs like CPT induce massive nonspecific DNA damage in cells and can affect any gene within the genome. The identification, over the last decade, of genes that play a key role in the progression and maintenance of a specific disease, such as oncogenes and tumor suppressor, calls for the development of drugs able to regulate the expression and functions of these genes. For this reason, the design of molecules that bind to specific sequences in DNA is urgently needed. To direct the topoisomerase I enzymatic reaction to particular sites, topoisomerase I poisons, including camptothecin and rebeccamycin derivatives, have been covalently attached to sequence-specific DNA ligands, such as triplex-forming oligonucleotides (TFO) (5-7) and...

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“…Camptothecin and analogues are an important class of potent antineoplastic drugs (Kehrer et al, 2001). Camptothecin showed strong cytotoxicity against a variety of tumour types in vitro and in vivo (Wall and Wani, 1996;Chabot, 1997).…”

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confidence: 99%

A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin

et al. 2002

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Polymeric drug conjugates are a new and experimental class of drug delivery systems with pharmacokinetic promises. The antineoplastic drug camptothecin was linked to a water-soluble polymeric backbone (MAG-CPT) and administrated as a 30 min infusion over 3 consecutive days every 4 weeks to patients with malignant solid tumours. The objectives of our study were to determine the maximal tolerated dose, the dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document anti-tumour activity. The starting dose was 17 mg m 72 day 71. Sixteen patients received 39 courses at seven dose levels. Maximal tolerated dose was at 68 mg m 72 day 71 and dose-limiting toxicities consisted of cumulative bladder toxicity. MAG-CPT and free camptothecin were accumulated during days 1 -3 and considerable amounts of MAG-CPT could still be retrieved in plasma and urine after 4 -5 weeks. The half-lives of bound and free camptothecin were equal indicating that the kinetics of free camptothecin were release rate dependent. In summary, the pharmacokinetics of camptothecin were dramatically changed, showing controlled prolonged exposure of camptothecin. Haematological toxicity was relatively mild, but serious bladder toxicity was encountered which is typical for camptothecin and was found dose limiting.

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Modulation of camptothecin analogs in the treatment of cancer: a review

Cited by 108 publications

References 107 publications

Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38

Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38

Design and Optimization of Camptothecin Conjugates of Triple Helix-forming Oligonucleotides for Sequence-specific DNA Cleavage by Topoisomerase I

A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin

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