Combination of the pro-apoptotic TRAIL-receptor antibody mapatumumab with ionizing radiation strongly increases long-term tumor control under ambient and hypoxic conditions.

Abstract

PURPOSE:

Mapatumumab, an agonistic tumor necrosis factor-related apoptosis inducing ligand-receptor antibody, exerts highly synergistic apoptotic effects in vitro and in short-term growth delay assays when combined with irradiation. Because it remained unclear in how far these effects influence local tumor control, long-term experiments using a colorectal xenograft model were undertaken.

MATERIAL AND METHODS:

Experiments were performed with irradiation (5 x 3 Gy, d1-5) and mapatumumab (10 mg/kg) in Colo205-xenograft-bearing NMRI (nu/nu) nude mice. Graded top up doses were delivered on the tumor-bearing hind leg under ambient and hypoxic conditions; follow-up was 270 days. Growth delay and local tumor control were end points of the study. Statistical analysis of the experiments included calculation of tumor regrowth and local tumor control.

RESULTS:

After combined treatment, a pronounced tumor regrowth-delay was observed when compared with irradiation alone. Long-term experiments revealed a highly significant increase in local tumor control for ambient (p = 0.00076) and hypoxic treatment (p = 0.000069).

CONCLUSIONS:

The present data demonstrate for the first time that combination of a pro-apoptotic antibody with irradiation results in evidently reduced tumor regrowth times and subsequently highly increased local tumor control under normoxic and hypoxic conditions in a xenograft mouse model.

• Authors: Patrizia Marini, Wilfried Budach, Maximilian Niyazi, Dorothea Junginger, Stefan Stickl, Verena Jendrossek, Claus Belka
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 75 Issue 1 Pg. 198-202 (Sep 01 2009) ISSN: 1879-355X [Electronic] United States
• PMID: 19695436 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• mapatumumab

Topics

• Adenocarcinoma (drug therapy, radiotherapy)
• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Apoptosis
• Cell Hypoxia
• Colorectal Neoplasms (drug therapy, radiotherapy)
• Combined Modality Therapy (methods)
• Dose Fractionation, Radiation
• Dose-Response Relationship, Radiation
• Mice
• Mice, Nude
• Neoplasm Recurrence, Local (prevention & control)
• Radiation Tolerance
• Random Allocation
• Regression Analysis
• Time Factors
• Xenograft Model Antitumor Assays (methods)