Therapeutic Efficacy Of Radiotherapy Research Articles

Radiation induced stress proteins

The major heat-inducible member of thestress proteins with a molecular weight ofabout 70 kDa (Heat shock protein 70, Hsp70)is a ubiquitous protein contributing to a num-berofcellularprocessesincludingtheprotec-tion of cells from apoptosis induced by envi-ronmental stress. Recently, we and otherscould show that a variety of tumor cells, incontrast to normal tissues, have the uniquefeature of expressing Hsp70 on their plasmamembrane [1]. Monitoring the clinical out-come (up to 5 years) demonstrated a negativecorrelation between the Hsp70 membranestatusandtheoverallsurvivalinpatientswithlowerrectalandsquamouscellcarcinomasofthe lung [2].In a recent study we were able to track theexpressionofHsp70locatedinthemembraneof tumor cells before and after stress [3]. Innon-stressed tumor cells Hsp70 is associatedwith Bag-4 [4] and the lipid-raft compoundglobotriaosylceramide (Gb3) in the plasmamembrane [5].Hypoxia is known to limit the therapeuticefficacy of radiation therapy. Therefore, weaddressed the question whether hypoxiamight affect the Hsp70 membrane expres-sion. In hypoxic tumor cells the Hsp70 mem-brane expression is elevated and Hsp70 isco-located with phosphatidylserine (PS) inthe plasma membrane.

The therapeutic activity of low-dose irradiation on experimental arthritis depends on the induction of endogenous regulatory T cell activity

BackgroundIt has been widely demonstrated that a quantitative and/or qualitative impairment of regulatory T cells (Tregs) play a fundamental role in the initiation and persistence of rheumatoid arthritis (RA) in...

Abstract 1408: Nicotine decreases the therapeutic efficacy of radiotherapy and chemoradiotherapy in vivo

Abstract Background: Continued tobacco use during cancer treatment has been associated with poor outcome. Nicotine replacement is currently used as a standard of care for smoking cessation in cancer patients; however, prior data demonstrates that nicotine can promote tumor growth and decrease the effectiveness of cancer treatment in vitro. Methods: Athymic nude mice with human H460 lung cancer cell xenografts were stratified into three Groups beginning when tumors reached 5 mm in maximal dimension: control (CON), short term nicotine (STN, 60 ug subcutaneously every other day x 6 days), or long term nicotine (LTN, 60 ug SC every other day until tumor endpoint). Within each Group, mice were further stratified into three Treatments consisting of saline (SAL), radiotherapy (RT, 3 Gy daily x 5 days), or chemoradiotherapy (CRT, RT + concurrent cisplatin intraperitoneally 3 mg/kg daily x 5 days). Tumor volumes were measured and compared between Treatments and Groups (n=10 per Treatment within each Group). This protocol was approved by the Institutional Animal Care and Use Committee at the University of Kentucky. Results: In CON animals, RT (199 uL at day 30) or CRT (100 uL at day 30) significantly prevented tumor regrowth as compared with control SAL animals (864 uL at day 10 requiring euthanasia as per protocol). As expected, CRT was more effective than RT (p<0.05). Nicotine administration alone (STN or LTN) had no effect on tumor growth rate as compared with CON. In contrast, administration of LTN significantly increased tumor regrowth in RT animals (356 uL at day 30, p<0.05) and CRT treated animals (170 uL ad day 30, p<0.05). To eliminate the effects of nicotine on proliferation following completion of RT or CRT, animals were treated with STN. Administration of STN also significantly increased tumor regrowth in RT animals (328 uL at day 30, p<0.05) and CRT animals (176 uL at day 30, p<0.05) with virtually identical regrowth curves as demonstrated for LTN animals. Conclusions: Results demonstrate that nicotine significantly reduces the efficacy of RT and CRT in vivo. Moreover, data suggest that nicotine use during treatment is the primary determinant of decreased therapeutic response. These results may significantly alter current recommendations for smoking cessation in cancer treatment populations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1408.

Abstract C138: Anti-αv integrin monoclonal antibody intetumumab (CNTO 95) enhances the therapeutic efficacy of radiation therapy and reduces metastasis of human cancer xenografts in nude rats

Abstract Radiation therapy is used to treat cancer in over 50% of all cancer patients. Interaction of tumor cells with the extracellular matrix via adhesion molecules is important for survival of cancer stem cells, and may play a role in resistance to radiation therapy. Preclinical and clinical studies from our lab and others have demonstrated that a fully human anti- v integrin monoclonal antibody intetumumab (CNTO 95) may enhance the therapeutic index of radiotherapy by selective targeting of upregulated integrins on tumor cells and vascular endothelial cells of tumors. We previously reported that intetumumab is a radiosensitizer in mice with xenograft tumors. However, since intetumumab does not cross-react with mouse integrins, but has limited cross-reactivity with rat integrins, we next studied the potential of combined use of fractionated local tumor radiation therapy and intetumumab in human cancer xenograft models in nude rats in order to assess effects on both tumor cells and vasculatures. We found that intetumumab alone had a moderate effect on tumor growth in human head and neck cancer and non-small cell lung cancer xenograft models. When combined with fractionated radiation therapy, intetumumab significantly inhibited tumor growth and produced a tumor response rate that was significantly better than with radiation therapy alone (P < 0.01). The total tumor response rate (complete response and partial response) was 67% in A549 NSCLC model for intetumumab plus radiotherapy compared with 17% for radiotherapy alone. Treatment with intetumumab reduces the lung metastasis by inhibiting the homing of A549 NSCLC cells, as well as spontaneous metastasis to lung from subcutaneous tumors in A549 NSCLC xenograft model. The blood perfusion and blood volume in xenograft tumors measured by micro-bubble enhanced ultrasound image was substantially improved by treatment of intetumumab. Immunohistochemistry staining of xenograft tumor sections demonstrated that the combined use of intetumumab and radiation therapy significantly reduced the microvessel density and increased apoptosis in tumor cells and the tumor microenvironment. The oxygenation and hypoxic status of tumors treated with intetumumab with or without radiotherapy is under investigation and will be presented. Furthermore, intetumumab alone and in combination with radiation was well-tolerated and did not produce any obvious signs of systemic toxicity. An in vivo toxicity study of crypt stem cell survival in the gastrointestinal tract demonstrated that treatment with intetumumab did not alter the number of surviving crypt stem cells of duodenum, jejunum, or ileum following irradiation, suggesting that intetumumab did not sensitize the sensitive GI epithelium to the effect of radiation therapy. These results demonstrate that intetumumab can potentiate the efficacy of fractionated radiation therapy in human cancer xenograft tumors in nude rats. These findings are promising and may have high translational relevance for the treatment of patients with solid tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C138.

The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer

Radiotherapy (RT) is a common treatment for localised prostate cancer, but can cause important side effects. The therapeutic efficacy of RT can be enhanced by pharmacological compounds that target specific pathways involved in cell survival. This would elicit a similar therapeutic response using lower doses of RT and, in turn, reducing side effects. This study describes the antitumour activity of the novel Akt inhibitor 8-(1-Hydroxy-ethyl)-2-methoxy-3-(4-methoxy-benzyloxy)-benzo[c]chromen-6-one (Palomid 529 or P529) as well as its ability to decrease radiation-activated phospho-Akt (p-Akt) signalling in a prostate cancer model. P529 showed a potent antiproliferative activity in the NCI-60 cell lines panel, with growth inhibitory 50 (GI50) <35 μM. In addition, P529 significantly enhanced the antiproliferative effect of radiation in prostate cancer cells (PC-3). Analysis of signalling pathways targeted by P529 exhibited a decrease in p-Akt, VEGF, MMP-2, MMP-9, and Id-1 levels after radiation treatment. Moreover, the Bcl-2/Bax ratio was also reduced. Treatment of PC-3 tumour-bearing mice with 20 mg kg−1 P529 or 6 Gy radiation dose decreased tumour size by 42.9 and 53%, respectively. Combination of both treatments resulted in 77.4% tumour shrinkage. Decreased tumour growth was due to reduced proliferation and increased apoptosis (as assessed by PCNA and caspase-3 immunostaining). Our results show the antitumour efficacy of P529 alone, and as a radiosensitiser, and suggest that this compound could be used in the future to treat human prostate cancer.

Radiation-Enhanced Vascular Targeting of Human Lung Cancers in Mice with a Monoclonal Antibody That Binds Anionic Phospholipids

New treatment strategies aimed at damaging tumor vasculature could potentially improve tumor response to radiation therapy. We recently showed that anionic phospholipids, principally phosphatidylserine, are specifically exposed on the luminal surface of tumor blood vessels. Here we tested the hypothesis that radiation therapy can increase phosphatidylserine exposure on lung tumor vasculature, thereby enhancing the antitumor properties of the anti-phosphatidylserine antibody 2aG4. The therapeutic efficacy of radiation therapy plus 2aG4 was tested in nude mice bearing radiation-resistant A549 human lung tumors. Radiation-induced phosphatidylserine exposure on endothelial cells and A549 tumor cells was analyzed by immunofluoresence staining. The mechanism of the enhanced antitumor effect was examined by histology and antibody-dependent cell-mediated cytotoxicity experiments. Focal irradiation of A549 human lung cancer xenografts increased the percentage of tumor vessels with exposed phosphatidylserine from 4% to 26%. Treatment of mice bearing A549 tumors with 2aG4 plus focal radiation therapy inhibited tumor growth by 80% and was superior to radiation therapy or 2aG4 alone (P < 0.01). Combination therapy reduced blood vessel density and enhanced monocyte infiltration into the tumor mass beyond that observed with individual treatments. In vitro, 2aG4 enhanced the ability of macrophages to kill endothelial cells with exposed phosphatidylserine in an Fc'-dependent manner. These results suggest that 2aG4 enhances the antitumor effects of radiation therapy by increasing antibody-dependent cell-mediated cytotoxicity toward tumor vessels with externalized phosphatidylserine. Bavituximab, a chimeric version of 2aG4 in clinical trials, has the potential to enhance the therapeutic efficacy of radiation therapy in lung cancer patients.

Combining Innate Immunity With Radiation Therapy for Cancer Treatment

Combining Innate Immunity With Radiation Therapy for Cancer Treatment

2049 Treatment of the axilla with radiation therapy (RT) without an axillary dissection (AD) in patients with invasive breast cancer

objective: To evaluate the therapeutic efficacy of RT to the axilla without AD in the management of patients with invasive breast cancer. Materials and Methods: From 1962 to 1994 data on 550 breast cancers in 537 patients (13 had bilateral cancer) were reviewed. All patients underwent lumpectomy without AD followed by RT to tbe breast and regional nodes including the axilla. Age ranged thorn 23 92 years (median 63 years). All cancers were histologically proven to be invasive and 91% had infiltrating duct cell cancer. The median T-size was 2 cm; 61 % had T1,35.8% bad T2 and 3.2 % had T3 lesions. Fifty seven axillae (10%) had palpable adenopathy and 493 (90%) were clinically NO. Megavoltage beam was used in all cases. The axilla was treated with an anterior tield + posterior axilla boost field. The median RT dose to the NO axilla was 50 Gy and 59 Gy to the axilla with palpable disease. Majority (76 %) of the patients did not receive adjuvant systemic or hormone therapy. Results: The median follow up is 74 months (range: 12 to 246). The recurrence rates in the axilla were as follows: