Polymer-bound camptothecin: initial biodistribution and antitumour activity studies

Caiolfa, Valeria R.; Zamai, Moreno; Fiorino, Antonio; Frigerio, E.; Pellizzoni, C.; d'Argy, R.; Ghiglieri, Alberto; Castelli, M. G.; Farao, M.; Pesenti, Enrico; Gigli, Matteo; Angelucci, Francesco; Suarato, Antonino

doi:10.1016/s0168-3659(99)00243-6

Cited by 144 publications

(88 citation statements)

References 17 publications

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

et al. 2002

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“…The action of CPT is most evident in the S-phase of the cell cycle; therefore, prolonged inhibition of topoisomerase I was postulated to be an important parameter in causing cytotoxicity (Hertzberg et al, 1989;Del Bino et al, 1991;Kingsbury et al, 1991;Caiolfa et al, 2000). The relation between bladder toxicity and the dose excreted in 24 h suggests that bladder toxicity may be explained by interindividual differences in pharmacokinetics.…”

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confidence: 99%

“…Experiments in healthy mice showed about five-fold lower plasma levels of MAG-CPT compared to the highest tolerated dose of CPT administered in classical vehicles (Caiolfa et al, 2000). Whole-body autoradiographs in HT29 human colon carcinomabearing mice demonstrated evident tumour radioactivity uptake after intravenous injection of MAG-( 3 H)CPT, but not after injection of ( 3 H)CPT (Caiolfa et al, 2000).…”

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“…Whole-body autoradiographs in HT29 human colon carcinomabearing mice demonstrated evident tumour radioactivity uptake after intravenous injection of MAG-( 3 H)CPT, but not after injection of ( 3 H)CPT (Caiolfa et al, 2000). MAG-CPT was better tolerated and tumour inhibition was observed at similar and even lower doses compared to CPT alone (Caiolfa et al, 2000). Recently, two phase I studies with MAG-CPT have been performed.…”

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A phase I study with MAG-camptothecin intravenously administered weekly for 3 weeks in a 4-week cycle in adult patients with solid tumours

Wachters¹,

Groen²,

Maring

et al. 2004

Br J Cancer

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In MAG-camptothecin (MAG-CPT), the topoisomerase inhibitor camptothecin is linked to a water-soluble polymer. Preclinical experiments showed enhanced antitumour efficacy and limited toxicity compared to camptothecin alone. Prior phase I trials guided the regimen used in this study. The objectives were to determine the maximum tolerated dose, dose-limiting toxicities, safety profile, and pharmacokinetics of weekly MAG-CPT. Patients with solid tumours received MAG-CPT intravenously administered weekly for 3 weeks in 4-week cycles. At the starting dose level (80 mg m À2 week À1 ), no dose-limiting toxicities occurred during the first cycle (n ¼ 3). Subsequently, three patients were enrolled at the second dose level (120 mg m À2 week À1 ). Two of three patients at the 80 mg m À2 week À1 cohort developed haemorrhagic cystitis (grade 1/3 dysuria and grade 2/3 haematuria) during the second and third cycles. Next, the 80 mg m À2 week À1 cohort was enlarged to a total of six patients. One other patient at this dose level experienced grade 1 haematuria. At 120 mg m À2 week À1 , grade 1 bladder toxicity occurred in two of three patients. Dose escalation was stopped at 120 mg m À2 week À1 . Cumulative bladder toxicity was dose-limiting toxicity at 80 mg m À2 week À1 . Pharmacokinetics revealed highly variable urinary camptothecin excretion, associated with bladder toxicity. Due to cumulative bladder toxicity, weekly MAG-CPT is not a suitable regimen for treatment of patients with solid tumours.

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“…Polymer conjugation is also an attractive opportunity to solubilise poorly water-soluble drugs (Caiolfa et al, 2000). Drug conjugation limits cellular uptake to the endocytic route, and once internalised the conjugate is trafficked via the endosomal compartments (acid pH 6.5 -5.5) to lysosomes and thereby exposed to pH B5.0 and an array of lysosomal hydrolases, that is lysosomotropic delivery.…”

Section: Polymeric Drug Delivery -Ruth Duncan and Jim Cassidymentioning

confidence: 99%

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

et al. 2003

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Polymer-bound camptothecin: initial biodistribution and antitumour activity studies

Cited by 144 publications

References 17 publications

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

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

A phase I study with MAG-camptothecin intravenously administered weekly for 3 weeks in a 4-week cycle in adult patients with solid tumours

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

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