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Title: Combination of integrin siRNA and irradiation for breast cancer therapy

Abstract

Up-regulation of integrin {alpha}{sub v}{beta}{sub 3} has been shown to play a key role in tumor angiogenesis and metastasis. In this study, we evaluated the role of integrin {alpha}{sub v}{beta}{sub 3} in breast cancer cell resistance to ionizing irradiation (IR) and tested the anti-tumor efficacy of combining integrin {alpha}{sub v} siRNA and IR. Colonogenic survival assay, cell proliferation, apoptosis, and cell cycle analysis were carried out to determine the treatment effect of siRNA, IR, or combination of both on MDA-MB-435 cells (integrin {alpha}{sub v}{beta}{sub 3}-positive). Integrin {alpha}{sub v}{beta}{sub 3}-negative MCF-7 cells exert more radiosensitivity than MDA-MB-435 cells. IR up-regulates integrin {alpha}{sub v}{beta}{sub 3} expression in MDA-MB-435 cells and integrin {alpha}{sub v} siRNA can effectively reduce both {alpha}{sub v} and {alpha}{sub v}{beta}{sub 3} integrin expression, leading to increased radiosensitivity. Integrin {alpha}{sub v} siRNA also promotes IR-induced apoptosis and enhances IR-induced G2/M arrest in cell cycle progression. This study, with further optimization, may provide a simple and highly efficient treatment strategy for breast cancer as well as other integrin {alpha}{sub v}{beta}{sub 3}-positive cancer types.

Authors:
 [1];  [1];  [2];  [2];  [1];  [2];  [3]
  1. Molecular Imaging Program at Stanford (MIPS) and Bio-X, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305 (United States)
  2. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305 (United States)
  3. Molecular Imaging Program at Stanford (MIPS) and Bio-X, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305 (United States). E-mail: shawchen@stanford.edu
Publication Date:
OSTI Identifier:
20857930
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 351; Journal Issue: 3; Other Information: DOI: 10.1016/j.bbrc.2006.10.100; PII: S0006-291X(06)02360-6; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; APOPTOSIS; CARCINOMAS; CELL CYCLE; CELL PROLIFERATION; IRRADIATION; MAMMARY GLANDS; METASTASES; OPTIMIZATION; RADIOSENSITIVITY; RADIOTHERAPY; RNA

Citation Formats

Cao Qizhen, Cai Weibo, Li Tianfang, Yang Yong, Chen Kai, Xing Lei, and Chen Xiaoyuan. Combination of integrin siRNA and irradiation for breast cancer therapy. United States: N. p., 2006. Web.
Cao Qizhen, Cai Weibo, Li Tianfang, Yang Yong, Chen Kai, Xing Lei, & Chen Xiaoyuan. Combination of integrin siRNA and irradiation for breast cancer therapy. United States.
Cao Qizhen, Cai Weibo, Li Tianfang, Yang Yong, Chen Kai, Xing Lei, and Chen Xiaoyuan. Fri . "Combination of integrin siRNA and irradiation for breast cancer therapy". United States. doi:.
@article{osti_20857930,
title = {Combination of integrin siRNA and irradiation for breast cancer therapy},
author = {Cao Qizhen and Cai Weibo and Li Tianfang and Yang Yong and Chen Kai and Xing Lei and Chen Xiaoyuan},
abstractNote = {Up-regulation of integrin {alpha}{sub v}{beta}{sub 3} has been shown to play a key role in tumor angiogenesis and metastasis. In this study, we evaluated the role of integrin {alpha}{sub v}{beta}{sub 3} in breast cancer cell resistance to ionizing irradiation (IR) and tested the anti-tumor efficacy of combining integrin {alpha}{sub v} siRNA and IR. Colonogenic survival assay, cell proliferation, apoptosis, and cell cycle analysis were carried out to determine the treatment effect of siRNA, IR, or combination of both on MDA-MB-435 cells (integrin {alpha}{sub v}{beta}{sub 3}-positive). Integrin {alpha}{sub v}{beta}{sub 3}-negative MCF-7 cells exert more radiosensitivity than MDA-MB-435 cells. IR up-regulates integrin {alpha}{sub v}{beta}{sub 3} expression in MDA-MB-435 cells and integrin {alpha}{sub v} siRNA can effectively reduce both {alpha}{sub v} and {alpha}{sub v}{beta}{sub 3} integrin expression, leading to increased radiosensitivity. Integrin {alpha}{sub v} siRNA also promotes IR-induced apoptosis and enhances IR-induced G2/M arrest in cell cycle progression. This study, with further optimization, may provide a simple and highly efficient treatment strategy for breast cancer as well as other integrin {alpha}{sub v}{beta}{sub 3}-positive cancer types.},
doi = {},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 351,
place = {United States},
year = {Fri Dec 22 00:00:00 EST 2006},
month = {Fri Dec 22 00:00:00 EST 2006}
}
  • Purpose: We present our ongoing clinical experience utilizing three-dimensional (3D)-conformal radiation therapy (3D-CRT) to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer treated with breast-conserving therapy. Methods and Materials: Ninety-one consecutive patients were treated with APBI using our previously reported 3D-CRT technique. The clinical target volume consisted of the lumpectomy cavity plus a 10- to 15 -mm margin. The prescribed dose was 34 or 38.5 Gy in 10 fractions given over 5 consecutive days. The median follow-up was 24 months. Twelve patients have been followed for {>=}4 years, 20 for {>=}3.5 years, 29 for >3.0 years,more » 33 for {>=}2.5 years, and 46 for {>=}2.0 years. Results: No local recurrences developed. Cosmetic results were rated as good/excellent in 100% of evaluable patients at {>=} 6 months (n = 47), 93% at 1 year (n = 43), 91% at 2 years (n = 21), and in 90% at {>=}3 years (n = 10). Erythema, hyperpigmentation, breast edema, breast pain, telangiectasias, fibrosis, and fat necrosis were evaluated at 6, 24, and 36 months after treatment. All factors stabilized by 3 years posttreatment with grade I or II rates of 0%, 0%, 0%, 0%, 9%, 18%, and 9%, respectively. Only 2 patients (3%) developed grade III toxicity (breast pain), which resolved with time. Conclusions: Delivery of APBI with 3D-CRT resulted in minimal chronic ({>=}6 months) toxicity to date with good/excellent cosmetic results. Additional follow-up is needed to assess the long-term efficacy of this form of APBI.« less
  • Purpose: To objectively evaluate the radiation dermatitis caused by accelerated partial breast irradiation (APBI) using high-dose-rate interstitial brachytherapy. Patients and Methods: The skin color and moisture changes were examined using a newly installed spectrophotometer and corneometer in 22 patients who had undergone APBI using open cavity implant high-dose-rate interstitial brachytherapy (36 Gy in six fractions) and compared with the corresponding values for 44 patients in an external beam radiotherapy (EBRT) control group (50-60 Gy in 25-30 fractions within 5-6 weeks) after breast conserving surgery. Results: All values changed significantly as a result of APBI. The extent of elevation in amore » Asterisk-Operator (reddish) and reduction in L Asterisk-Operator (black) values caused by APBI were similar to those for EBRT, with slightly delayed recovery for 6-12 months after treatment owing to the surgical procedure. In contrast, only APBI caused a change in the b Asterisk-Operator values, and EBRT did not, demonstrating that the reduction in b Asterisk-Operator values (yellowish) depends largely on the surgical procedure. The changes in moisture were less severe after APBI than after EBRT, and the recovery was more rapid. The toxicity assessment using the Common Toxicity Criteria, version 3, showed that all dermatitis caused by APBI was Grade 2 or less. Conclusion: An objective analysis can quantify the effects of APBI procedures on color and moisture cosmesis. The radiation dermatitis caused by APBI using the present schedule showed an equivalent effect on skin color and a less severe effect on moisture than the effects caused by standard EBRT.« less
  • Purpose: Late toxicities and cosmetic analyses of patients treated with accelerated partial breast irradiation (APBI) on RTOG 0319 are presented. Methods and Materials: Patients with stages I to II breast cancer ≤3 cm, negative margins, and ≤3 positive nodes were eligible. Patients received three-dimensional conformal external beam radiation therapy (3D-CRT; 38.5 Gy in 10 fractions twice daily over 5 days). Toxicity and cosmesis were assessed by the patient (P), the radiation oncologist (RO), and the surgical oncologist (SO) at 3, 6, and 12 months from the completion of treatment and then annually. National Cancer Institute Common Terminology Criteria for Adversemore » Events, version 3.0, was used to grade toxicity. Results: Fifty-two patients were evaluable. Median follow-up was 5.3 years (range, 1.7-6.4 years). Eighty-two percent of patients rated their cosmesis as good/excellent at 1 year, with rates of 64% at 3 years. At 3 years, 31 patients were satisfied with the treatment, 5 were not satisfied but would choose 3D-CRT again, and none would choose standard radiation therapy. The worst adverse event (AE) per patient reported as definitely, probably, or possibly related to radiation therapy was 36.5% grade 1, 50% grade 2, and 5.8% grade 3 events. Grade 3 AEs were all skin or musculoskeletal-related. Treatment-related factors were evaluated to potentially establish an association with observed toxicity. Surgical bed volume, target volume, the number of beams used, and the use of bolus were not associated with late cosmesis. Conclusions: Most patients enrolled in RTOG 0319 were satisfied with their treatment, and all would choose to have the 3D-CRT APBI again.« less
  • Postmastectomy radiation therapy (PMRT) has been shown in randomized trials to improve overall survival for patients with locally advanced breast cancer. The standard PMRT clinical target volume (CTV) encompasses the chest wall and undissected regional lymphatics. Conformal isodose distributions covering the standard CTV with acceptable dose limits to normal tissue can typically be achieved with a combination of photon and electron fields. Field borders are marked on the patient's skin using a light field projection of each beam and are subsequently used to verify daily field matching clinically. Initial imaging of a patient with oligometastatic inflammatory breast cancer demonstrated directmore » extension of disease from the involved internal mammary lymph node chain into the anterior mediastinum as the only site of metastatic disease. The patient achieved a pathologic complete response to neoadjuvant chemotherapy and underwent mastectomy. The initial sites of gross disease, including the anterior mediastinal node was included in the CTV for PMRT, and treatment planning demonstrated a clear advantage to the inclusion of proton fields in this case. The absence of a light source on the proton delivery system that accurately projects proton field edges onto the patient's skin posed a significant challenge for daily verification of proton-to-photon and -electron field matching. Proton field-specific radiographic imaging devices were designed and used such that proton field edges could be delineated on the patient's skin and used for daily matching with photon and electron fields. Manufacture of the imaging devices was quick and inexpensive. Weekly verification of proton field alignment with the proton field delineation on the skin demonstrated agreement within 3-mm tolerance. The patient remains with no evidence of disease 18 months after completing radiation. Other patients with similar indications may benefit from multimodality radiation therapy.« less
  • Purpose: Image-guided radiation therapy (IGRT) may be beneficial for accelerated partial breast irradiation (APBI). The goal was to validate the use of intraparenchymal textured gold fiducials in patients receiving APBI. Methods and Materials: Twenty-six patients were enrolled on this prospective study that had three or four textured gold intraparenchymal fiducials placed at the periphery of the lumpectomy cavity and were treated with three-dimensional (3D) conformal APBI. Free-breathing four-dimensional computed tomography image sets were obtained pre- and posttreatment, as were daily online megavoltage (MV) orthogonal images. Intrafraction motion, variations in respiratory motion, and fiducial marker migration were calculated using the 3Dmore » coordinates of individual fiducials and a calculated center of mass (COM) of the fiducials. We also compared the relative position of the fiducial COM with the geometric center of the seroma. Results: There was less than 1 mm of intrafraction respiratory motion, variation in respiratory motion, or fiducial marker migration. The change in seroma position relative to the fiducial COM was 1 mm {+-} 1 mm. The average position of the geometric seroma relative to the fiducial COM pretreatment compared with posttreatment was 1 mm {+-} 1 mm. The largest daily variation in displacement when using bony landmark was in the anteroposterior direction and two standard deviations (SD) of this variation was 10 mm. The average variation in daily separation between the fiducial pairs from daily MV images was 3 mm {+-} 3 mm therefore 2 SD is 6 mm. Conclusion: Fiducial markers are stable throughout the course of APBI. Planning target volume margins when using bony landmarks should be 10 mm and can be reduced to 6 mm if using fiducials.« less