Camptothecin delivery systems: enhanced efficacy and tumor accumulation of camptothecin following its conjugation to polyethylene glycol via a glycine linker

Conover, Charles D.; Greenwald, Richard B.; Pendri, Annapurna; Gilbert, Carl W.; Shum, Kwok

doi:10.1007/s002800050837

Cited by 120 publications

(63 citation statements)

References 17 publications

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“…75-fold higher than for CPT (p < 0.05) and very similar to the results for PEG-CPT. 14 Mean tumor-to-muscle ratios were 2.4 and 1.5, respectively (p < 0.2 for the difference between two different xenografts).…”

Section: Both 3 H-cpt and 111mentioning

confidence: 93%

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

et al. 2004

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A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t 1/2 = 2.2 ± 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t 1/2 = 2.1 ± 0.2 h, while the conjugate half-life was 14.2 ±1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.

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Section: Both 3 H-cpt and 111mentioning

confidence: 93%

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

et al. 2004

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“…Whereas systemic exposure of the cytotoxic drug is diminished by attachment to the polymeric carrier, an accumulation takes place at the tumour site due to the increased vasopermeability of many tumours. In pre-clinical experiments decreased toxicity of normal tissue and improved anti-tumour efficacy probably due to prolonged intra-tumour retention could be demonstrated (Caiolfa et al, 2000;Conover et al, 1998). To study the pharmacokinetics of MAG-CPT polymer bound drug as well as free drug should be considered.…”

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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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“…Second, pegamotecan is passively targeted to tumors via the enhanced permeability and retention effect as described by Maeda (13,20). In preclinical studies, the enhanced permeability and retention effect was shown to result in a higher accumulation of pegamotecan in tumors compared with native camptothecin (21). Third, the low-pH milieu of the tumor shifts the equilibrium of camptothecin towards the active lactone.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 Study of Weekly Polyethylene Glycol-Camptothecin in Patients with Advanced Solid Tumors and Lymphomas

Posey

Saif

Carlisle

et al. 2005

Clinical Cancer Research

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Purpose:To determine the maximal tolerated dose and dose-limiting toxicities (DLT) of pegamotecan (polyethylene glycol-camptothecin) in patients with advanced malignancies when administered in cycles of once weekly for 3 of 4 weeks. Experimental Design: Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, including also the following criteria: measurable disease, Eastern Cooperative Oncology Group performance status of V2, and acceptable organ function. Pegamotecan was administered as a 60-minute infusion, with successive patient cohorts receiving escalating doses from 800 to 4,300 mg/m 2 . The primary end point was to determine the maximal tolerated dose. Other end points were toxicity, pharmacokinetics, pharmacodynamics, and efficacy. Pharmacokinetic analysis measured free camptothecin. Pharmacodynamic analysis correlated drug effects with pegamotecan dose and pharmacokinetic variables. Results: Twenty-seven patients were enrolled. The maximal tolerated dose was 3,240 mg/m 2 . Grade 4 neutropenia, the DLT, was noted in two of four patients treated at 4,300 mg/m 2 . Other grade 3 and 4 toxicities were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic cystitis, dysuria, and urinary frequency. Pharmacokinetic analysis showed the apparent terminal elimination half-life to be 46 F 12.8 hours. Pharmacodynamic analysis showed that hematuria occurred in 8 of 15 patients with an area under the curve extrapolated to infinity (AUC 0-1 ) > 20 ng h/mL and 0 of10 patients with an AUC 0-1 V 20 ng h/mL. Unconfirmed partial responses were observed in two patients, one with metastatic small bowel adenocarcinoma and the other with metastatic esophageal cancer. Conclusions: The maximal tolerated dose of pegamotecan when administered weekly for 3 of 4 weeks is 3,240 mg/m 2 . The DLT was neutropenia. Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was low, but genitourinary toxicity seems to occur in the same effective dose range as noted with native camptothecin in earlier trials (27-43 mg/m 2 ). The observed antitumor activity suggests that pegamotecan has single-agent activity and merits further investigation in phase 2 studies.

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Camptothecin delivery systems: enhanced efficacy and tumor accumulation of camptothecin following its conjugation to polyethylene glycol via a glycine linker

Abstract: This soluble transport form of CPT and its underlying technology may have clinical application especially for the treatment of solid tumors.

Cited by 120 publications

References 17 publications

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

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

Phase 1 Study of Weekly Polyethylene Glycol-Camptothecin in Patients with Advanced Solid Tumors and Lymphomas

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