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Sauter ER , Herlyn M , Liu SC , Litwin S , Ridge JA
Prolonged response to antisense cyclin D1 in a human squamous cancer xenograft model
Clinical Cancer Research. 2000 Feb;6(2) :654-660
AbstractLocal recurrence of squamous cell cancer (SCC) causes high morbidity and is often readily accessible, making such patients potential candidates for gene therapy. Cyclin Df (CD1), critical in the G(1)-S transition in the cell cycle, is amplified in 20-50% and overexpressed in up to 80% of head and neck SCC, Our earlier studies indicated that CD1 expression increased with progression from low grade to high grade dysplasia, and that treatment of established tumors Kith antisense cyclin D1 (AS-cyclin D1) led to tumor regression during a one week evaluation period. We hypothesized that: I) CD1 expression increases with disease progression to advanced SCC, and 2) AS-cyclin Df therapy would lead to prolonged tumor regression in a xenograft model of human SCC, CD1 expression, evaluated by immunostain in 30 stage III/IV head and neck SCC, increased in the basal layer from normal-dysplasia (P = 0.06) and from dysplasia-carcinoma (P = 0.004), In the germinative layer CD1 expression increased from dysplasia-carcinoma (P = 0.002) but not from normal-dysplasia, Western blotting of eight SCC and two transformed keratinocyte cell lines demonstrated CD1 overexpression in 8/10 (80%) Lines. An 11th cell Line (A431) had previously been shown to overexpress cyclin D1, 8/9 (89%) cell lines overexpressing CD1 formed tumors in immunodeficient mice, whereas 0/2 cell lines without CD1 overexpression formed a tumor, Three established SCCs, one fast growing, one with moderate growth rate with CD1 overexpression and one slow growing (without increased CD1), shrank significantly for 2-4 weeks after AS-cyclin D1 treatment, while tumors transduced with control vector grew. Cyclin D1 expression increases in frequency with disease progression, and antisense cyclin Df was effective In a xenograft model of human cancer, independent of tumor growth rate.
NotesTimes Cited: 4 English Article 287JK CLIN CANCER RES