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


METHODS
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.
Nyati
Mukesh K
MK
Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109-0010, USA.
Maheshwari
Divya
D
Hanasoge
Sheela
S
Sreekumar
Arun
A
Rynkiewicz
Susan D
SD
Chinnaiyan
Arul M
AM
Leopold
Wilbur R
WR
Ethier
Stephen P
SP
Lawrence
Theodore S
TS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D066246:ErbB Receptors / Q000378:metabolism; D005434:Flow Cytometry; D016193:G1 Phase; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D000970:Antineoplastic Agents; D001973:Bromodeoxyuridine; D004396:Coloring Agents; D004247:DNA; D066246:ErbB Receptors; D009025:Morpholines; D011505:Protein-Tyrosine Kinases; D011799:Quinazolines; D012313:RNA; D011838:Radiation-Sensitizing Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; C420268:Canertinib