Radiosensitization by pan ErbB inhibitor CI-1033 in vitro and in vivo.

Abstract

PURPOSE:

Overexpression of the ErbB family of receptor tyrosine kinases has been associated with uncontrolled growth of many tumor types and, therefore, presents a promising molecular target for cancer therapy. CI-1033 is a small molecule tyrosine kinase inhibitor that differs from other 4-anilinoquinazolines by being a pan ErbB (instead of epidermal growth factor receptor-specific) irreversible (instead of reversible) inhibitor. Therefore, we investigated the antitumor effect of CI-1033 alone and in combination with ionizing radiation in vitro and in vivo.

EXPERIMENTAL DESIGN:

We selected three human colon carcinoma cell-lines (LoVo, Caco-2, which express activated epidermal growth factor receptor and ErbB-2 family members, and SW620, which does not), and analyzed the effects of CI-1033 both in vitro and in vivo. For in vivo studies LoVo and Caco-2 cells were implanted s.c. in the flank of nude mice. After the tumor reached approximately 100 mm(3), treatment was initiated with 20 mg/kg of CI-1033 (orally once daily x 5 for 3 successive weeks), radiation treatment (a total of 30 Gy given in 2 Gy once daily x 5 for 3 successive weeks), or a combination of both CI-1033 and radiation treatment.

RESULTS:

We found that exposure of LoVo and Caco-2, but not SW620 cells, to CI-1033 in the range of 1-3 micro M could inhibit constitutive signaling by tyrosine kinases, arrest cell growth, inhibit cells in G(1), stimulate expression of p53, and induce apoptosis. The inhibition of cell growth by CI-1033 seemed to produce only minimal radiosensitization in LoVo and Caco-2 cells. In contrast, the combination of CI-1033 and radiation produced significant (P < 0.0005 and P = 0.0002, respectively) and prolonged suppression of tumor growth in both the tumor types when compared with either treatment alone.

CONCLUSIONS:

These findings suggest that CI-1033 can increase the effectiveness of radiation therapy. The extent of suppression of tyrosine kinase activity by CI-1033, rather than the amount of activity in untreated cells, seemed to be more closely associated with the efficacy of combination treatment.

• Authors: Mukesh K Nyati, Divya Maheshwari, Sheela Hanasoge, Arun Sreekumar, Susan D Rynkiewicz, Arul M Chinnaiyan, Wilbur R Leopold, Stephen P Ethier, Theodore S Lawrence
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 2 Pg. 691-700 (Jan 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 14760092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Coloring Agents
• Morpholines
• Quinazolines
• Radiation-Sensitizing Agents
• RNA
• DNA
• Canertinib
• ErbB Receptors
• Protein-Tyrosine Kinases
• Receptor, ErbB-2
• Bromodeoxyuridine

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Bromodeoxyuridine (pharmacology)
• Cell Line, Tumor
• Cell Survival
• Coloring Agents (pharmacology)
• DNA (metabolism)
• Dose-Response Relationship, Radiation
• ErbB Receptors (metabolism)
• Flow Cytometry
• G1 Phase
• Humans
• Immunohistochemistry
• In Vitro Techniques
• Mice
• Mice, Nude
• Morpholines (pharmacology)
• Neoplasm Transplantation
• Oligonucleotide Array Sequence Analysis
• Precipitin Tests
• Protein-Tyrosine Kinases (metabolism)
• Quinazolines (pharmacology)
• RNA (metabolism)
• Radiation, Ionizing
• Radiation-Sensitizing Agents (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Time Factors