Role of immunoglobulin G fragment C receptor polymorphism-mediated antibody-dependant cellular cytotoxicity in colorectal cancer treated with cetuximab therapy.

Antibody-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via immunoglobulin G (IgG) fragment C receptors (FcRs), was proposed as a mechanism of cetuximab efficacy. Peripheral blood mononuclear cells (PBMCs) from 23 healthy donors and 13 patients with metastatic colorectal cancer (mCRC) treated with cetuximab were tested for FcγR polymorphisms and cetuximab-mediated ADCC. ADCC was measured by chromium-51 release on a epidermal growth factor receptor (EGFR)-positive human colon cancer cell line. Overall, 86 mCRC patients were genotyped for study purposes. PBMCs harbouring the FcγRIIIa 158 V/V genotype had a significantly higher cetuximab-mediated ADCC. No correlation was found between FcγR polymorphisms and response rate or time to progression after cetuximab-based therapy. Despite the in vitro analysis showing that the FcγRIIIa 158 V/V genotype is associated with higher ADCC, clinical data do not support a predictive role of FcγRIIIa polymorphisms in mCRC treated with cetuximab.

IDN 5390: an oral taxane candidate for protracted treatment schedules.

The recognition of the antiangiogenic properties of taxanes provides a basis for novel therapeutic approaches. A prolonged exposure to low drug concentrations has been proposed to be the most suitable approach to exploit the antiangiogenic potential of cytotoxic agents. Such schedule is required to target preferentially slowly dividing endothelial cells. The protracted use of taxanes could benefit from the availability of a taxane endowed with a favourable tolerability profile. Among compounds of a novel series of C-seco taxanes, IDN 5390 was originally selected on the basis of its potent antimotility activity and poor cytotoxicity on endothelial cells. The aim of the study was to investigate the preclinical pharmacologic profile of IDN 5390 in a variety of human tumour xenografts, including ovarian and colon carcinoma and a glioblastoma. IDN 5390, delivered by s.c. injection, daily for 5 days per week, exhibited a high activity against all tumours investigated (tumour growth inhibition was always >85%) in the range of well-tolerated doses. The maximum tolerated dose/injection (MTD), with no signs of systemic or local vesicant toxicity, was 120 mg kg(-1). In contrast, paclitaxel, delivered according to the same schedule, exhibited a variable antitumour efficacy associated with a substantial local toxicity (MTD=10 mg kg(-1)). Considering the remarkable efficacy of IDN 5390 delivered s.c. by protracted treatment schedule, the oral route of administration was further investigated, as the most suitable for daily treatment. Indeed, a good bioavailability of oral IDN 5390 was found. Oral IDN 5390 maintained a substantial efficacy against human tumour xenografts, including paclitaxel-resistant tumours, without loss of potency with respect to s.c. administration. In conclusion, the therapeutic advantages of IDN 5390, over paclitaxel, in protracted daily treatment schedules are represented by the oral efficacy and the high tolerability, which are favourable features to exploit the antiangiogenic potential and to design combinations with other effective agents.

A novel taxane active against an orthotopically growing human glioma xenograft.

BACKGROUND: The development of effective chemotherapy for central nervous system tumors is hampered by the blood-brain barrier and by limited drug diffusion in the brain tissue. BAY 59-8862 is a new taxane analog that was selected and developed for its activity against tumors with a P-glycoprotein-mediated, multidrug-resistant phenotype. Because P-glycoprotein is implicated in limiting the access of drugs to central nervous system tumor targets, the objective of this study was to evaluate the ability of intravenously administered BAY 59-8862 to affect the growth of central nervous system tumors. METHODS: The U-87 MG human glioma cell line was xenografted orthotopically (intracranially) in nude mice. Paclitaxel or BAY 59-8862 was delivered intravenously four times every fourth day, and antitumor efficacy was assessed by examining the effects on mouse survival time and by histologic examination of mouse brain. Drug levels in plasma and brain were determined according to a high-performance liquid chromatography method. RESULTS: The analog was as potent as paclitaxel in inhibiting the proliferation of three human glioma cell lines (U-87 MG, SW1783, and GBM) and was as effective as paclitaxel in inhibiting the heterotopic (subcutaneous) tumor growth in nude mice of U-87 MG cells (tumor weight inhibition, approximately 60%). In contrast, BAY 59-8862 was more active than paclitaxel (P < 0.05 in two of three experiments) in increasing the survival time of mice that were injected orthotopically with U-87 MG cells. The results were supported by the pharmacokinetic data, which indicated a much higher (about 15-fold) brain:plasma level ratio in BAY 59-8862-treated animals compared with paclitaxel-treated animals. CONCLUSIONS: The study provides evidence of an additional pharmacologic advantage of BAY 59-8862, i.e., the ability to affect the growth of intracranial tumors, probably due to the lack of recognition by the P-glycoprotein-mediated transport systems. The favorable behavior of BAY 59-8862 supports the potential interest in the analog for clinical studies in patients with brain tumors or metastases.