Medullary thyroid carcinoma (MTC) is a rare endocrine tumor that frequently metastasizes, and treatment with irinotecan (CPT-11) is limited because of side effects. Mutations in the Rearranged during transfection (RET) proto-oncogene are considered the causative event of MTC. The objective of this study was to examine whether small interfering RNA (siRNA) and its combined treatment with CPT-11 could inhibit MTC cell growth in vitro and in vivo. The transfection of RET siRNA suppressed RET expression, reduced proliferation, and increased caspase-3 ⁄ 7 activity via the down-regulation of Bcl-2 expression. Combined treatments with CPT-11 or SN-38 significantly increased caspase 3 ⁄ 7 activity compared with RET siRNA, CPT-11 or SN-38 treatment alone. Importantly, intratumoral injection of RET siRNA along with intravenous injection of CPT-11 significantly inhibited the tumor growth of MTC xenografts via an increased apoptotic effect. These findings that RET siRNA enhanced sensitivity for CPT-11 will provide a novel strategy for the treatment of MTC with RET mutation. (Cancer Sci 2010; 101: 941-947) M edullary thyroid carcinoma (MTC) is a rare endocrine tumor originating from calcitonin-secreting C cells. MTC may be sporadic or hereditary, including multiple endocrine neoplasia (MEN) type 2A, MEN type 2B and familial medullary thyroid carcinoma (FMTC).(1) MTC has an overall 10-year cause-specific survival of 60-70%, with a particularly poor prognosis for patients with MEN2B and sporadic MTC, who have a 5-year mortality of 30-50%.(2) Hereditary MTC is caused by a germline mutation in the Rearranged during transfection (RET) gene. About 40% of sporadic MTCs harbor a somatic RET mutation.(1) The RET gene encodes a receptor tyrosine kinase with an extracellular ligand-binding domain and a cysteine-rich domain, a signal transmembrane domain and an intracellular domain containing the catalytic tyrosine kinase domain.(3) RET has a glial cell line-derived neurotrophic factor as a ligand, (4) but mutated RET leads to a constitutive active RET tyrosine kinase, causing malignant behavior of C cells. (5) Surgery is currently the only effective treatment for primary MTC.(6) Radioactive iodine has no benefit since C cells do not take up iodine. The role of chemotherapeutic regimens is also limited.(7) Imatinib specifically inhibits the tyrosine kinase activity of Abl, Kit and platelet-derived growth factor receptor (PDGFR).(8) However, imatinib therapy for MTC yielded no objective responses and induced considerable toxicity in patients.(9) CPT-11 injected intraperioneally was relatively effective for TT tumor xenografts.(10) There is, therefore, no curative therapy for patients with metastatic MTC, which is responsible for many of the deaths caused by MTC. Gene therapy is a potentially useful alternative treatment for MTC. Specific inhibition of RET signaling using the dominant-negative RET mutant and ribozyme resulted in both growth suppression and subsequently the death of MTC cells.(11-13) Expressions of thymidine kinase, int...
Abstract. Therapeutic agents targeting HER-2/neu have been intensively addressed over the past decades. Previously, we reported that HER-2 synthetic small interfering RNA (HER-2 siRNA) could suppress the growth of human nasopharyngeal KB tumor xenografts by intratumoral injection with lipidbased nanoparticles; however, complete regression of the tumor was not achieved. In this study, we investigated antitumor activity by RNA interference in combination with paclitaxel (PTX) for KB cells using HER-2 siRNA and HER-2 short hairpin RNA-expressing plasmid DNA (HER-2 shRNA pDNA). Suppression of HER-2 expression by siRNA or shRNA pDNA caused significant reduction of proliferation by inducing apoptosis and enhancing the sensitivity for PTX in HER-2 positive KB cells. Interestingly, an HER-2 antibody trastuzumab could not increase the antitumor effect by PTX in KB xenografts. Combination therapy by intratumoral injection of HER-2 siRNA or HER-2 shRNA pDNA with PTX significantly inhibited the tumor growth of xenografts compared with each therapy used individually. In particular, HER-2 shRNA pDNA plus PTX largely extended the mean survival days compared with HER-2 siRNA plus PTX. Collectively, these findings suggest that HER-2 shRNA-based combined therapy with PTX could be a novel strategy to inhibit the progression of HER-2-positive cancer.
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