Assessment of normal and tumor tissue uptake of MAG-CPT, a polymer-bound prodrug of camptothecin, in patients undergoing elective surgery for colorectal carcinoma

Sarapa, Nenad; Britto, Margaret; Speed, William C.; Jannuzzo, MariaGabriella; Breda, Massimo; James, Christopher; Porro, M G; Rocchetti, Maurizio; Wanders, Alkvin; Mahteme, Haile; Nygren, Peter

doi:10.1007/s00280-003-0685-x

Cited by 50 publications

(25 citation statements)

References 27 publications

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“…The linkage of camptothecin to the polymer carrier was designed for pHcatalysed esterolytic cleavage, in contrast to the proteasebased release of doxorubicin employed here, making it hard to compare the pharmacology of the two drug conjugates. Nevertheless, a further study administered PNU166148 to patients with colorectal cancer prior to tumour resection, and found disappointingly low levels of the drug within resected tumour tissue (24). This suggests that the EPR effect does not operate very effectively in clinical colorectal cancer, and this may contribute to the lack of activity seen against colorectal cancer in the present study as well (although the minor response in colorectal cancer observed in the phase I study should not be completely overlooked).…”

Section: Discussioncontrasting

confidence: 44%

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Seymour¹

2009

Int J Oncol

266

124

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Abstract. Phase I studies of [N-(2-hydroxypropyl)methacrylamide] (HPMA) copolymer-doxorubicin previously showed signs of activity coupled with 5-fold decreased anthracycline toxicity in chemotherapy-refractory patients. Here we report phase II studies using a similar material (FCE28068) in patients with breast (n=17), non-small cell lung (NSCLC, n=29) and colorectal (n=16) cancer. Up to 8 courses of PK1 (280 mg/m 2 doxorubicin-equivalent) were given i.v., together with 123 Ilabelled imaging analogue. Toxicities were tolerable, with grade 3 neutropenia more prominent in patients with breast cancer (4/17, 23.5% compared with 5/62, 8.1% overall). Of 14 evaluable patients with breast cancer 3 had partial responses (PR), all anthracycline-naïve patients. In 26 evaluable patients with NSCLC, 3 chemotherapy-naïve patients had PR. In contrast, none of the 16 evaluable patients with colorectal cancer responded. Imaging of 16 patients (5 with breast cancer, 6 NSCLC, 5 colorectal cancer) showed obvious tumour accumulation in 2 metastatic breast cancers, although unfortunately no images were obtained from patients who responded. These results show 6/62 PR with limited side effects, supporting the concept that polymer-bound therapeutics can have modified and improved anticancer activities and suggesting the approach should be explored further for breast cancer and NSCLC.

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Section: Discussioncontrasting

confidence: 44%

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Seymour¹

2009

Int J Oncol

266

124

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“…Gamma camera imaging has shown some evidence to support EPR174-mediated tumour localisation in patients (Vasey et al 1999). However, when colorectal cancer patients were given HPMA copolymer-camptothecin (MAG-CPT) 24 h before surgical removal of the tumour, the levels of conjugate measured in tumour tissue did not show preferential localisation compared to normal tissue (Sarapa et al 2003). Further studies are needed in the clinical setting to clarify the clinical significance of the EPR effect in human tumours of different tissue origin and the extent of targeting at different stages of tumour development (primary, metastatic, postsurgery, etc.).…”

Section: Polymer-drug Conjugates: Rationale For Designmentioning

confidence: 99%

Polymer–drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

Duncan

Vicent²,

Greco³

et al. 2005

Endocr Relat Cancer

161

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The last decade has seen successful clinical application of polymer-protein conjugates (e.g. Oncaspar, Neulasta) and promising results in clinical trials with polymer-anticancer drug conjugates. This, together with the realisation that nanomedicines may play an important future role in cancer diagnosis and treatment, has increased interest in this emerging field. More than 10 anticancer conjugates have now entered clinical development. Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four-to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m 2 (doxorubicin equivalent), no cardiotoxicity was observed. Antitumour activity in chemotherapy-resistant/refractory patients (including breast cancer) was also seen at doxorubicin doses of 80-320 mg/m 2 , consistent with tumour targeting by the enhanced permeability (EPR) effect. Hints, preclinical and clinical, that polymer anthracycline conjugation can bypass multidrug resistance (MDR) reinforce our hope that polymer drugs will prove useful in improving treatment of endocrine-related cancers. These promising early clinical results open the possibility of using the water-soluble polymers as platforms for delivery of a cocktail of pendant drugs. In particular, we have recently described the first conjugates to combine endocrine therapy and chemotherapy. Their markedly enhanced in vitro activity encourages further development of such novel, polymer-based combination therapies. This review briefly describes the current status of polymer therapeutics as anticancer agents, and discusses the opportunities for design of second-generation, polymer-based combination therapy, including the cocktail of agents that will be needed to treat resistant metastatic cancer.Endocrine-Related Cancer (2005) 12 S189-S199

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“…They demonstrated delivery of CPT to the target tumour tissue and found the equilibrium between plasma and tumour tissue concentrations of released CPT being established within 24 h after dosing. No evidence for selective delivery or retention of MAG-CPT or preferential release of free CPT in tumour tissue was found (Sarapa et al, 2003).…”

Section: Discussionmentioning

confidence: 96%

“…An interesting approach to investigate CPT accumulation in human tumour tissue was recently published by Sarapa et al Normal and tumour tissue uptake of MAG-CPT was assessed in patients undergoing elective surgery for colorectal carcinoma (Sarapa et al, 2003). Patients received a single dose of 60 mg m À2 of MAG-CPT either 24 h, 3 days, or 7 days prior to surgery.…”

Section: Discussionmentioning

confidence: 99%

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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Assessment of normal and tumor tissue uptake of MAG-CPT, a polymer-bound prodrug of camptothecin, in patients undergoing elective surgery for colorectal carcinoma

Cited by 50 publications

References 27 publications

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Polymer–drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

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

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