Combined-modality radioimmunotherapy: synergistic effect of paclitaxel and additive effect of bevacizumab.

Abstract

INTRODUCTION:

This study was undertaken to investigate the effect of paclitaxel and bevacizumab on the therapeutic efficacy of (90)Y-labeled B3 monoclonal antibody, directed against Le(y) antigen, for the treatment of Le(y)-positive A431 tumors implanted subcutaneously in the right hind flank of nude mice.

METHODS:

When the tumor size reached ~200 mm(3), the mice received a single dose of intravenous (iv) (90)Y-labeled B3 (60 μCi/150 μg or 100 μCi/150 μg B3), intraperitoneal paclitaxel (40 mg/kg) or iv bevacizumab (5 mg/kg) for monotherapy. To investigate the effect of combined therapies on survival, the mice were treated with two or three agents in the following combinations: (90)Y-B3 on day 0 and paclitaxel on day 1; bevacizumab on -1 day and (90)Y-B3 on day 0; bevacizumab on -1 day and paclitaxel on day 1; bevacizumab, (90)Y-B3 and paclitaxel each at 1-day intervals. The mice with no treatment were used as a control. The tumor volume at 1000 mm(3) was used as a surrogate end point of survival.

RESULTS:

Compared to control animals, paclitaxel delayed tumor growth with a significantly longer median survival time (P<.001), whereas bevacizumab alone showed a less pronounced effect on a median survival time (P=.18). (90)Y-B3 increased the median survival time in a dose-dependent manner (P<.05). The combined therapy of bevacizumab with paclitaxel produced a trend toward an increase of the median survival time compared to paclitaxel alone (P=.06), whereas bevacizumab combined with (90)Y-B3 showed a statistically insignificant increase in the median survival time compared to (90)Y-B3 alone (P=.25). The tumor sizes of all animals in these groups reached the surrogate end point of survival by day 35. In contrast, the combined therapy involving (90)Y-B3 with paclitaxel showed a striking synergistic effect in shrinking tumors and prolonging the survival time (P<.001); on day 120, three of nine mice (33%) and six of six mice (100%) were alive without tumor when treated with 60 μCi (90)Y-B3 and 100 μCi (90)Y-B3, respectively. The addition of bevacizumab treatment 1 day before the combined therapy of 60 μCi (90)Y-B3 with paclitaxel did not produce a statistically significant increase in survival when compared to the (90)Y-B3 with paclitaxel (P>.10). Fluorescence microscopy analysis indicated that paclitaxel increased, whereas bevacizumab decreased, the accumulation and penetration of Alexa Fluor 647-B3 into tumor microenvironment compared to the control (P<.05).

CONCLUSION:

Our findings on the paclitaxel effect support a hypothesis that the increased tumor accumulation and penetration of (90)Y-B3 as well as the high radiosensitization of tumor cells by paclitaxel may be the major factors responsible for the synergistic effect of the combined therapy involving (90)Y-B3 with paclitaxel.

• Authors: Beom-Su Jang, Sang-Myung Lee, Hyung Sub Kim, In Soo Shin, Faezeh Razjouyan, Shutao Wang, Zhengsheng Yao, Ira Pastan, Matthew R Dreher, Chang H Paik
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 39 Issue 4 Pg. 472-83 (May 2012) ISSN: 1872-9614 [Electronic] United States
• PMID: 22172384 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier Inc.

Chemical References

• Antibodies, Monoclonal, Humanized
• Yttrium Radioisotopes
• Bevacizumab
• Paclitaxel

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Bevacizumab
• Carcinoma, Squamous Cell (blood supply, drug therapy, pathology, radiotherapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects, radiation effects)
• Combined Modality Therapy
• Drug Synergism
• Humans
• Mice
• Microscopy, Fluorescence
• Microvessels (drug effects, metabolism, radiation effects)
• Paclitaxel (pharmacology, therapeutic use)
• Radioimmunotherapy (methods)
• Xenograft Model Antitumor Assays
• Yttrium Radioisotopes (therapeutic use)