bluuebunny/crossref_metadata_2025_split huggingface dataset:
The activity of CKD601, telomerase inhibitor, against gastric cancer cell lines and resistance mechanism, which is associated with hTERT expression and ALT
Authors: Jung J. , Park Y. , Jong H. , Im S. , Song Y. , Kim W. , Bang Y. 
Published: March 2020

13126 Background: CKD601, a newly developed telomerase inhibitor, shows an anti-cancer effect through its inhibitory effect on telomerase, by intercalation of the drug into the structures of the G-quadruplex. No study has been conducted to assess the anti-cancer effects of CKD601 in regards to gastric cancer. We attempted to confirm the anti-cancer effect of CKD601 in the gastric cancer cell line, and to investigate the mechanisms of the anti-cancer effect and resistance in some cell lines. Methods: After long-term drug exposure, we performed Southern analysis, TRAP, and β-Gal staining about the extracted DNA, RNA, and protein from the gastric cancer cell lines and the U2OS cell line to confirm the anti-cancer effect of CKD601. We attempted to investigate the change in the hTERT expression of cancer cells as a result of exposure to CKD601 by RT-PCR and real-time PCR, and to confirm the presence of the ALT (alternate lengthening of telomere) mechanism by metaphase telomere FISH and IF. Results: The anticancer effect of CKD601, including the shortening of telomere, inhibition of telomerase activity, cellular aging, and decreased growth rates, was observed in some gastric cancer cell lines (SNU-1 and SNU-601). SNU-484 and SNU-668 cell lines showed no anti-cancer effect of CKD601. The resistance mechanism of SNU-484 was the significant overexpression of hTERT following exposure to CKD601. ALT, another mechanism that functions in the maintenance of telomere length, was detected in SNU-668 following exposure to CKD601, and it is the resistance mechanism against CKD601. Conclusions: CKD601 is active in gastric cancer by the inhibition of telomerase activity. The resistance mechanisms of gastric cancer cell lines against CKD601 are the induction of the overexpression of hTERT and the ALT mechanism. [Table: see text] No significant financial relationships to disclose.
iMTD (individualized maximal tolerated dose) protocol: A clinical strategy to address interindividual heterogeneity to antiangiogenic therapy
Authors: Li V. W. , Li W. W. 
Published: March 2020

13130 Background: The determination of optimal biological dose is critical to the successful development of antiangiogenic agents. Recent studies suggest that genetic heterogeneity of angiogenesis and interindividual variations in efficacy response to angiogenic inhibitors and their side effects exist. Imiquimod, approved to treat skin cancer, is a topical immune response modifier with antiangiogenic effects mediated by interferons and interleukins. Although efficacy is associated with increased dosing frequency, adverse events are dose limiting. In clinical studies, imiquimod had a 75% efficacy rate in treating basal cell carcinoma (BCC) when dosed 5×/week × 12 weeks, but moderate to severe local inflammation was seen in up to 50%. Methods: The dose frequency that results in gross clinical skin inflammation is one marker of individual heterogeneity. To optimize efficacy while minimizing side effects, we devised a treatment algorithm termed Individualized Maximal Tolerated Dose (iMTD) to determine the optimal treatment frequency per patient. Imiquimod was applied in an incremental titrating fashion to BCC neoplasms (N=52): 2×/wk × 2 wks escalating to 3×/wk × 2 wks, then M-F × 2 wks, then daily × 2 wks. Dose frequency was increased until the threshold of inflammation, then lowered to the last best-tolerated dose. Tumor response and the maximal required/tolerated dose frequency (MTD) for each patient was recorded. Results: The iMTD protocol resulted in 52/52 complete responses with 0/52 cases of undesired inflammation. In order to achieve these results, a significant interindividual variation in dose tolerance was observed: 62% (32/52) required/tolerated 3×/week dosing for complete clearance, 29% (15/52) daily treatment, and 8% (4/52) 5×/week treatment. Conclusions: Because interindividual heterogeneity to response is not addressed in most clinical trial protocols, a single dose frequency among study cohorts generates outcomes that includes both responders and non-responders. When therapy is titratable by dose scheduling, the iMTD strategy may optimize clinical results while minimizing toxicities, a goal of antiangiogenic therapy. No significant financial relationships to disclose.
Dual targeting of EGFR and HER-2 in breast cancer cell lines
Authors: O’Donovan N. , Crown J. P. , Clynes M. 
Published: March 2020

13132 Background: ErbB2 is overexpressed in approximately 25–30% of breast cancers. Recent studies have shown that overexpression of ErbB2 is also frequently associated with expression of ErbB1 and that ErbB1 expression influences response to ErbB2 inhibition. The aim of this study was to investigate the effects of dual targeting of ErbB1 and ErbB2 in ErbB2 overexpressing breast cancer cell lines. Methods: Combinations of Trastuzumab (Herceptin), Gefitinib (Iressa) and Lapatinib (GW572016) were tested in two ErbB2 and ErbB1 positive breast cancer cell lines, SKBR3 and BT474. Proliferation assays were performed using the acid phosphatase assay and apoptosis was measured using the Cell Death Detection ELISA (Roche). The average combinations index (CI) values at ED25, ED50 and ED75 were determined using CalcuSyn. Results: With regard to inhibition of proliferation, dual targeting with Trastuzumab and Gefitinib is additive (CI=0.8) in SKBR3 cells and synergistic (CI=0.6) in BT474 cells. Combined treatment with Trastuzumab and Lapatinib is synergistic (CI=0.5) in SKBR3 cells and additive (CI=1.0) in BT474 cells. Dual targeting with Gefinitib and Lapatinib is antagonistic in both cell lines. Trastuzumab (10 nM) alone and Gefitinib (5 μM) alone did not induce significant apoptosis in SKBR3 cells whereas Lapatinib (0.75 μM) alone induced apoptosis and in combination with Trastuzumab enhanced apoptosis induction. Combined treatment with Trastuzumab (10 nM) and Gefitinib (5 μM) induced apoptosis comparable to Lapatinib alone (0.75 μM). Conclusions: Our results suggest that dual targeting of ErbB1 and ErbB2 with combinations of the monoclonal antibody, Trastuzumab and tyrosine kinase inhibitors may improve response to treatment in a sub-group of patients with ErbB2 overexpressing tumours that also express ErbB1. Interestingly, the apoptosis assays suggest that inhibition of both ErbB1 and ErbB2 is required to efficiently induce apoptosis in cells which express both receptors. [Table: see text]
A phase 1 study of daily oral perifosine (P) with every 3-week paclitaxel (T)
Authors: Goggins T. F. , Nemunaitis J. J. , Shiffman R. , Birch R. , Berdeaux D. H. , Rettenmaier M. , Diaz-Lacayo M. , Henderson I. C. 
Published: March 2020

13134 Background: Perifosine is a novel alkylphospholipid that has been shown to affect multiple signal transduction pathways including Akt, MAPK and JNK (Kondapaka, Mol. Canc. Ther 2: 1093–1103. 2003). Treatment with a taxane initially activates Akt, and persistent activation increases resistance to the drug (Vanderweele, Mol. Canc. Ther. 3: 1605–13, 2004). Methods: Twelve patients (pts) were enrolled on this study. T was given at a dose of 175 mg/m2 on day 8 (after 7 days of perifosine) of a 21 day cycle; this was to obtain a steady state level of P at the tumor before exposure to T. The intent of the protocol was to determine if full dose P could be delivered with 50 mg of perifosine given orally 1, 2 or 3 times a day on days 1–14 of each cycle. Results: Disease sites included lung 3, thyroid 3, breast 1, esophagus 1 and other 4, Median age was 66 (range 45 - 83); 6 pts were male and median ECOG performance status was 1 (range 0–2). All pts had received prior chemotherapy (median 2 regimens); 3 had prior treatment with a taxane. Three pts were entered at each dose level and the cohort expanded to 6 pts if 2 or more pts experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose level was toxic if 4 or more pts experienced a DLT during cycle 1. A total of 30 cycles and a median of 2 cycles (range 1–11) per patient were delivered. There were no grade 3/4 hematologic toxicities. Full dose T was given in all treatment cycles. P dose reductions were required in 6% of cycles (50 mg - 7%, 100 mg - 0%, 150 mg - 7%). One patient missed one dose due to nausea and one pt was stopped due to diarrhea. The grade 3 toxicities for each cohort are given in the table below. The elevated glucose value was 321. Nine pts were evaluable for response; two pts with thyroid cancer had stable disease by the RECIST criteria for 9 and 10+ months. Conclusions: In this study the usual single agent doses of P (150 mg daily) & T (175 mg/m2 q 3 weeks) were given together without increasing the toxicities that would be expected from using each drug alone. Phase II studies are warranted to define activity of the combination. [Table: see text] [Table: see text]
Modification in expression of EGFr, p53, and pTEN in non small cell lung cancer (NSCLC)
Authors: Bayle S. , Penault-Llorca F. , Robinet G. 
Published: March 2020

13151 Background: Treatment inhibiting tyrosine kinase domain of EGFr have proved dramatically efficient in NSCLC. Even if several studies have revealed predictors of treatment response, - such as gender, adenocarcinoma histology, gene mutations, or Asian origin-, response to treatment remains random and is not correlated with an initial overexpression of EGFr by the tumor. The efficiency of those EGFr inhibitors was only shown in second- or third-line treatments, and studies using them in first-line treatments, particularly when combined, had no positive outcome. We have therefore assessed the expression of EGFr in NSCLC before and after cisplatin-based chemotherapy to see if it modified the level of expression of either EGFr, or of molecules including its chain of activation, such as P53 or pTEN. Methods: Tumor samples were obtained from patients treated for NSCLC. We retrospectively studied the bronchial samples of all the patients treated for NSCLC in Brest University Hospital for 6 months. Patients with treatment response whose control samples were negative were not included. We extracted paraffin embedded samples from NSCLC before and after cisplatin-based chemotherapy. For all cases EGFr expression has been assessed with the Ventana CONFIRM TM EGFr 3C6 antibody, P53 expression with the DAKO P53 D07 kit, and pTEN expression with Novocastra antibody. Intensity was scored 0, 1+, 2+, 3+. Results: Data on 30 patients are available, 27 males and 3 females. 70% of tumors show overexpression of EGFr before chemotherapy, and 63.3% after, which has no stastistical significance. The same was observed for pTEN and P53, whose level of expression is similar before and after treatment. The level of expression of P53, pTEN, and EGFr is not correlated with gender or histological type. However, EGFr expression tends to increase after chemotherapy for the subsets of adenocarcinoma and women, but this remains statistically non-significant. Conclusions: Cisplatin-based chemotherapy does not seem to modify the expression of EGFr nor its chain of activation. However, the level of expression, particularly for EGFr, seems to be higher after chemotherapy for the subsets of adenocarcinoma and women. No significant financial relationships to disclose.
Sensitization of pancreatic cancer cells to ApoG2 induced killing by curcumin
Authors: Thoutreddy S. , Ali S. , Mohammad R. , Sarkar F. H. 
Published: March 2020

13152 Background: In pancreatic cancer, several important survival molecules such as NF-kappa B and Bcl-2 or Bcl-XL are highly activated. Thus agents that inhibit NF-KappaB activation, together with agents that inhibit Bcl-2 or Bcl-XL protein function, may lead to enhanced cell killing. ApoG2, a new derivative of natural product gossypol, is a potent small molecule inhibitor of Bcl-2 and Bcl-XL proteins. Curcumin, an active ingredient from the rhizome of the plant, Curcuma longa, has anti-inflammatory and anti-cancer activities and works by inactivation of NF-Kappa B activity. In this study we have investigated the effects of curcumin on ApoG2 induced apoptosis. Methods: The BxPC-3 human pancreatic cancer cell line was used in this study. ApoG2 was dissolved in DMSO at 1 mM stock solution, and curcumin was dissolved in DMSO at 20 mM stock solution. Cell viability was determined by the standard MTT assay and apoptosis was measured by histone/DNA ELISA method. Results: Pretreatment of human pancreatic cell line BxPC-3 with curcumin sensitizes ApoG2 induced cell killing. In the dose escalation with ApoG2 at 48 hrs on MTT assay, 250 nM showed 75% cell viability, while 2.5 uM of curcumin at 72 hrs showed 80% cell viability. Pretreatment with curcumin for 24 hrs followed by ApoG2 at 48 hrs showed 55% cell viability (p = 0.0005). Apoptosis by histone/DNA ELISA showed 4-fold induction of cell death with ApoG2 at 48 hrs, 7-fold induction of cell death with curcumin at 72 hrs. However, pretreatment with curcumin for 24 hrs followed by ApoG2 at 48 hrs showed 10-fold induction in apoptosis compared to the control. Conclusions: From these results, we conclude that curcumin enhanced ApoG2 induced cell growth inhibition and apoptosis of BxPC-3 cells. No significant financial relationships to disclose.
Response to EGFR inhibitors in fibroblast cell lines and its association with germline polymorphisms
Authors: Liu W. , Montenegro R. C. , Zhang W. , Ratain M. J. 
Published: March 2020

13167 Background: Only a small number of cancer patients benefit from therapy with EGFR inhibitors. It is therefore important to understand the mechanism of action of these drugs and to find predictive markers for drug response. Although somatic mutations and gene amplification have been correlated with the efficacy of EGFR-targeting therapy, cancer cells and/or patients with normal EGFR expression are also sensitive to these drugs. We then aim to further understand the mechanism underlying the predisposition to sensitivity to EGFR inhibitors in germline cells. Methods: We chose 70 human normal fibroblasts cell lines as an in vitro model. Cytotoxicity studies were performed on these cells using two EGFR inhibitors, gefitinib (G) and AG1478 (AG). Cells were incubated with serial concentrations of the drugs (10, 20, 40 and 60 μM for G and 5, 10, 15 and 20 μM for AG) dissolved in DMSO. Growth inhibition was measured by Alamar Blue. Three polymorphisms, −216G/T, R497K and intron 1 (CA)n, were genotyped in these cells. EGFR expression was measured with real-time PCR. Results: There was considerable variability in drug response in a dose-dependent manner among these cells. The two drugs behaved quite differently. The fibroblasts had a much more variable response to G (mean of coefficient of variance of survival rates under all 4 concentrations, 61%) when compared to the response to AG (26%). Drug response was not correlated with EGFR expression. A significant correlation was observed between the R497K polymorphism and the survival rate of cells treated with AG at 5 μM (p<0.01) and 10 μM (p<0.05) with higher growth inhibition in K allele-carriers. No correlation was observed between any of the three EGFR polymorphisms and G cytotoxicity. Conclusions: These observations suggest that the cytotoxic effects of G and AG are due to different mechanisms, and that other genes such as transporters may also contribute to drug response. The R497K polymorphism may be useful as a predictive marker for response to AG and/or similar agents. No significant financial relationships to disclose.
Fluorescent antibody tagging of colon cancer in the nude mouse; a model for improved surgical accuracy in the oncologic patient
Authors: Luiken G. A. , Xu M. , Quigley M. M. , Hoffman R. M. , Chan A. D. 
Published: March 2020

13501 Background: Induced fluorescence of malignant tumors has the potential to improve the surgeon’s ability to accurately identify and excise all malignant tissue. Tumors can be made fluorescent using fluorophore-tagged anti-tumor antigen antiboies. We present here our results using a human colon cancer cell line in the nude mouse model. Methods: HCT 116 colon cancer cells were subcutaneously or orthotopically implanted in 16 nude mice (12 study mice and 4 control mice). Two to 8 weeks after injection, tumor nodules were easily detectable. Using the tail vein method, all mice were injected with fluorophore-tagged anti-CEA or fluorophore-tagged IgG. Mice were examined using a small animal imaging system with a 470 nm light source and appropriate filters. They were also examined using a simple blue LED flashlight fitted with a fixed 470 nm band pass filter for illumination and were observed through filtered goggles. Results: All tumor nodules in the study mice demonstrated green fluorescence when visualized through the skin. On dissection and exposure of the tumor nodules, this fluorescence was intense and clearly distinguishable from the surrounding normal tissue using either the imaging system or the blue LED. Very small (<0.5mm) metastatic nodules were easily identified. Bright tumor fluorescence remained visible up to 5 days after injection. Control mice injected with fluorophore-tagged IgG and examined in a similar manner revealed no tumor fluorescence. Minimal non-specific dull fluorescence was occasionally observed in gut mucosa and ovarian tissue but was easily distinguished from the bright tumor fluorescence. Conclusions: When tumor surface antigens are known and antibodies to those antigens are available, this technology is simple, easy to perform, requires no technically complex equipment or operator expertise and could be readily adapted for cancer surgery in the academic or community hospital setting. Major indications for this technology would be in those patients where tumor resection offers an excellent chance for cure or significantly improves survival. The implications for increased accuracy of procedures such as resection of primary colorectal cancer or resection of solitary hepatic or pulmonary metastases are clear. No significant financial relationships to disclose.
Patterns of failure and outcomes in anal adenocarcinoma
Authors: Gonzalez R. J. , Chang G. J. , Skibber J. M. , Feig B. W. , Eng C. , Janjan N. , Crane C. H. , Rodriguez-Bigas M. A. 
Published: March 2020

13503 Background: Adenocarcinoma of the anal canal is a rare malignancy with an aggressive natural history. The purpose of this study is to evaluate the outcomes of a multidisciplinary approach in patients with anal adenocarcinoma. Methods: A retrospective review was performed of patients with anal adenocarcinoma identified from the M.D. Anderson Cancer Center (MDACC) tumor registry between 1983 and 2004. Distal rectal cancers were excluded by pathologic review. Patients were classified according to treatment type: chemoradiotherapy (CXRT) ± local excision or radical surgery (RS) ± chemoradiation. Overall survival, and patterns of failure were assessed. Results: 41 candidate patients were identified. Thirteen patients were excluded (10 misclassified, 3 no treatment or followup at MDACC). Of the remaining 30 patients, 27 had localized disease and were treated with curative intent. 26 patients received radiation, 23 of the 26 with concurrent 5-FU based chemotherapy. Eleven patients (41%) received additional 5-fluorouracil-based adjuvant chemotherapy following primary treatment. Twelve patients were in the CXRT treatment group and 15 were in RS (1 did not receive chemoradiation). Median follow-up was 28 months (range 5–195). Median overall survival for the entire cohort was 59 months with an actuarial 5-year survival of 47%. Rates of recurrence are shown in the table below. Three patients with local failure were treated with salvage abdominoperineal resection and all developed subsequent failure (2 distant, 1 local). The fourth patient refused surgery and subsequently developed disease progression. Conclusions: Adenocarcinoma of the anal canal has a poor prognosis and accurate histologic diagnosis should be pursued. Although limited, our experience demonstrates that the most common pattern of failure is distant. An aggressive multimodal approach results in good local control but improvements in chemotherapeutic strategies are needed. [Table: see text] No significant financial relationships to disclose.
Capecitabine plus oxaliplatin (XELOX) followed by capecitabine plus irinotecan (XELIRI) in a sequential schedule in first-line metastatic colorectal cancer (MCRC): a phase II multicenter study
Authors: Cassinello J. , Álvarez J. V. , García-López M. J. , Pujol E. , Colmenarejo A. , De Segovia F. , Marcos F. , Filipovich E. , García Castro I. , Arcediano A. 
Published: March 2020

13516 Background: In phase II trials, XELOX and XELIRI were highly active and well tolerated in first-line MCRC. The aim of this study is to explore the efficacy and safety of XELOX followed by XELIRI as first-line treatment in MCRC. Specifically, we wanted to evaluate the impact of sequential scheduling on the dose-limiting neurotoxicity associated with oxaliplatin accumulation. Methods: Eligible patients (pts) had histologically or cytologically confirmed MCRC, ECOG PS ≤ 2 and adequate bone marrow, renal and hepatic function. Prior chemotherapy for MCRC was not allowed. Pts received 4 cycles of XELOX (capecitabine 1000mg/m2 orally bid d1–14 + oxaliplatin 130mg/m2 i.v. d1, q3w) followed by 4 cycles of XELIRI (capecitabine 1000mg/m2 bid d1–14 + irinotecan 240mg/m2 i.v. d1, q3w). This sequential schedule was repeated until unacceptable toxicity or disease progression. Results: Of the 35 pts analized to date: M/F (69%/31%); median age 68 years (range 41–78); ECOG PS 0–1 (94%); surgery (77%) and adjuvant chemotherapy (31%). 240 cycles (median 6, range 1–16) have been administered. 35 pts received XELOX (123 cycles, median 4), and 21 pts received XELIRI (83 cycles, median 4) in the first sequential schedule. In the second sequential schedule 6 pts received XELOX (22 cycles, median 4) and 4 pts received XELIRI (12 cycles, median 3.5). Median relative dose intensity was 88% for XEL, 96% for OX and 92% for IRI. In 27 efficacy evaluable pts, the ORR was 48% (95% CI, 29–67%). Eight pts were not evaluable due to adverse events (n=6), ongoing treatment (n=1) and lost of follow up (n=1). Conclusions: This sequential schedule is active and well tolerated in first-line MCRC. The improvement/recovery of the oxaliplatin-related neurotoxicity during the XELIRI phase is also promising and allows the re-treatment with oxapliplatin in the next sequence without accumulating neurotoxicity. Final results will be presented at the meeting. [Table: see text] No significant financial relationships to disclose.