Abstract | PURPOSE: RESULTS: All nine human breast cancer cell lines expressed DR5 with TRA-8 reactivity varying from strongly to weakly positive. Four cell lines were sensitive to TRA-8 cytotoxicity with IC(50) of 17-299 ng/ml, whereas other cell lines had weak cytotoxicity or were resistant. In vivo studies demonstrated significant inhibition of growth of 2LMP xenografts by TRA-8 treatment alone. The combination of TRA-8 + Adriamycin or paclitaxel produced significant inhibition of tumor growth as compared with controls or either agent alone. An aggregate analysis of all 166 animals studied demonstrated that TRA-8 alone or in combination with Adriamycin, paclitaxel, or radiation produced a significant increase in tumor doubling time compared with any modality alone with mean doubling time in days of 12 (untreated), 14 (radiation), 17 ( Adriamycin), 25 ( paclitaxel), 39 ( Adriamycin + radiation), 47 (TRA-8), 65 (TRA-8 + radiation), 71 (TRA-8 + paclitaxel), 81 (TRA-8 + Adriamycin), and >140 (TRA-8 + Adriamycin and radiation). Complete tumor regressions occurred in 1 of 42 untreated animals, 1 of 54 animals receiving chemotherapy and/or radiation, and 28 of 68 animals receiving TRA-8 alone or TRA-8 combination regimens. Fourteen of those 28 complete regressions did not relapse over periods of follow-up between 99 and 171 days, with a mean of 146 +/- 24 days. CONCLUSIONS: The TRA-8 anti-DR5 antibody alone or in combination with chemotherapy and/or radiation has striking antitumor efficacy in breast cancer xenograft models. Additional studies with other tumor types and chemotherapy agents are warranted. These studies support the generation of a humanized TRA-8 for introduction into early clinical trials.
|
Authors | Donald J Buchsbaum, Tong Zhou, William E Grizzle, Patsy G Oliver, Charlotte J Hammond, Sijian Zhang, Mark Carpenter, Albert F LoBuglio |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 9
Issue 10 Pt 1
Pg. 3731-41
(Sep 01 2003)
ISSN: 1078-0432 [Print] United States |
PMID | 14506165
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
|
Chemical References |
- Antibodies, Monoclonal
- Antineoplastic Agents
- Receptors, TNF-Related Apoptosis-Inducing Ligand
- Receptors, Tumor Necrosis Factor
- TNFRSF10B protein, human
- Tnfrsf10b protein, mouse
|
Topics |
- Animals
- Antibodies, Monoclonal
(therapeutic use)
- Antineoplastic Agents
(therapeutic use)
- Apoptosis
- Breast Neoplasms
(therapy)
- Cell Death
- Cell Line, Tumor
- Cell Survival
- Combined Modality Therapy
- Dose-Response Relationship, Drug
- Drug Therapy
(methods)
- Female
- Flow Cytometry
- Fluorescent Antibody Technique, Indirect
- Humans
- Immunotherapy
(methods)
- Inhibitory Concentration 50
- Mice
- Mice, Nude
- Neoplasm Transplantation
- Protein Binding
- Radiotherapy
(methods)
- Receptors, TNF-Related Apoptosis-Inducing Ligand
- Receptors, Tumor Necrosis Factor
(chemistry)
- Time Factors
|