- Email: [email protected]
P-958 Synergistic interaction between PPAR-γ agonist and gefitinib onlung cancer A549 cells
Posters I Targeted therapies
$372
Results: In each bisphosphonato, there was suggested direct antltumor effects of non-small cell lung cancer calllinos, dependent on concentration and IC50 of pemidronate was 2 4 ,53 3 p.M. IC,50 of ineardroeate was 1 ,5 32 0 p.M. and ICb0 of minedronate was 2 1 8. 0p.M by measunng oftheir O D in MTI" assey In flowoytometTic analysis, each bisphosphonatos was suggested indu~on of S-phase call oyde arrest and apoptosis in these non-small cell lung cancer. dependent on these concent~'ation It was suggested that bisphosphnates have been cirect antltumor effects in human non-small cell lung canco~ Conclusions: Bisphosphonates have clroct antltumor effects and induced of apoptosis of human non small coil lung cancer in v~b-o, it was thought that the apoptos~s of cancer cell essoc~ated w~th activating MAPK pathway and inhibiting mevalonato pathway.
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SynerglsUc Interaction between PPAR~ agonlst and gefltlnlb on lung cancer A549 cells
S. Lee ~. G. Hur ~. H. Jung~. S. Lee ~. J. Kim ~. C. Shin ~. J. Shim ~. K. In~. K Kang~. S Yoo ~ ~Department ~ tnfamal Medicine, Guro Hospfal, Korea
Umvers~ Seoul, South Korea: ~Department ot tntemal Medicine, Anam Hosptal, Korea Umvereity, South Korea: 3Department of Internal Medlone, Ansan Hospital, Korea Umversity, Ansan, South Korea
Results: Forty seven patients were enrolled in this protocol (19 in cohort I. 22 in cohort I1. and 6 in cohort III) The main tmdcitles were grades 1 and 2 nausea and esophagitls, and they were independent of the dose of calecoxib or radiotherapy schedule Only two patients in Group II developed grade-3 pneumonitls one month after treatment, one on 200 mg and the other on 400 mg calecoxib Celecoxib-related toxicity developed in 3 of 47 patients: an uncontrolled hypertension in one patient on 800 mg celecoxib and hemorrhagic episodes in 2 patients (shoulder hematoma in one and hemoptysis in the other) on 200 mg colocoxlb who wore on warfann for other moclcal reasons. Of 37 patients evaluablo for tumor response (see Results section). 14 had oomplete response. 13 pad]al response, and 10 stable or progressive disease. ]he actuarial local progression free survival (LPFS) was 66.0% at 1 year and 42.2% at 2 years, followtng irltlatlon of radiotherapy. Conclusions: Those results show that celecc0cib can be safely administered ooncurmntly with thoracic radiotherapy when given qo to the highest FDA approved dose of 800mg per day. which we used The tTeatment resulted in actuanal LPFS of 66 0% at 1 year and 42 2% at 2 years, an encouraging outcome that warrants further assessment in a phase Will tnal ~o]
Delivering blodegradeble PLGA mlcropartlculates to thoracic lymph nodes
J Liu 1. M Johnston 1. B Bowen 2. × Wu 2 1l n s ~ a
~ Me~/Science,
Background: Gofitinib that targets the epidermal growth factor receptor (EGFR). has ant]tumor activity in patient with non small cell lung cancer (NSCLC). However. only 10 to 20 percent of patients have clinical response to this drug The molecular mechanisms underlying sensitivity to gefitinib are unknown Pero~dseme prcliferators-ac0vated receptor-y (PPAR-y) is a member of the nuclear receptor superfamily of ligand-actlvated tTanschption factors which regulates cellular differentiation and growth This regulation was mediated by increasing PTEN levels PTEN has a role in the modulation of the phosphatldylinosltol 3-1dnase pathway(PI3K), which is involved in cell proliferation and survival, so it can inhibit cell cycle progression and induce G1 arrest. We analyzed the effoots of PPAR-f agonist (Rosiglltazone) on PTEN espresslon and EGFR tyrosine kinese inhibitor's antltumor activity in A549 coils Methods: A549 cells were b-eated with re=glltazone (0. 1. 10. 40 uM). gofitinib(10 uM) and the PPAR "~ inhibitor GW9662(10 uM) for48 h. Cell growth was analysed by MTT assay after 48 h. The optical density (OD) was then recorded at 540 nrn. The cell cycle analysis was evaluated by using prop~dium iodide stain and flow cytomelry. PPAR -f and P~_N esprossion wore analysed by Western blotting Results: Treatment of A`549 cells with rosiglltazone decreased growth of A549 calls, dosa dependently and facilitated gefitinib's anti-proliferative effect In the cell oycle analysis, time dependently, rosiglitazone and gertinib increased G0/G~ phase In Western analysis, PPAR-y and PTEN expression were increased in gefil~nib and rosiglltazone tTeated calls This suggests that the growth ir~ibitory effect of gefitinib can be potentiated if followed by a tTeatment with PPAR -f agonists. Conclusions: Our data demonstrate that PPAR-f agonist (rosiglltazone) potentiate gefit]nlb's anti proliferative effect by increased of PTEN expression and suggest that PPAR -f ligands may serve as potential therapeutic agents for NSCLC
Background: MicropartJculatos have applications in lymphatic mapping or targeting for cancer b-eatment through vanous routes of administTation However. their lymphatic distribution in the thoracic cavity has not been adequately investigated The objective of this study was to examine the lymphatic disthbutlon of biodegradable polylac~de co-giycolide (PLGA) microspheres following intrapieural administ?ation Methods: PLGA microspheros labeled v~th rhodamine wore synthesized in the laboratory using spray drying technique. The average particle size ranges 1-Sp.m Both healthy rats and rats beanng orthotopic lung cancer with predominant lymph node metastases were employed in the study. The preparation of PLGA~-hodamine (20 mg in 0.5 ml saline) was administered into the loft pieural space of each rat in both healthy and lung cancer rat models (3/group). After 24 h. animals wore sacnfK:ed for macroscopic esamination 13ssue samples including regional lymph nodes, lymphoid tissue. lungs, and tumors were harvested and prepared for both light microscopic and fluorescence microscopic esaminatlon to detect pa~culates in the thoracic lymphatic system Results: Active lymphatic particle uptake was identified 24 h after intT"apleural administration PLGA-rhodamine microspheres were ef~c0vely taken up by both normal and cancerous regional lymph nodes ] h e particles appeared predominantly in the hilar lymph nodes, bilateral mediastlnal lymph nodes. parastemal lymph nodes, and posterior mediastlnal lymphoid tissue. Few particle uptake was found in the pulmonary and tumor parenchyma. Conclusions: Regional thoracic lymphatlos and lymph nodes can be accessed by colloidal particles inb-oducod into the pleural space. Biodegradable PLGA micropartlculatos could be potentially used as drug carners for lymphatic targeting therapy.
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dose escalaUon clinical tdal using thoradc radiotherapy and concurrent celecoxlb for patients wlth unfavorable performance status Inoperable/unresectable non-small cell lung cancer (NSCLC)
Z Liao~ R Komald ~.L Milas 2 . Y c h e n 3.M Kiea 4.J Chang 1. M Jeter ~. T. Guermro ~. G. Blumenschein ~. J. Cos ~. I t i e UmversIty ot Texas M. D.
Andersen Cancer Center, Department ot Rad/at]on Ontology, Houston, TX, USA, 2 UTMDACC, Department of Expedmenfal Radiation Oncotogy, Houston, TX, USA: 3 Tong~/ MeScal School, Tonglt Hospita/, Wuhan, Hut~e/, China, ~Tha University of Texas M 0 Anderson Cancer Center, Department ot Head and NecYJlioractc Medtcal Oncolog~, Houston, iX, USA Background: Predinical observations that selective COX 2 inhibltors enhance tn wtro cell redo sensitivity and m vrvo tumor radorosponse led to clinical tnals testing therapeutic efficacy of these agents. Our study was designed to determine whether the COX 2 inhibitor coleoo)ub could be safely administered in doses within those approved by FDA when used concurrently with thoracic radiotherapy in patients with poor prognosis NSCLC Methods: ] h e trial consisted of 3 cohorts of patients: (I) locally advanced NSCLC with obstTuc0ve pneumonia, hemeptysis, and/or minimal metastatic disease treated with 45Gy in 15 fra~ons (fx): (11) medically inoperable early stage NSCLC tTeated with definitive radiation of 66 Gy in 33 5(: and (111)patients who received indu~on chemotherapy but who were not eligible for concurrent chemoradiotherapy tnals. These patients received 63 Gy in 35 fx. Celocc0cib was administered orally on daly bas~s 5 days prlor to and throughout the oourse of radiotherapy. Celoooxib doses wore escalated fi'om 200 mg. 400 mg. 600 mg. to 800 mg per day given in two oqJally di~dod doses. Two to 8 patients of each cohort wore assigned to each dose level of celecc~ib.
Dept of f:~narmaceutJcal Science, University of Toronto, Toronto, Canada
Buccal rnucosa cells as "In r i v e " model to evaluate gefltlnlb response In NSCLC patients
M. Loprevite ~. M Chiaramondia 2. M 13see~. F Grossi ~ . P Dadati 2. A Kunld 2. R Nizzoli 3. V Franciosi 3. R Rosse I . A Arci~ohi 3 ~Madical Onco/ogyA,
Nabonal /ns~tute for Cancer Research, Genoa, Ita/y, 2Department of Pathology, S. Marline Hospital, Genoa, Italy;, ~Medtcal Oncology, Untversrty Hospital of Parma, Parma, Italy Background: Epidermal Growth Factor Receptor (EGFR) activation plays an important role in the cascade of inb-acellular signalling events that regulate tumor cell proliferation, migration, resistance to apoptos~s and angiogenesis in NSCLC. EGFR phosphorylation is associated with aotlvatlon of Res toJVIAPK (mitogen activated protein kinases) and PI3K. toAKT pathways. Gofitinib. an EGFR ]K. inhibitor, has been found to determine an objective response in <10% of advanced NSCLC patients. ]he aim of this study wee to evaluate the predictive role of both beseline expression and aady vanatlon of expression of cifferent signal Imansductlon markers activated by EGFR. including phespherylated4=GFR (EGFR~). p-MAPK and p-AKT, in buocal mucosa cells of NSCLC patients treated with gefi'dni b (250 mg/day) Methods: Buocal smears ware obtained before therapy and after 2 weeks of tTeatment, by scraping Protein espression was evaluated by immunooftcohamislT,/and flow cytomet]-y Toxicity was assessed monthly by clinieal esaminatlon and blood oounts and chemistry. Objective response was assessed every 2 months by CT scan. Forty one patients were enrolled and 31 are so far fully evaluablo. Results: Four patients had a partial response (PR). and all showed a t]'ond to reduction in expression of EGFR p (I.e. 40%+ vs 15%+). p M A P K (50%
$372
Results: In each bisphosphonato, there was suggested direct antltumor effects of non-small cell lung cancer calllinos, dependent on concentration and IC50 of pemidronate was 2 4 ,53 3 p.M. IC,50 of ineardroeate was 1 ,5 32 0 p.M. and ICb0 of minedronate was 2 1 8. 0p.M by measunng oftheir O D in MTI" assey In flowoytometTic analysis, each bisphosphonatos was suggested indu~on of S-phase call oyde arrest and apoptosis in these non-small cell lung cancer. dependent on these concent~'ation It was suggested that bisphosphnates have been cirect antltumor effects in human non-small cell lung canco~ Conclusions: Bisphosphonates have clroct antltumor effects and induced of apoptosis of human non small coil lung cancer in v~b-o, it was thought that the apoptos~s of cancer cell essoc~ated w~th activating MAPK pathway and inhibiting mevalonato pathway.
[•
SynerglsUc Interaction between PPAR~ agonlst and gefltlnlb on lung cancer A549 cells
S. Lee ~. G. Hur ~. H. Jung~. S. Lee ~. J. Kim ~. C. Shin ~. J. Shim ~. K. In~. K Kang~. S Yoo ~ ~Department ~ tnfamal Medicine, Guro Hospfal, Korea
Umvers~ Seoul, South Korea: ~Department ot tntemal Medicine, Anam Hosptal, Korea Umvereity, South Korea: 3Department of Internal Medlone, Ansan Hospital, Korea Umversity, Ansan, South Korea
Results: Forty seven patients were enrolled in this protocol (19 in cohort I. 22 in cohort I1. and 6 in cohort III) The main tmdcitles were grades 1 and 2 nausea and esophagitls, and they were independent of the dose of calecoxib or radiotherapy schedule Only two patients in Group II developed grade-3 pneumonitls one month after treatment, one on 200 mg and the other on 400 mg calecoxib Celecoxib-related toxicity developed in 3 of 47 patients: an uncontrolled hypertension in one patient on 800 mg celecoxib and hemorrhagic episodes in 2 patients (shoulder hematoma in one and hemoptysis in the other) on 200 mg colocoxlb who wore on warfann for other moclcal reasons. Of 37 patients evaluablo for tumor response (see Results section). 14 had oomplete response. 13 pad]al response, and 10 stable or progressive disease. ]he actuarial local progression free survival (LPFS) was 66.0% at 1 year and 42.2% at 2 years, followtng irltlatlon of radiotherapy. Conclusions: Those results show that celecc0cib can be safely administered ooncurmntly with thoracic radiotherapy when given qo to the highest FDA approved dose of 800mg per day. which we used The tTeatment resulted in actuanal LPFS of 66 0% at 1 year and 42 2% at 2 years, an encouraging outcome that warrants further assessment in a phase Will tnal ~o]
Delivering blodegradeble PLGA mlcropartlculates to thoracic lymph nodes
J Liu 1. M Johnston 1. B Bowen 2. × Wu 2 1l n s ~ a
~ Me~/Science,
Background: Gofitinib that targets the epidermal growth factor receptor (EGFR). has ant]tumor activity in patient with non small cell lung cancer (NSCLC). However. only 10 to 20 percent of patients have clinical response to this drug The molecular mechanisms underlying sensitivity to gefitinib are unknown Pero~dseme prcliferators-ac0vated receptor-y (PPAR-y) is a member of the nuclear receptor superfamily of ligand-actlvated tTanschption factors which regulates cellular differentiation and growth This regulation was mediated by increasing PTEN levels PTEN has a role in the modulation of the phosphatldylinosltol 3-1dnase pathway(PI3K), which is involved in cell proliferation and survival, so it can inhibit cell cycle progression and induce G1 arrest. We analyzed the effoots of PPAR-f agonist (Rosiglltazone) on PTEN espresslon and EGFR tyrosine kinese inhibitor's antltumor activity in A549 coils Methods: A549 cells were b-eated with re=glltazone (0. 1. 10. 40 uM). gofitinib(10 uM) and the PPAR "~ inhibitor GW9662(10 uM) for48 h. Cell growth was analysed by MTT assay after 48 h. The optical density (OD) was then recorded at 540 nrn. The cell cycle analysis was evaluated by using prop~dium iodide stain and flow cytomelry. PPAR -f and P~_N esprossion wore analysed by Western blotting Results: Treatment of A`549 cells with rosiglltazone decreased growth of A549 calls, dosa dependently and facilitated gefitinib's anti-proliferative effect In the cell oycle analysis, time dependently, rosiglitazone and gertinib increased G0/G~ phase In Western analysis, PPAR-y and PTEN expression were increased in gefil~nib and rosiglltazone tTeated calls This suggests that the growth ir~ibitory effect of gefitinib can be potentiated if followed by a tTeatment with PPAR -f agonists. Conclusions: Our data demonstrate that PPAR-f agonist (rosiglltazone) potentiate gefit]nlb's anti proliferative effect by increased of PTEN expression and suggest that PPAR -f ligands may serve as potential therapeutic agents for NSCLC
Background: MicropartJculatos have applications in lymphatic mapping or targeting for cancer b-eatment through vanous routes of administTation However. their lymphatic distribution in the thoracic cavity has not been adequately investigated The objective of this study was to examine the lymphatic disthbutlon of biodegradable polylac~de co-giycolide (PLGA) microspheres following intrapieural administ?ation Methods: PLGA microspheros labeled v~th rhodamine wore synthesized in the laboratory using spray drying technique. The average particle size ranges 1-Sp.m Both healthy rats and rats beanng orthotopic lung cancer with predominant lymph node metastases were employed in the study. The preparation of PLGA~-hodamine (20 mg in 0.5 ml saline) was administered into the loft pieural space of each rat in both healthy and lung cancer rat models (3/group). After 24 h. animals wore sacnfK:ed for macroscopic esamination 13ssue samples including regional lymph nodes, lymphoid tissue. lungs, and tumors were harvested and prepared for both light microscopic and fluorescence microscopic esaminatlon to detect pa~culates in the thoracic lymphatic system Results: Active lymphatic particle uptake was identified 24 h after intT"apleural administration PLGA-rhodamine microspheres were ef~c0vely taken up by both normal and cancerous regional lymph nodes ] h e particles appeared predominantly in the hilar lymph nodes, bilateral mediastlnal lymph nodes. parastemal lymph nodes, and posterior mediastlnal lymphoid tissue. Few particle uptake was found in the pulmonary and tumor parenchyma. Conclusions: Regional thoracic lymphatlos and lymph nodes can be accessed by colloidal particles inb-oducod into the pleural space. Biodegradable PLGA micropartlculatos could be potentially used as drug carners for lymphatic targeting therapy.
[
[ ~
•
A
dose escalaUon clinical tdal using thoradc radiotherapy and concurrent celecoxlb for patients wlth unfavorable performance status Inoperable/unresectable non-small cell lung cancer (NSCLC)
Z Liao~ R Komald ~.L Milas 2 . Y c h e n 3.M Kiea 4.J Chang 1. M Jeter ~. T. Guermro ~. G. Blumenschein ~. J. Cos ~. I t i e UmversIty ot Texas M. D.
Andersen Cancer Center, Department ot Rad/at]on Ontology, Houston, TX, USA, 2 UTMDACC, Department of Expedmenfal Radiation Oncotogy, Houston, TX, USA: 3 Tong~/ MeScal School, Tonglt Hospita/, Wuhan, Hut~e/, China, ~Tha University of Texas M 0 Anderson Cancer Center, Department ot Head and NecYJlioractc Medtcal Oncolog~, Houston, iX, USA Background: Predinical observations that selective COX 2 inhibltors enhance tn wtro cell redo sensitivity and m vrvo tumor radorosponse led to clinical tnals testing therapeutic efficacy of these agents. Our study was designed to determine whether the COX 2 inhibitor coleoo)ub could be safely administered in doses within those approved by FDA when used concurrently with thoracic radiotherapy in patients with poor prognosis NSCLC Methods: ] h e trial consisted of 3 cohorts of patients: (I) locally advanced NSCLC with obstTuc0ve pneumonia, hemeptysis, and/or minimal metastatic disease treated with 45Gy in 15 fra~ons (fx): (11) medically inoperable early stage NSCLC tTeated with definitive radiation of 66 Gy in 33 5(: and (111)patients who received indu~on chemotherapy but who were not eligible for concurrent chemoradiotherapy tnals. These patients received 63 Gy in 35 fx. Celocc0cib was administered orally on daly bas~s 5 days prlor to and throughout the oourse of radiotherapy. Celoooxib doses wore escalated fi'om 200 mg. 400 mg. 600 mg. to 800 mg per day given in two oqJally di~dod doses. Two to 8 patients of each cohort wore assigned to each dose level of celecc~ib.
Dept of f:~narmaceutJcal Science, University of Toronto, Toronto, Canada
Buccal rnucosa cells as "In r i v e " model to evaluate gefltlnlb response In NSCLC patients
M. Loprevite ~. M Chiaramondia 2. M 13see~. F Grossi ~ . P Dadati 2. A Kunld 2. R Nizzoli 3. V Franciosi 3. R Rosse I . A Arci~ohi 3 ~Madical Onco/ogyA,
Nabonal /ns~tute for Cancer Research, Genoa, Ita/y, 2Department of Pathology, S. Marline Hospital, Genoa, Italy;, ~Medtcal Oncology, Untversrty Hospital of Parma, Parma, Italy Background: Epidermal Growth Factor Receptor (EGFR) activation plays an important role in the cascade of inb-acellular signalling events that regulate tumor cell proliferation, migration, resistance to apoptos~s and angiogenesis in NSCLC. EGFR phosphorylation is associated with aotlvatlon of Res toJVIAPK (mitogen activated protein kinases) and PI3K. toAKT pathways. Gofitinib. an EGFR ]K. inhibitor, has been found to determine an objective response in <10% of advanced NSCLC patients. ]he aim of this study wee to evaluate the predictive role of both beseline expression and aady vanatlon of expression of cifferent signal Imansductlon markers activated by EGFR. including phespherylated4=GFR (EGFR~). p-MAPK and p-AKT, in buocal mucosa cells of NSCLC patients treated with gefi'dni b (250 mg/day) Methods: Buocal smears ware obtained before therapy and after 2 weeks of tTeatment, by scraping Protein espression was evaluated by immunooftcohamislT,/and flow cytomet]-y Toxicity was assessed monthly by clinieal esaminatlon and blood oounts and chemistry. Objective response was assessed every 2 months by CT scan. Forty one patients were enrolled and 31 are so far fully evaluablo. Results: Four patients had a partial response (PR). and all showed a t]'ond to reduction in expression of EGFR p (I.e. 40%+ vs 15%+). p M A P K (50%