bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Brazilian native medicinal plants on VEGF and PDGF receptors expression by glioblastoma cell line GL-15
Authors: Mathias C. , Nascimento I. , Carvalho G. , Meyer R. , Queiroz A. , Freitas S. , Freire S. , Veloso E. , Barbosa P. , Costa S. , Azevedo C. 
Published: March 2020

12532 Background: Malignant gliomas are typically angiogenic and express greater amounts of angiogenic factors. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are prominent glioblastoma-associated multifunctional cytokines that stimulate migration, invasion and angiogenesis. Their receptor inhibiton is considered an important target for anitumoral therapy. Flavonoids obtained from Dimorphandra mollis and Croton betulaster, native medicinal plants from Bahia-Brazil, have been described as proliferation inhibitors of a human glioblastoma derived cell line and reduce VEGF production by GL-15. In this study, VEGF and PDGF receptors expression by GL-15 cultures treated with bevacizumab and flavonoids were evaluated. Methods: GL-15 cultures were treated or not with pendulitin and rutin flavonoids (100μM) and bevacizumab (1μg/mL). After 24 hours VEGF and PDGF receptors were analyzed by flow cytometry using monoclonal antibodies labeled with FITC. Results: Flow cytometry showed that the GL-15 cells expressed PDGFR alfa (10%), PDGFR beta (52%), VEGFR 1 (26%) and VEGFR 2 (95%). It was observed that the pendulitin and rutin flavonoids treated cells showed a reduction on PDGFR alfa expression (2 and 1,6 % respectively) but the other receptors expression was similar to the non-treated or DMSO treated controls. Conclusions: GL-15 human glioblastoma derived cell line expresses receptors to the angiogenic cytokines studied. VEGFR 2 expression was predominant and bevacizumab didn’t alter the receptors production. Flavonoids extracted from D. mollis and C. betulaster seem to have an inhibitory action on the PDGRF alfa expression but not on the others receptors. No significant financial relationships to disclose.
Comparing carboplatin dose administered to the calculated dose using the Modification of Diet and Renal Disease (MDRD) equation
Authors: Villano J. L. , Bressler L. , Radhakrishnan L. , Cuellar S. , Shord S. S. 
Published: March 2020

13003 Background: Renal function assessment is vital for dosing of chemotherapy drugs. GFR is usually estimated by creatinine clearance (CrCl). The MDRD equation is thought to provide a more accurate estimation of GFR than the Cockcroft-Gault or 24-hour CrCl measurement. Although this formula has been validated in kidney disease, it has not been extensively studied in cancer patients. Methods: We retrospectively reviewed records for patients who received carboplatin from the University of Illinois at Chicago for a 4-year study period. General demographic information, carboplatin dose for cycles one to three, and common laboratory parameters at baseline and following cycles one to three were collected. The MDRD derived value of GFR was then used in the Calvert equation to calculate carboplatin dose. This calculated dose was compared to the actual dose administered in the first cycle. From this comparison, the records were divided into two groups: (A) actual vs. calculated dose ≥ 20% and (B) actual vs. calculated dose < 20%. We then assessed toxicity by determining the frequency in each group requiring dose reduction on the second cycle of carboplatin. Results: Data are available for 116 patient comparisons. 78 patient comparisons were in group B with agreement between actual vs. calculated MDRD dose. 38 were in group A with 36 having the actual dose being ≥ 20% less than the MDRD-calculated dose. Wilcoxin and Chi analysis reveals statistical significance for African American, women, lower serum creatinine, and older age for Group A. In Group A, cycle 2 dose reductions were made in 3 cases (8% and due to hematologic). In Group B, cycle 2 dose reductions were made in 12 cases. In 8 of these cases (10%), dose reductions were based on ANC, and in 4 cases dose reductions were made likely on the basis of changes in weight or creatinine. Conclusion: In the comparisons examined to date, differences in carboplatin doses due to different methods of calculation do not appear to significantly influence the frequency of dose reduction. Factors used in calculating MDRD such as age, sex, serum creatinine, and ethnicity were variables associated with ≥ 20% difference in actual vs. calculated MDRD dose. No significant financial relationships to disclose.
Prevention of base excision repair by TRC102 (methoxyamine) potentiates the anti-tumor activity of pemetrexed in vitro and in vivo
Authors: Liu L. , Bulgar A. , Donze J. , Adams B. J. , Theuer C. P. , Gerson S. L. 
Published: March 2020

13005 Background: TRC102 (methoxyamine) reverses resistance to alkylating agents by inhibiting base excision repair (BER; a mechanism of DNA repair), thereby increasing DNA strand breaks and potentiating the anti-tumor activity of alkylating agents without additional toxicity, Based on these data, TRC102 is currently being studied in combination with temozolomide in a phase 1 trial. We hypothesized that inhibition of BER by TRC102 would also increase DNA strand breaks and improve the anti-tumor activity of anti-metabolite chemotherapeutics, including pemetrexed, because these agents also produce AP sites that are recognized and repaired by BER. Methods: Pemetrexed- induced AP sites and BER inhibition was quantified using an apurinic/apyrimidinic (AP) site assay in vitro. Single and double DNA strand breaks were quantified by the Comet assay in vitro and anti-tumor activity was assessed in an in vivo xenograft study of subcutaneously implanted H460 human lung cancer cells. Results: Pemetrexed induced and TRC102 reduced the number of available AP sites in pemetrexed- treated H460 cells (by 60–80%), indicating successful inhibition of BER. TRC102 treatment increased DNA strand breaks in pemetrexed-treated H460 cells (2 fold increase versus treatment with pemetrexed alone). Premetrexed treatment alone and in combination with TRC 102 delayed tumor growth in vivo (tumor growth delay of 4.7 days in the 150 mg/m2 pemetrexed alone group, 5.7 days in the 150 mg/m2 pemetrexed + 2 mg/m2 TRC102 group and 6.9 days in the 150 mg/m2 pemetrexed + 4 mg/m2 TRC102 group); in vivo systemic toxicity was not increased. TRC102 alone had no effect in vitro or in vivo. Conclusions: TRC102 effectively inhibits BER in lung cancer cells treated with pemetrexed. Inhibition of DNA repair by TRC102 results in an increase in DNA strand breaks and improved anti-tumor activity versus treatment with pemetrexed alone. Given its preclinical efficacy and safety profile, study of TRC102 combined with pemetrexed in a phase 1 trial is warranted. No significant financial relationships to disclose.
The effect of five different administration intervals on the pharmacokinetics (pk) of paclitaxel (PTX) and pegylated liposomal doxorubicin (PLD) association regimen
Authors: Airoldi M. , Cattel L. , Passera R. , Milla P. , Cerutti E. , Pedani F. , Zanon C. , Crova A. 
Published: March 2020

13012 Background: The PTX-PLD association is a promising schedule for recurrent head/neck cancer. Their pk behavior could be dependent not only on PTX excipient (polyethoxylated castor oil) interference, but even on different i.v. administration intervals between the two drugs. This study evaluated any possible administration interval-dependent pk interaction, when PLD infusion started 0, 1, 3, 12 or 24 h after PTX infusion end. Methods: 25 patients, affected by recurrent cisplatin pre-treated squamous cell head/neck cancer, were randomized to receive PTX 80 mg/m2 q1w and PLD 12.5 mg/m2 q2w at administration intervals of 0, 1, 3, 12 or 24 h. Pk parameters were evaluated during the first course by non-compartmental analysis, while statistical analysis was performed by non-parametric Kruskal Wallis test. Results: Median PK parameters are reported in the table . PTX pk profile is strongly affected by PLD administration. PTX total exposure is highly reduced, with a consequent increase in Cltot; this alteration is totally due to Kel modifications. On the other side, no statistically significant interactions affected PLD pk parameters. Some in vitro experiments indicate that PLD is able to partially absorb PTX, driving to PTX plasmatic concentration reduction, when PLD is administered at 0–1 h intervals. Conclusions: PLD liposomal components seem to be able to entrap PTX, therefore reducing PTX plasmatic concentrations; so, it is very important to choose the ideal administration interval. In order to avoid pk interaction, the i.v. administration interval between PTX and PLD had to be 3 h at least. For shorter intervals, patients could be underexposed to PTX, with lesser clinical efficacy. [Table: see text] No significant financial relationships to disclose.
A mechanistic model predicting hematopoiesis and tumor growth to optimize docetaxel + epirubicin (ET) administration in metastatic breast cancer (MBC): Phase I trial
Authors: You B. , Meille C. , Barbolosi D. , Tranchand B. , Guitton J. , Rioufol C. , Iliadis A. , Freyer G. 
Published: March 2020

13013 Background: Mathematical modeling is a powerful approach to provide functional description of a real process. In medicine and biology, models are established on the basis of available clinical observations and biological covariates. Modeling applied in cancer treatment is a valuable tool to perform drug dosage adjustments. We used this methodology to regulate ET administration by predicting haematopoiesis and tumor growth in patients with MBC in a phase I trial. Methods: We developed a mechanistic model to describe leukopoiesis / thrombopoiesis / tumor growth in MBC patients under bimonthly ET + G-CSF. The model was first validated using data from clinical trials [Viens, Am J Clin Oncol. 2001;24:328, Chugai lenograstim database] and prospectively applied to individualize ET administration (dose rate and duration). The model optimizes the drug doses that could minimize the tumour burden while respecting a priori fixed constraints on deepness / duration of neutropenia and thrombocytopenia. First course administration was fixed ahead. At following courses, schedules were individually adjusted. At first dose level, patients received ET: 85/85 mg over a 48 h period with various, electronically- controlled infusion rates every 2 weeks. At dose level 2, doses were 100/100 mg. Results: Between 06/2005 and 06/2006, 3.5 median courses (range: 2–6) were administered to 6 patients (level 1: 3; level 2: 3). Rates of grade 3–4 neutropenia and thrombocytopenia were 47 and 0 % respectively. Observed toxicities were close to those predicted by the model. Predicted vs. observed neutrophil counts linear regression was significant (p<0.001). Moreover, 83 and 95 % weighted residuals were comprised between [-2; +2] at all courses and first course respectively. No grade 3–4 non-hematological toxicity was observed. Partial responses were noted in 2 patients (33%) and disease stabilization in 3 patients (50%). Conclusions: We report the preliminary results of the first trial using mechanistic modeling to improve cancer chemotherapy. Using this approach, we have successfully predicted the behavior of a complex biological system and individualized drugs administration in a phase I trial. No significant financial relationships to disclose.
Effect of ketoconazole administration on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib in patients with advanced solid tumors
Authors: Chatta G. S. , Rader M. E. , Belani C. P. , Ramalingam S. , Chen E. X. , Cooper M. R. , von Moltke L. L. , Musguire L. A. , Egorin M. J. , Karol M. D. 
Published: March 2020

13016 Background: Bortezomib (btz; VELCADE) is a first-in-class small molecule proteasome inhibitor used to treat patients with multiple myeloma and mantle cell lymphoma. In vitro and in vivo studies indicate that btz is primarily metabolized by CYP3A4 and CYP2C19. We conducted a study to evaluate the effect of inhibition of CYP3A4 with ketoconazole (keto) on the PK of btz in humans. Methods: The study enrolled patients with advanced malignancies for whom standard therapy was not available. Patients received btz 1.0mg/m2 (IV) on days 1, 4, 8, and 11 of a 21-day cycle, and were randomized to receive keto 400mg (PO) on days 6, 7, 8, and 9 of either the first or second cycle of treatment. Blood samples for plasma btz determination were collected over 72 hours following the Day 8 dose in Cycles 1 and 2. PK parameters were computed non-compartmentally. PD parameters were derived from an Emax model of percentage proteasome inhibition in whole blood. Results: Of the 21 patients enrolled, 13 had sufficient PK sampling in Cycles 1 and 2 to assess the effect of keto on the PK of btz. No statistically significant difference in AUC0–72h for btz ± keto was observed (p=0.2248). The mean AUC0–72h ratio was 1.22 (90% CI, 0.92–1.61). The exposure-PD relationships for btz ± keto were similar (Table). Adverse events were similar in the presence and absence of keto. Conclusions: Although the AUC0–72h difference was not statistically significant, the 90% CI for the AUC0–72h ratio extends beyond the FDA- specified range of 0.80–1.25 for DDI studies, precluding a declaration of no effect. The presence of a strong CYP3A4 inhibitor increased mean btz exposure by only 22% and had no apparent effect on the exposure-PD relationship. [Table: see text] No significant financial relationships to disclose.
Multicenter phase II study of chemo-immunotherapy in the treatment of metastatic breast cancer (MBC)
Authors: Recchia F. , Saggio G. , Di Blasio A. , Amiconi G. , Candeloro G. , Necozione S. , Rea S. 
Published: March 2020

13501 Background: Several maintenance chemotherapy (CT) strategies have failed to improve the outcome of MBC. With the aim of enhancing the immune function that could eradicate minimal residual disease, we have previously shown that low dose inteterleukin-2 (IL-2) and 13-cis- retinoic acid (RA) restored the immune function of advanced cancer patients that had a clinical benefit (CB) from CT (Clin Cancer Res, 2001). In this study we report on 100 consecutive patients with MBC treated with sequential CT and immunotherapy. Methods: Patients with MBC were eligible if they had no evidence of progression after 6–8 courses of an anthracycline-paclitaxel induction CT. Treatment consisted of IL-2, 1.8 X 106 IU and oral RA, 0.5 mg/Kg for 5 days/week for 2 cycles of 3 weeks, with a 1- week rest, with intermittent schedules, until progression. Hormonal therapy was given to estrogen receptor (ER) + patients. In order to increase ER expression, beta interferon (1 X 106 IU) was added, subcutaneously, twice a week, to 10 patients with low ER content. Primary endpoint was progression-free survival (PFS); secondary endpoints were toxicity, overall survival (OS) and the evaluation of immunological parameters. Results: From 9/1996 to 9/2001, 100 consecutive patients (median age of 59 years), exhibiting a CB from CT were entered into the study. Grade 2 cutaneous toxicity and fever occurred in 19% and 16% of patients, respectively, while grade 2 autoimmune reaction was observed in 10% of patients. After a median follow-up of 49 months, overall median PFS and OS were 37.1 months and 57.5 months, respectively. Patients with ER+ tumors had a similar response rate to that of patients with ER- tumors but had significantly longer PFS (medians of 44.7 and 32.7 months, respectively) and OS (medians of 64.5 and 51.4 months, respectively). With respect to baseline values, a statistically significant decrease of vascular endothelial growth factor (VEGF) and an improvement in lymphocyte, natural killer cell count and CD4+/CD8+ ratio were observed. Conclusions: IL-2 and RA treatment of women with MBC who achieve a CB after 6–8 courses of anthracycline-paclitaxel based CT, is well tolerated, decreases VEGF, improves the immunological parameters, and seems to delay disease recurrence. A randomized trial is warranted. No significant financial relationships to disclose.
Synergistic antitumor efficacy and altered gene expression signature in breast cancer cells treated with immunotoxins and cyclosporin A
Authors: Fodstad O. , Xi Y. , Risberg K. , Ju J. , Anderson Y. G. 
Published: March 2020

13505 Background: Immunotoxins (ITs) has shown limited clinical success related to liver toxicity and development of anti-IT antibodies. To delay the immune response we tested combinations of ITs and the Cyclosporin A (CsA). we have shown that one IT, currently in a phase I/II clinical trial, acts by inducing apoptosis and protein synthesis inhibition, but gene expression analysis of IT treated cells has never been reported. Hence, we also studied changes in gene expression induced by ITs alone and the effects of adding (CsA) on both treatment efficacy and gene expression signature. Methods: Human MA-11 breast cancer cells were treated in vitro with antiEGFR- and antiEPCAM-based ITs alone and in combinations with CsA. Therapeutic efficay was assessed by MTS cell viability assay. Total RNA from untreated and treated cells was isolated and CodeLink Uniset Human 20 k Oligo Bioarray (GE Healthcare, Amersham Biosciences, NJ), containing approximately 20,289 gene probes, was used to generate gene expression profiles. Gene expression analysis was carried out using GeneSpring software version 7.2 using One-way ANOVA with p<0.05. Comparisons of gene list across different groups were performed using Venn Diagrams. Results: Combination therapy produced remarkable synergistic effects in MA-11 cells in vitro and in metastasis models in vivo. Moreover, in conventional rats receiving repeated injections of ITs and CsA the formation of anti-IT antibodies was virtually abrogated. Changes in gene expression profiles induced by the ITs alone and in combination with CsA were evaluated to elucidate the underlying molecular mechanisms for the synergistic effects. The ITs each induced specific changes in expression of some apoptosis-related genes but also fogenes in pathways unrelated to apoptosis and protein synthesis. The addition of CsA induced up- or down-regulation of a number of interesting non-immune-associated genes Conclusions: Important shortcomings for successful clinical use of ITs may be overcome by combination therapy with CsA. The possibility for further improvement is provided by results of gene profiling studies identifying therapy-induced genes belonging to different cell signaling pathways. No significant financial relationships to disclose.
Preclinical activity of combinations of capecitabine (C), docetaxel (D), and trastuzumab (T) in a breast cancer xenograft model
Authors: Kolinsky K. , Zhang Y. , Moisa C. , Dugan U. , Packman K. , Higgins B. 
Published: March 2020

13508 Background: C is highly active, well tolerated, and extends survival when added to D in pretreated metastatic BC. We report preclinical data on CD doublets ± T, a humanized monoclonal antibody against HER2-neu, in the KPL-4 human BC xenograft model (ER-, HER2+). Methods: Initially, the antitumor activity of optimal dose (OD) and ½ OD C and D monotherapy was evaluated alongside ½ OD C + ½ OD D or ½ OD C + OD D. Data showed ½ OD C + OD D was toxic; thus, OD C + OD D was not considered further. The OD C + ½ OD D doublet and the optimal doublet from the initial study (½ OD C + ½ OD D) were tested ± T in this HER2+ model. Results: In the initial study, tumor response (TR) and increased life span (ILS) were significantly better for ½ OD C + ½ OD D than for ½ OD C, OD C, ½ OD D, or OD D. In the follow-up study, TR and ILS were not significantly different in the ½ OD C + ½ OD D and OD C + ½ OD D doublets but were better with the addition of T to each doublet. In comparing triplicates, TR was not statistically different, and survival was equivalent at this point because of complete responses (CRs) in both groups. At day 127, there were 2/10 CRs in the ½ OD C + ½ OD D + T group (ILS=267%) vs 6/10 CRs in the OD C + ½ OD D + T group (ILS>370%, ongoing). Conclusions: Adding T to the non-toxic CD doublets increases TR and ILS. Thus far, results argue for the most dense dose of C in triplicate combinations for sustaining CRs. However, since CRs are present in both triplicate groups of limited sample size (n=10), an overall survival difference is not yet significant. The data support clinical testing of CD doublets with or without T, which is ongoing in the neoadjuvant setting in HER2- and HER2+ BC patients, respectively. [Table: see text] No significant financial relationships to disclose.
A trial of vaccination with the carcinoembryonic antigen (CEA) peptide CAP 1–6D with montanide ISA 51 adjuvant or granulocyte- macrophage colony stimulating factor (GM-CSF) in HLA-A2+ patients with CEA producing adenocarcinomas of gastrointestinal (GI) track
Authors: Whitehead R. P. , Jantz K. , Simmons A. 
Published: March 2020

13513 Advances in drug therapy have improved the survival of patients with GI tumors but most patients with metastatic disease are not cured. Immunotherapy is an additional modality of treatment. In this trial, the CEA peptide, CAP 1–6D, was combined with either GM-CSF or montanide ISA 51 as adjuvants and used to vaccinate patients with CEA producing GI tumors. End points were development of peptide responsive immunity, toxicity, and anti-tumor effects. To be eligible, patients were required to have a histologic diagnosis of adenocaricnoma of GI tract origin with a life expectancy of at least 6 months and to have either metastatic disease or to have completed standard adjuvant therapy after resection. Patients were required to have a CEA producing tumor, be HLA-A2 positive, have a performance status of 0–1, test negative for HIV, hepatitis B and C, and have adequate bone marrow, liver and kidney function. Treatment consisted of 1 mg of CAP 1–6D peptide combined with either 250 ug of GM-CSF given intradermally, or 2 ml of Montanide ISA 51 given subcutaneously every 3 weeks for 6 treatments. Blood was drawn for ELISpot assay at each visit. Nine (out of a planned 10) patients, 8 with colorectal cancer and 1 with pancreatic cancer, were entered before the peptide was deemed expired and withdrawn from clinical use by the NCI. Of five colorectal patients with metastatic disease at baseline 4 progressed and 1 had stable disease. The pancreatic cancer patient was treated adjuvantly but progressed during therapy. Three colorectal cancer patients treated adjuvantly were free of disease at baseline and at the completion of therapy. Treatments were well tolerated. ELISpot data on 5 patients showed that 4 patients developed peptide responsive immunity. Responsive patients included those receiving either GM-CSF or Montanide ISA 51 and both adjuvantly treated and progressive metastatic colorectal patients and the progressed pancreatic cancer patient. This vaccine regimen can be safely given to cancer patients and can produce peptide responsive immunity in the ELISpot assay but this does not correlate with clinical anti-tumor effect. No significant financial relationships to disclose.