Radiosensitization of squamous cell carcinoma by the alkylphospholipid perifosine in cell culture and xenografts.

Abstract

PURPOSE:

Combined modality treatment has improved outcome in various solid tumors. Besides classic anticancer drugs, a new generation of biological response modifiers has emerged that increases the efficacy of radiation. Here, we have investigated whether perifosine, an orally applicable, membrane-targeted alkylphospholipid, enhances the antitumor effect of radiation in vitro and in vivo.

EXPERIMENTAL DESIGN:

Several long-term and short-term in vitro assays (clonogenic survival, sulforhodamine B cytotoxicity, apoptosis, and cell cycle analysis) were used to assess the cytotoxic effect of perifosine in combination with radiation. In vivo, the response of human KB squamous cell carcinoma xenografts was measured after treatment with perifosine, irradiation, and the combination. Radiolabeled perifosine was used to determine drug disposition in tumor and normal tissues. At various intervals after treatment, tumor specimens were collected to document histopathologic changes.

RESULTS:

In vitro, perifosine reduced clonogenic survival, enhanced apoptosis, and increased cell cycle arrest after radiation. In vivo, radiation and perifosine alone induced a dose-dependent tumor growth delay. When combining multiple perifosine administrations with single or split doses of radiation, complete and sustained tumor regression was observed. Histopathologic analysis of tumor specimens revealed a prominent apoptotic response after combined treatment with radiation and perifosine. Radiation-enhanced tumor response was observed at clinically relevant plasma perifosine concentrations and accumulating drug disposition of >100 microg/g in tumor tissue.

CONCLUSIONS:

Perifosine enhances radiation-induced cytotoxicity, as evidenced by reduced clonogenic survival and increased apoptosis induction in vitro and by complete tumor regression in vivo. These data provide strong support for further development of this combination in clinical studies.

• Authors: Stefan R Vink, Saskia Lagerwerf, Elly Mesman, Jan H M Schellens, Adrian C Begg, Wim J van Blitterswijk, Marcel Verheij
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 5 Pg. 1615-22 (Mar 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16533789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Radiation-Sensitizing Agents
• Rhodamines
• Phosphorylcholine
• lissamine rhodamine B
• perifosine

Topics

• Animals
• Apoptosis (drug effects, radiation effects)
• Carcinoma, Squamous Cell (drug therapy, pathology, radiotherapy)
• Combined Modality Therapy
• Female
• G2 Phase (drug effects, radiation effects)
• Head and Neck Neoplasms (drug therapy, pathology, radiotherapy)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Phosphorylcholine (analogs & derivatives, pharmacokinetics, therapeutic use)
• Radiation-Sensitizing Agents (pharmacokinetics, therapeutic use)
• Rhodamines (metabolism)
• Transplantation, Heterologous
• Tumor Cells, Cultured
• Tumor Stem Cell Assay
• X-Rays