Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development

Gerrits, C. J. H.; Jonge, Maja J.A. de; Schellens, Jan H.M.; Stoter, G.; Verweij, Jaap

doi:10.1038/bjc.1997.491

Cited by 113 publications

(54 citation statements)

References 55 publications

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“…Thus far, however, clinical trials with 9-AC have been disappointing, and this has limited further development [13]. As an S phase-specific drug whose cytotoxicity operates during DNA synthesis, optimal therapeutic efficacy requires prolonged exposure to 9-AC concentrations exceeding a minimum threshold [14]. Due to greater sensitivity of humans (compared to animals) to its myelosuppressive effects, dose-dependent myelosuppression has precluded the use of the 9-AC levels required to achieve plasma concentrations necessary for optimal antitumor activity [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Gao

Lü

Kopečková

et al. 2007

Journal of Controlled Release

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A water soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer -9-aminocamptothecin (9-AC) conjugate was designed for oral colon-specific drug delivery for the treatment of colon cancer. Comparative studies between the polymer conjugate and free drug have been performed to assess their biodistribution and pharmacokinetics in mice. After oral administration of equal doses of the polymer conjugate or free 9-AC, the drug concentrations in major organs at fixed time points were determined using an HPLC-fluorescence assay. Only 2±1% of 9-AC released from the polymer conjugate was detected in small intestine (SI), and the mean peak concentration of free 9-AC was 45-fold higher than that from released drug. Colon-specific release of 9-AC produced high local concentrations. The mean peak concentration of released 9-AC in cecal contents, feces, cecal tissue, and colon tissue were, respectively, 3.2-fold, 3.5-fold, 2.2-fold and 1.6-fold higher than that using free 9-AC. In plasma, the high and sharp drug concentration profile from free drug was in contrast to the relatively low and flat pharmacokinetic profile obtained from drug released from the HPMA copolymer. There was no significant difference between released and free drug for the area under the concentration-time curve (AUC) and bioavailability values. As a consequence of the colonspecific release of unmodified 9-AC from the polymer conjugate, antitumor efficacy can be anticipated to be enhanced due to prolonged colon tumor exposure to higher and more localized drug concentrations.

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Section: Introductionmentioning

confidence: 99%

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Gao

Lü

Kopečková

et al. 2007

Journal of Controlled Release

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“…Enhanced lipid peroxidation may also contribute to CPT-11-induced cell death (Sadzuka and Hirota, 1997). Clinically, CPT-11 has been used to treat a number of cancer types including colorectal, breast, cervical, ovarian, gliomas, lymphoma and small-cell and nonsmall-cell lung (Rothenberg, 1996;Gerrits et al, 1997;Colvin et al, 1998). CPT-11 was found to be the most effective chemotherapeutic agent in our recent comparison of the efficacies of doxorubicin, cisplatin, CPT-11 and topotecan against xenografts of colon (SW 620, COLO 205 and HT29), lung (H 460, A549, H 226) and breast (MDA-MB 231, MCF7 and T47D) cancer cell lines in nude mice (manuscript in preparation).…”

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confidence: 99%

Fish oil supplementation enhanced CPT-11 (irinotecan) efficacy against MCF7 breast carcinoma xenografts and ameliorated intestinal side-effects

1999

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SummaryThe cancer chemotherapeutic efficacy of the topoisomerase I inhibitor, is often limited by the induction of severe delayed diarrhoea. In animal studies, CPT-11 use is associated with histopathological damage to the mucosa of the small and large intestines. Results from the present study demonstrate that 60 mg CPT-11 per kg body weight (i.v. q4d ϫ 6) halted the growth, but did not cause significant regression, of MCF7 human breast carcinoma xenografts in mice fed a diet containing 7% corn oil. However, when the diet of the MCF7-bearing mice was supplemented with 3% or 6% fish oil, the same CPT-11 treatment caused significant regression of the MCF7 xenograft. Histomorphometric analyses of intestinal mucosa of mice treated with CPT-11 and fed the diet containing 7% corn oil indicated that treatment with CPT-11 induced structural changes in the intestinal mucosa which persisted at least 5 days after the last dose of CPT-11. The intestinal mucosal architecture of mice that were treated with CPT-11 and fed the diets containing fish oil was largely unchanged from the architecture of the group of mice which did not receive CPT-11. These findings indicate that fish oil supplements may be a useful adjunct to CPT-11 treatment.

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“…In this particular case, a couple of studies have demonstrated the relevance of prolonged exposure of topoisomerase I inhibitors might be beneficial in improving the clinical efficacy of such drug [32,33]. From this basis, the attempt in this work was to sustain the release of topotecan in order to optimize its therapeutic outcome following oral administration.…”

Section: Effect Of Formulation and Process Variables On Drug Release mentioning

confidence: 99%

Design, Development and Optimization of Topotecan Hydrochloride Solid Lipid Nanoparticles for Oral Chemotherapy

P³

et al. 2016

JNMR

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The objective of this research work was to formulate and evaluate solid lipid nanoparticles of anticancer drug topotecan hydrochloride in order to sustain its release and therefore improve its therapeutic outcomes. SLNs were prepared by hot micro emulsion method using glyceryl monostearate as lipid carrier and Tween 80 as surfactant in specific proportions. FT-IR and DSC studies revealed that there was no interaction between drug and lipid. The effect of drug: lipid ratio, surfactant concentration, speed and time of homogenizer on drug release, particle size and EE were studied. The results of particle size, encapsulation efficiency and in vitro drug release at 12hr fell between 111.9 nm and 255nm, 65.12% and 77.63%, and 72.31 and 79.79% respectively. Optimized formulation showed release of drug up to 73.47 % at 12 hrs, entrapment efficiency of 81.75% and particle size of 158.0 nm. The analysis of 3-D graphs revealed that parameters such as drug: lipid ratio and time of homogenization have a profound effect on both encapsulation efficiency and cumulative drug release. Scanning electron microscopy studies showed particles with disuniform surface and shape. The drug release from optimized formulation was found to fit best into first order kinetic model. It also showed almost linear regression in Higuchi's plot suggesting that diffusion is one of the mechanisms for drug release and n value of KorsmeyerPeppas plot was found to be 0.716 indicating that the drug release did not follow fickian diffusion controlled mechanism.

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Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development

Cited by 113 publications

References 55 publications

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Fish oil supplementation enhanced CPT-11 (irinotecan) efficacy against MCF7 breast carcinoma xenografts and ameliorated intestinal side-effects

Design, Development and Optimization of Topotecan Hydrochloride Solid Lipid Nanoparticles for Oral Chemotherapy

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