Effects of the novel alphav integrin antagonist SM256 and cis-platinum on growth of murine squamous cell carcinoma PAM LY8.
Increased density of proliferating and migrating tumor cells and neovascular endothelial cells has been associated with tumor progression and poor prognosis in patients with squamous cell carcinoma (SCC). Tumor and neovascular endothelial cells in squamous cell carcinoma have been reported to express integrin heterodimers containing the alphav subunit, which binds to vitronectin and other extracellular matrix proteins that contain the amino acid recognition sequence Arg-Gly-Asp (RGD). In the present study, we examined the effect of the novel non-peptide alphav integrin antagonist SM256 on growth of SCC line PAM LY8 in BALB/c SCID mice, and determined whether SM256 has direct inhibitory effects on growth of murine endothelial and PAM LY8 SCC cells in vitro. SM256 inhibits cell adhesion of murine cells expressing alphavbeta3 and alphavbeta5 integrins in vitro with an IC50 of 35 nM and 30 nM, respectively. Growth of Pam LY8 tumors in vivo was inhibited with 14-day continuous administration of SM256 by subcutaneous osmotic diffusion pump, during which a mean serum concentration of 56 nM was detected. While both murine aortic endothelial cells and PAM LY8 were found to express alphav integrins by fluorescence cytofluorometry, SM256 at 50 nM in MTT assay completely inhibited growth of endothelial cells, but had no significant direct effect on growth of PAM LY8 cells. We compared the effect on growth of PAM LY8 of SM256 infusion versus single agent or combination chemotherapy with a maximally tolerated dose of cis-platinum, which is used as a standard chemotherapy for SCC. When treatment was initiated at either 7 or 21 days following establishment of tumor, 14-day infusion of SM256 had an inhibitory effect on growth that was similar to that obtained with single dose cis-platinum, but no additive effect of concurrent therapy with SM256 and cis-platinum was observed. These results demonstrate the activity and feasibility of use of alphav antagonists such as SM256 for therapy of SCC.
Van Waes
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C
Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892-1419, USA.
Enamorado-Ayala
I
I
Hecht
D
D
Sulica
L
L
Chen
Z
Z
Batt
D G
DG
Mousa
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002945:Cisplatin / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D016023:Integrins / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D013449:Sulfonamides / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007191:Indazoles; D016023:Integrins; C119284:SM 256; D013449:Sulfonamides; D002945:Cisplatin