Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors

301

150

Promising preclinical activity with agents blocking the function of vascular endothelial growth factor (VEGF) has been observed in various cancer types, especially with combination therapy. However, these drugs decrease microvessel density, and it is not known whether this reduced vessel density (VD) results in decreased delivery of concomitantly administered classical anticancer drugs. We designed an in vivo study to investigate the relation between VEGF-blocking therapy, tumoral blood vessels, and intratumoral uptake of anticancer drugs. Nude NMRI mice bearing colon adenocarcinoma (HT29) were treated with the anti-VEGFmAb A4.6.1 or placebo. After 1 week, CPT-11 was administered 1 h prior to killing the animals. In A4.6.1 treated tumours, there was a significant decrease in VD, more pronounced with potentially functional large vessels than endothelial cords. Interestingly, a trend to increased intratumoral CPT-11 concentration was observed (P ¼ 0.09). In parallel, we measured an increase in tumour perfusion, as estimated by high-performance liquid chromatography determination of intratumoural Hoechst 33342 concentration. In the growth delay study, CPT-11 was at least equally effective with or without pretreatment with A4.6.1. These data suggest that tumour vascular function and tumour uptake of anticancer drugs improve with VEGF-blocking therapy, and indicate the relevance for further investigations.

Section: Tumour Growth Delaymentioning

confidence: 97%

Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11

Wildiers¹,

Guetens²,

Boeck³

et al. 2003

301

150

“…Additional studies with prolonged exposure schedules in mice bearing xenografts of colon adenocarcinoma, rhabdomyosarcoma and brain tumours showed less toxicity and better anti-tumour activity than dose-intensive short-exposure schedules (Houghton et al, 1995). These in vivo studies show that oral administration is as efficacious as parental application, although the AUC is lower with oral administration.…”

Section: Preclinical Studies In Vitro Studiesmentioning

confidence: 78%

“…TPT administration resulted in responses of xenografts not responsive to a short-term parental intermittent high-dose schedule (Houghton et al, 1991(Houghton et al, , 1995.…”

Section: Preclinical Studies In Vitro Studiesmentioning

confidence: 99%

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

Gerrits

Jonge²,

Schellens³

et al. 1997

113

Summary Topoisomerase inhibitors constitute a new class of anti-cancer agents. Recently, topotecan and irinotecan were registered for clinical use in ovarian cancer and colorectal cancer respectively. Cytotoxicity of topoisomerase inhibitors is S-phase specific, and in vitro and in vivo studies have suggested that, for efficacy, prolonged exposure might be more important than short-term exposure to high concentration. Clinical development of those topoisomerase inhibitors that have reached this stage is also focused on schedules aiming to achieve prolonged exposure. In this review, we summarize all published preclinical studies on this topic for topoisomerase inhibitors in clinical development, namely 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, topotecan, irinotecan and G1147211. In addition, preliminary data on clinical studies concerning this topic are also reviewed. The data suggest that prolonged exposure may indeed be relevant for anti-tumour activity. However, the optimal schedule is yet to be determined. Finally, clinical data are yet too immature to draw definitive conclusions.

“…Preclinical data have indicated that topoisomerase I inhibitors, like topoisomerase II inhibitors, demonstrate more efficacy with prolonged continuous exposure (Houghton et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

The bioavailability of oral GI147211 (GG211), a new topoisomerase I inhibitor

Gerrits

Schellens²,

Creemers³

et al. 1997

Summary Topoisomerase I inhibitors are new compounds of interest for cancer chemotherapy. We performed a study with Gl147211, a new semisynthetic camptothecin analogue, to determine the absolute bioavailability of the drug given orally. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard forms of therapy were eligible for the study. Gi147211 was given orally on day 1 and as a 30-min infusion daily on days 2-5. The treatment course was repeated every 3 weeks. In subsequent patient cohorts, the dose of the oral formulation was escalated from 1.5 mg m-2 to 6.0 mg m-2; the dose for i.v. administration was fixed at 1.2 mg m-2. Plasma pharmacokinetics was performed on day 1 and 2 of the first course and on day 1 of the second course using a validated high-performance liquid chromatographic assay. Nineteen patients were entered into the study; one patient was not evaluable because the treatment course was stopped prematurely. Eighteen patients received a total of 47 treatment courses. The absolute bioavailability of G1147211 averaged 1.3 ± 5.2%. Drug appeared quickly in plasma with a median Tma, at 0.5 h. Fasting or fed state had no significant influence on the bioavailability of G1147211. The terminal half-life after administration of oral G1147211 was 6.85 ± 3.13 h, similar to the half-life after intravenous administration. The major toxicities were neutropenia and thrombocytopenia. Nadirs for neutropenia and thrombocytopenia occurred on day 8 and day 15 respectively. Other toxicities predominantly consisted of mild and infrequent nausea and vomiting, and fatigue. The oral administration of the drug is well tolerated. Oral administration of topoisomerase I inhibitor G1147211 results in a low bioavailability with relatively wide interpatient variation. The intravenous route of administration is advised for further development of this promising topoisomerase I inhibitor.