dianne052506 wrote:Without the immunotherapy, wouldn't you expect something new to be popping up somewhere while these original nodules were growing?
Just my opinion, but yes -well, more than an opinion... we all know what happens when you have unresectable (not SBRT, RFA, surgery) lung mets and you don't do some kind of chemo during months... right? That's something similar to what happened to Marc (lohidoc) since July 2012. Some people can think 'hey, fancy thing the immunotherapy, but you still have progression'. Well, it's not a cure (yet) but certainly it's an effective treatment, equal or better than chemo.
My girl is smart in other senses -she has some developmental delays, 7 y.o. and struggling to write her name and some few words, reading less than what she writes and counting and starting with some notion of addition. She had a severe hypoglycemia from 3 to 10 days old, so these may be the sequels. Still had some motor problems but we worked a lot on them, during her first years, so now she skates and she's the queen of the monkey bars since she's 2, so she's almost 'there' now, about motor issues. But she's very outgoing and happy, and she's quite confident, so she's doing well and will be better, I'm positive : )
The two *possible* (only possible, ok... doesn't mean it'll happen to you) complications from radiation to the lung are radiation pneumonitis and pulmonary fibrosis. Can't really find the articles right now. They are trying many things, more unaccesible to us mortal, without a willing doctor to prescribe them, but one thing that I remember is that they tried a liposomal curcumin with great success. However, there are proof that also dietary curcumin
works (in mice, but well...): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873679/
It's in my favorite category ('it's unlikely that it hurts, it may help') so... there you go.
The other thing that I've found interesting that sensitizes tumors to radiation and protects good cells is... oh you guess: Celebrex (celecoxib). When my friend had IMRT (targeted radiation) to the site where they removed the brain met (January 2013), both her oncologist and her radiation oncologist agreed it was a good idea for her to continue (she was using it) celecoxib during her IMRT sessions, because there is certain evidence about celecoxib being a good radiosensitizer for the cancer cells. They are for different cancers. I'm copying again here what I posted back then:
*********************************Cancer Biother Radiopharm. 2012 Dec 26.
[Epub ahead of print]Different Cell Cycle Modulation by Celecoxib at Different Concentrations.
Kim YM, Pyo H.
Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul, Republic of Korea.
Different cyclooxygenase (COX)-2 inhibitors were known to cause different cell cycle changes. We investigated whether this different effect on cell cycle change was due to concentration-dependent effect. We investigated the effects of celecoxib, a COX-2 selective inhibitor, on cell cycle regulation in irradiated cancer cells that express high or low levels of COX-2. Four stably COX-2 knocked-down or overexpressed cell lines were treated with various concentrations of celecoxib with or without radiation. Celecoxib differentially modulated the cell cycle according to the concentrations applied. G(1) arrest was induced at lower concentrations, whereas G(2)/M arrest was induced at higher concentrations in each cell line tested. Radiation-induced G(2)/M arrest was enhanced at lower concentrations but reduced at higher concentrations. The cutoff values to divide lower and higher concentrations were cell-type specific. Celecoxib treatment activated Cdc25C and inhibited p21 expression in both unirradiated and irradiated cells, regardless of COX-2 expression. Apoptosis was induced in irradiated cells 48 hours after treatment with celecoxib dependent of COX-2. These results imply that celecoxib deactivates the G(2) checkpoint via both Cdc25C- and p21-dependent pathways in irradiated cells, which subsequently die by secondary apoptosis. Cell cycle modulating effects in irradiated cells resulting from treatment with celecoxib may have clinical importance with regard to the potential application of celecoxib in cancer patients undergoing radiotherapy.http://www.ncbi.nlm.nih.gov/pubmed/23268707
[This is for glioblastoma but CD133(+) are desirable targets for CRC too]J Neurosurg. 2011 Mar
;114(3):651-62. doi: 10.3171/2009.11.JNS091396. Epub 2010 Nov 5.Celecoxib and radioresistant glioblastoma-derived CD133+ cells: improvement in radiotherapeutic effects. Laboratory investigation.
Ma HI, Chiou SH, Hueng DY, Tai LK, Huang PI, Kao CL, Chen YW, Sytwu HK.
Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. firstname.lastname@example.org
Glioblastoma, the most common primary brain tumor, has a poor prognosis, even with aggressive resection and chemoradiotherapy. Recent studies indicate that CD133(+) cells play a key role in radioresistance and recurrence of glioblastoma. Cyclooxygenase-2 (COX-2), which converts arachidonic acid to prostaglandins, is over-expressed in a variety of tumors, including CD133(+) glioblastomas. The COX-2-derived prostaglandins promote neovascularization during tumor development, and conventional radiotherapy increases the proportion of CD133(+) cells rather than eradicating them. The aim of the present study was to investigate the role of celecoxib, a selective COX-2 inhibitor, in enhancing the therapeutic effects of radiation on CD133(+) glioblastomas.
Cells positive for CD133 were isolated from glioblastoma specimens and characterized by flow cytometry, then treated with celecoxib and/or ionizing radiation (IR). Clonogenic assay, cell irradiation, cell cycle analysis, Western blot, and xenotransplantation were used to assess the effects of celecoxib alone, IR alone, and IR with celecoxib on CD133(+) and CD133(-) glioblastoma cells. Three separate xenotransplantation experiments were carried out using 310 severe combined immunodeficient (SCID) mice: 1) an initial tumorigenicity evaluation in which 3 different quantities of untreated CD133(-) cells or untreated or pretreated CD133(+) cells (5 treatment conditions) from 7 different tumors were injected into the striatum of 2 mice (210 mice total); 2) a tumor growth study (50 mice); and 3) a survival study (50 mice). For these last 2 studies the same 5 categories of cells were used as in the tumorigenicity (untreated CD133(-) cells, untreated or pretreated CD133(+) cells, with pretreatment consisting of celecoxib alone, IR alone, or IR and celecoxib), but only 1 cell source (Case 2) and quantity (5 × 10(4) cells) were used. Results: High levels of COX-2 protein were detected in the CD133(+) but not the CD133(-) glioblastoma cells. The authors further demonstrated that 30 μM celecoxib was able to effectively enhance the IR effect in inhibiting colony formation and increasing IR-mediated apoptosis in celecoxib-treated CD133(+) glioblastoma cells. Furthermore, reduction in radioresistance was correlated with the induction of G2/M arrest, which was partially mediated through the increase in the level of phosphorylated-cdc2. In vivo xenotransplant analysis further confirmed that CD133(+)-associated tumorigenicity was significantly suppressed by celecoxib treatment. Importantly, pretreatment of CD133(+) glioblastoma cells with a combination of celecoxib and IR before injection into the striatum of SCID mice resulted in a statistically significant reduction in tumor growth and a statistically significant increase in the mean survival rate of the mice.
CONCLUSIONS:Celecoxib combined with radiation plays a critical role in the suppression of growth of CD133(+) glioblastoma stemlike cells. Celecoxib is therefore a radiosensitizing drug for clinical application in glioblastoma.http://www.ncbi.nlm.nih.gov/pubmed/21054139
*******************************Childs Nerv Syst.
2010 Nov;26(11):1605-12. doi: 10.1007/s00381-010-1190-2. Epub 2010 Jun 5.Celecoxib enhances radiosensitivity in medulloblastoma-derived CD133-positive cells.
Chen KH, Hsu CC, Song WS, Huang CS, Tsai CC, Kuo CD, Hsu HS, Tsai TH, Tsai CY, Woung LC, Chiou SH, Lu KH, Chen YW.
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandins, is overexpressed in a variety of tumors, including medulloblastoma (MB). CD133, a transmembrane glycoprotein, has been suggested as a marker for cancer stem cells in brain tumors. The aim of the present study was to investigate the role of celecoxib, a selective COX-2 inhibitor, in enhancing the effects of ionizing radiotherapy (IR) on medulloblastoma-derived CD133-positive cells (MB-CD133(+)).
MATERIALS AND METHODS:
MB-CD133(+) were isolated from two medulloblastoma cell lines (Daoy and UW228). Then, they were treated with celecoxib in different concentrations, and cell viability was assessed. The assays of cell survival, soft agar, radiosensitivity, colony formation, and apoptotic activity in MB-CD133(+) treated with celecoxib alone, radiation alone, or celecoxib combined with radiation were further evaluated.
MB-CD133(+) showed the self-renew ability to form sphere bodies in vitro and regenerate tumors in vivo. The levels of COX-2 mRNA and protein in MB-CD133(+) were significantly higher than those in MB-CD133(-). The treatment of 30 μM celecoxib could effectively inhibit the abilities of cell proliferation and colony formation and increase IR-induced apoptosis in treated MB-CD133(+). Furthermore, in vivo study demonstrated that celecoxib significantly enhanced radiosensitivity in MB-CD133(+)-transplanted grafts. Notably, xenotransplantation analysis demonstrated that the treatment of celecoxib could further suppress the expressions of angiogenic and stemness-related genes in treated MB-CD133(+) grafts of SCID mice.
CONCLUSIONS:Celecoxib presents the potential of radiosensitizing effect in MB-derived cancer stem cells. Therefore, it should be warranted in future trials to enhance the radiotherapeutic effects in MB patients.http://www.ncbi.nlm.nih.gov/pubmed/20526717
. 2005 Oct 15;65(20):9501-9.Radiosensitivity enhancement by celecoxib, a cyclooxygenase (COX)-2 selective inhibitor, via COX-2-dependent cell cycle regulation on human cancer cells expressing differential COX-2 levels.
Shin YK, Park JS, Kim HS, Jun HJ, Kim GE, Suh CO, Yun YS, Pyo H.
Yonsei Institute for Cancer Research, Brain Korea 21 Project for Medical Science, College of Medicine, Yonsei University, South Korea .
To characterize the radiation-enhancing effects on human cancer cells and underlying mechanisms of celecoxib, a cyclooxygenase (COX)-2 selective inhibitor, and to ascertain whether its effects are COX-2 dependent. Clonogenic cytotoxicity assays and radiation survival assays after treatment with celecoxib +/- radiation were done on four human cancer cell lines that expressed differential COX-2 levels. Stably COX-2 knocked down or overexpressed cell lines were developed, and clonogenic assays, apoptosis assays, or cell cycle change measurements were conducted after treatment with celecoxib +/- radiation. Prostaglandin E(2) (PGE2) was applied to medium after treatment with celecoxib +/- radiation to determine whether the radiation-enhancing effect associated with celecoxib results from reduced generation of prostaglandin. Celecoxib's radiation-enhancing effect was observed in COX-2-expressing A549 and NCI-H460 cells but was not observed in the COX-2 nonexpressing MCF-7 and HCT-116 cells. Celecoxib's radiation-enhancing effects in A549 cells were shown to disappear after the administration of COX-2 knocked down. In contrast, the HCT-116 cells were radiosensitized by celecoxib after being transfected with COX-2 expression vector. The addition of PGE2 after treatment with celecoxib +/- radiation had no significant effects on celecoxib's radiation-enhancing effects in A549 and COX-2 transfected HCT-116 cells. Radiation-induced G2-M arrest was enhanced and sustained in the COX-2-overexpressing cells compared with that seen in COX-2 low-expressing cells. Celecoxib or NS-398 effected no changes or attenuated radiation-induced G(2)-M arrest in the COX-2-overexpressing cells but further enhanced the radiation-induced G(2)-M arrest in the COX-2 low-expressing cells. Celecoxib's radiation-enhancing effects seem to occur in a COX-2 expression-dependent manner in the cancer cells. This effect does not seem to be the result of reduced PGE2 generation. Celecoxib may exert an inhibitory effect on enhanced radiation-induced G2-M arrest in the COX-2-overexpressing cells, which may allow the arrested cells to enter mitosis and die after radiation, but may also further enhance radiation-induced G2-M arrest in the COX-2 low-expressing cells, by virtue of another mechanism.http://www.ncbi.nlm.nih.gov/pubmed/16230415
(Williston Park). 2003 May;17(5 Suppl 5):15-24.
Improvement of radiotherapy or chemoradiotherapy by targeting COX-2 enzyme.
Milas L, Mason KA, Crane CH, Liao Z, Masferrer J.
Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. email@example.com
Radiation therapy has traditionally been the treatment of choice for locally or regionally advanced cancer, but its therapeutic efficacy is often hindered by limited tolerance of normal tissues and by tumor radioresistance. To improve therapeutic outcome, radiotherapy is frequently combined with chemotherapeutic drugs that are themselves cytotoxic and may sensitize cells to radiation. Solid evidence exists that administering standard chemotherapeutic agents during the course of radiotherapy (concurrent chemoradiotherapy) increases both local tumor control and patient survival in a number of cancer sites. These therapeutic improvements, however, have been achieved at the expense of considerable normal tissue toxicity. To improve chemoradiotherapy further, there have been extensive explorations of the potential of newer chemotherapeutic agents, including irinotecan (CPT-11, Camptosar) and other topoisomerase inhibitors. Preclinical studies have shown that these agents are potent radiosensitizers, providing a strong biologic rationale for using these drugs in combination with radiotherapy. These studies also generated information critical for designing effective treatment schedules in clinical settings. The therapeutic efficacy of topoisomerase inhibitor-radiation combinations is currently being tested clinically. Recent advances in molecular biology have discovered many cellular molecules, including the cyclooxygenase-2 (COX-2) enzyme, that promote tumor cell survival and are responsible for tumor resistance to cytotoxic agents, and hence may serve as potential targets for augmentation of radio (or chemo) response. COX-2 is often overexpressed in premalignant lesions and cancer, and is involved in carcinogenesis, tumor growth, and metastatic spread. Preclinical studies provided solid evidence that inhibition of this enzyme with selective COX-2 inhibitors prevents carcinogenesis, slows the growth of established tumors, and enhances tumor response to radiation without appreciably affecting normal tissue radioresponse. The mechanisms of enhancement of tumor radioresponse involve direct actions on tumor cells and indirect actions, primarily on tumor vasculature. COX-2 inhibitors also improve tumor response to chemotherapeutic agents, including irinotecan. Additional therapeutic benefit was observed for celecoxib (Celebrex), a selective COX-2 inhibitor, consisting of a strong reduction in irinotecan-induced diarrhea. Thus, selective targeting of COX-2 may potentially improve radiotherapy, chemotherapy, or chemoradiotherapy--a therapeutic strategy that is currently being tested in clinical trials.
****************************J Natl Cancer Inst.
2003 Oct 1;95(19):1440-52.Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance?
Choy H, Milas L.
Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. firstname.lastname@example.org
Results of preclinical studies suggesting that the efficacy of molecular therapies is enhanced when they are combined with radiation have generated a surge of clinical trials combining these modalities. We reviewed the literature to identify the rationale and experimental foundation supporting the use of cyclooxygenase-2 (COX-2) inhibitors with standard radiotherapy regimens
in current clinical trials. Radiation affects the ability of cells to divide and proliferate and induces the expression of genes involved in signaling pathways that promote cell survival or trigger cell death. Future advances in radiotherapy will hinge on understanding mechanisms by which radiation-induced transcription of genes governs cell death and survival, the selective control of this process, and the optimal approaches to combining this knowledge with existing therapeutic modalities. COX-2 is expressed in all stages of cancer, and in several cancers its overexpression is associated with poor prognosis. Evidence from clinical and preclinical studies indicates that COX-2-derived prostaglandins participate in carcinogenesis, inflammation, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis. Clinical trial results have demonstrated that selective inhibition of COX-2 can alter the development and the progression of cancer. In animal models, selective inhibition of COX-2 activity is associated with the enhanced radiation sensitivity of tumors without appreciably increasing the effects of radiation on normal tissue, and preclinical evidence suggests that the principal mechanism of radiation potentiation through selective COX-2 inhibition is the direct increase in cellular radiation sensitivity and the direct inhibition of tumor neovascularization.
Results of current early-phase studies of non-small-cell lung, esophageal, cervical, and brain cancers will determine whether therapies that combine COX-2 inhibitors and radiation will enter randomized clinical trials.http://www.ncbi.nlm.nih.gov/pubmed/14519750
. 2012 Dec 17.
[Epub ahead of print]Celecoxib Downregulates CD133 Expression Through Inhibition of the Wnt Signaling Pathway in Colon Cancer Cells.
Deng Y, Su Q, Mo J, Fu X, Zhang Y, Lin EH.
1Department of Medical Oncology, Gastrointestinal Hospital, Sun Yatsen University.
AbstractCD133-positive cancer stem cells in colon cancer are resistant to conventional chemotherapy
. The aim of the present study was to investigate the effect of celecoxib, a COX-2 inhibitor, on CD133 expression in HT29 and DLD1 cells. HT29 and DLD1 cells were treated with celecoxib using different concentrations and duration. CD133 expression was detected by flow cytometry, Western blotting, immunofluorescence, and quantitative real-time PCR. Wnt signaling pathway activity was measured by luciferase assay and gene expression changes were monitored using microarray analysis. HT29 cells showed significantly decreasing levels of CD133 expression with increasing concentrations of or duration of exposure to celecoxib. CD133 mRNA relative expression in HT29 and DLD1 cells also decreased with drug exposure. Furthermore, Wnt activation in HT29 and DLD1 cells decreased with celecoxib treatment. Gene expression microarray showed stemness genes, including Lgr5, Oct4, Prominin-1, Prominin-2, CXCR4, E2F8, CDK-2, were downregulated and differentiation genes, including CEACAM5, GDF, ADFP, ICAM1, were upregulated. Our results show that CD133 expression was downregulated by celecoxib through inhibition of the Wnt signaling pathway, which may be lead to cell differentiation.
(The article, here: http://informahealthcare.com/doi/abs/10 ... 012.754458
This article is not about celecoxib as radiosensitizer but gives you some context about why
it maybe making the cells less resistant.
It would mean that the celecoxib would be helping to restore the paths for the cells to make the right signals so the angry (colon cancer) stem
cells will differentiate and die instead of lying dormant and repopulating the tumor)