bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pharmacokinetic study of Genetaxyl (G) together with cyclosporin A (CsA) administered orally in cancer patients
Authors: Liau C. , Lepper E. , Wang H. , Yang M. , Chiou T. , Chen P. , Chu Z. , Figg W. , Sparreboom A. , Chen J. 
Published: March 2020

12002 Background: Oral administration of paclitaxel given with CsA has shown promising activity in Phase II trials, but the apparent bioavailability is low and dose-dependent due to the presence of high concentrations of Cremophor EL (CrEL). We hypothesized that the use of a novel oral paclitaxel formulation containing only 20% CrEL (Genetaxyl [G]; Genovate Biotechnology Ltd., Taiwan), given with CsA is associated with an improved pharmacokinetic (PK) profile. Methods: Cohorts of 6 patients with cancer were treated with oral G at a dose of 60, 120, or 180 mg/m2 and 10 mg/kg of oral CsA in cycle 1. In cycle 2, patients received IV G (175 mg/m2, 3-h infusion). Three additional patients received generic IV paclitaxel (GIP). Serial blood samples were analyzed by LC/MS/MS and equilibrium dialysis, to determine total and unbound paclitaxel PK. Results: The mean (± SD) total paclitaxel AUCs were 1299±189, 1682±636, and 2204±1407 ng.h/mL at the 3 consecutive dose levels, suggesting nonlinear PK. However, based on unbound AUC, the oral bioavailability was dose-independent (P=.62), with a mean value of 37.2±18.6% (n=15). As expected, the total paclitaxel AUC following IV G (9024±4648 ng·h/mL) was lower than that for IV GIP (13,732±3983 ng·h/mL), as a result of increased clearance (39.6 vs 18.3 L/h) and a larger volume of distribution (768 vs 268 L). Interestingly, the unbound paclitaxel AUC was similar between the two IV formulations (P=.25), as the ratio of unbound/total paclitaxel for G was 2.5 times higher than that for GIP (12.5 vs 4.9%). Toxicity profiles were mild, with only 2 patients experiencing ≥ Gr 3 myelosuppression following oral G at 180 mg/m2. Conclusions: The mean bioavailability of paclitaxel following oral Genetaxyl with CsA was about 37%, which is higher than that observed previously with paclitaxel (range, 21–31%). Further clinical exploration of oral Genetaxyl in taxane-sensitive diseases is warranted. [Table: see text]
Phase I trial of bortezomib in combination with topotecan in advanced solid tumor malignancies
Authors: Morgan R. , Valdes-Albini F. , Synold T. , Somlo G. , Shibata S. , Chow W. A. , Lim D. , Koehler S. , Frankel P. , Doroshow J. 
Published: March 2020

12004 Background: Bortezomib (B) and topotecan (T) have been shown in pre-clinical testing to be synergistic. Based on this data we have performed a phase I study to determine the maximally tolerated dose and toxicities (tox) of B and T delivered sequentially. Methods: 24 pts (KPS<ECOG 3) with advanced malignancies were treated with T (2.0, 2.5, 3.0 or 3.5 mg/m2 in sequential cohorts) IV on days 1 and 8 of each three week cycle. B 1.3 mg/m2 iv was administered six hours following T on days 1 and 8, and alone on days 4 and 12. Pts were treated in cohorts of 3, the MTD dose was expanded to include 10 additional pts for PK analysis. There was no limit on prior therapies. DLT was defined as any gr 3 or 4 non-hematologic toxicity not reversible in 48h or any gr 3 thrombocytopenia lasting >7 days or associated with bleeding or any gr 4. Results: Tumor types included: breast (4), ovary (5), lung (3), others (12). 24 pts were entered (11M 13F). The median age was 55 (range: 34–83). DLT was thrombocytopenia, observed in two pts at 3.5 mg/m2 and one pt at 3.0 mg/m2 (MTD). Other grade 3 or 4 tox included fatigue, lymphopenia, hypomagnesemia, and hypertriglyceridemia. Of the 24 enrolled pts, stable disease was observed in 4 (4 or 5 cycles), 9 progressed, 5 were inevaluable and 6 are too early. PK analysis is pending. Conclusions: T and B delivered sequentially are well tolerated on a weekly schedule. DLT is thrombocytopenia. PK will be presented.(Supported by NCI Grant CA33572). [Table: see text]
Chemosensitisation by poly(ADP-ribose) polymerase-1 (PARP-1) inhitor 5-aminoisoquinoline (5-AIQ) on various melanoma cell lines
Authors: Radulovic S. , Bjelogrlic S. , Todorovic Z. , Prostran M. 
Published: March 2020

12019 Background: PARP-1 facilitates DNA strand brakes repair and PARP inhibitors were investigated as enhancers of chemoradiotherapy. We investigated whether 5-AIQ potentates the effect of doxorubicin (DOXO), cisplatin (CDDP) and paclitaxel (Ptx) on human (slow-growing) FemX and murine (fast-growing) B16 melanoma cell lines. Methods: Twenty-four hours after cells were seeded in 96 well plates, cytotoxic drugs and 5-AIQ were added to cell medium. For evaluation of single-agent activity, drugs were applied in concentration ranges as follows: CDDP (0.3–30 μM), DOXO (0.1–3 μM), Ptx (1–100 ηM), 5-AIQ (1–100 μM). 5-AIQ (3μM) was combined with CDDP (0.1, 0.3, 1 μM), DOXO (10, 3, 100 ηM), or Ptx (1, 3, 10 ηM). Incubation lasted for 72 hrs when SRB assay was utilized to determine individual and combine activity (interactions calculated with isobole method). For cell cycle analysis B16 cells were seeded on 6 well plates and treated with each drug alone and combinations, using the same concentrations as those for investigation of combine cytotoxic activity. Cell cycle was determined after 72 hrs, on FACS Calibur with propidium iodide dye. Results: 5-AIQ induced minimal changes in cell viability and cell cycle progression on both cell lines, compared to non-treated control. CDDP revealed high activity against FemX (IC50 = 2.85 μM) and B16 cells (IC50 = 8.84 μM), and G0/G1 arrest. In B16 cells 5-AIQ multiply enhanced CDDP’s activity with strong synergistic interaction and cells slightly driven to S phase. Synergism was also detected on B16 cells treated with combination of DOXO (IC50 = 0.2 μM on B16 and 0.89 μM on FemX) and 5-AIQ when DOXO was applied in low concentrations (10 and 30 ηM), while 5-AIQ did not interfere with cell cycle changes. Cytotoxicity of Ptx (IC50 = 6.16 ηM on B16 and <1 ηM on FemX) was stimulated only at higher concentrations. 5-AIQ stimulated G0/G1 and S phase arrest on B16 cells with Ptx of 3 and 10 ηM, respectively. In FemX cells, most of the interactions of 5-AIQ with CDDP, DOXO, and Ptx revealed as antagonistic. Conclusions: PARP-1 inhibitor 5-AIQ enhances cytotoxic activity of both DNA damaging and agents with different mechanism of action, but the effect varies between cell lines with different proliferation rate. No significant financial relationships to disclose.
A dose escalation trial of fixed dose gemcitabine and capecitabine
Authors: Morgan Meadows S. , Van Ummersen L. , Brandon H. , Oliver K. , Houston M. , Eickhoff J. , Wilding G. 
Published: March 2020

12026 Background: Gemcitabine can be administered as a 30-minute infusion or a prolonged, fixed-dose infusion (FDR). FDR may have improved clinical activity. Gemcitabine and capecitabine have non-overlapping mechanism of activity. This phase I trial explored the combination of FDR gemcitabine plus capecitabine. Methods: Patients received gemcitabine (G) as a fixed dose on day (D) 1 and 8 and capecitabine orally D1–14 of a 21-day cycle. Capecitabine (C) dose was fixed at 500 mg/m2 twice daily (BID) with escalating doses of G, beginning at 400 mg/m2. The trial was a standard phase I trial with cohorts of three. Dose-limiting toxicity (DLT) was defined as febrile neutropenia, grade 3/4 neutropenia lasting > 7 days, grade 3/4 thrombocytopenia lasting > 7 days, grade ¾ nausea/vomiting despite maximal anti-emetic therapy, grade 3/4 diarrhea, or grade 3/4 hand-foot syndrome. Results: Nine patients have enrolled to date, receiving a total of 56 courses at dose level one (G 400 mg/m2, C 500 mg/m2 BID). Median age is 61 (range 47–61). Grade 3 neutropenia has been the predominate toxicity, occurring in 12.5% of courses. One patient with renal cell carcinoma had a partial response. Four additional patients had prolonged stable disease lasting 7–15 months. Prolonged stable disease was observed in two patients with cholangiocarcinoma, one patient with renal cell carcinoma and one patient with anal squamous cell carcinoma. Conclusions: This combination has manageable toxicity with some evidence of activity at G 400 mg/m2 and C 500 mg/m2 BID. Dose escalation continues. No significant financial relationships to disclose.
A biodistribution of 5-fluorouracil co-administered with and without galactomannan derivative, in athymic mice implanted with COLO 205 human xenografts
Authors: Zomer E. , Klyosov A. , Platt D. , Stevens R. 
Published: March 2020

12027 Background: The polysaccharide [(1–4)-linked β-D-mannopyranose]17- [(1–6)-linked-α-D-galactopyranose]10 (Davanat [D]), enhances activity of 5-Fluorouracil (5-FU) in 5-FU refractory murine colon tumor models. D binds to surface lectins and promotes transport of 5-FU into the tumor cells. Lectins are present in large amounts on the surface of metastatic tumor cells, and may mediate cell association, apoptosis and metastasis. Method: A preclinical biodistribution study was initiated to evaluate the intravenous (i.v.) administration of 5-FU (36 mg/kg/dose) in the absence and presence of D (60 mg/kg/dose) in female athymic mice with tumors. Forty mice either received 5-FU alone or with D on days 24–27 (Q1d × 4) after tumor implantation. On day 27, a (2-14C) labeled 5-FU was added to the regimen. After the injection, ten mice per time point (0.5, 1.5, 4 and 24 h) were bled, euthanized and then the plasma, tumor and tissues were assayed for radioactivity by a liquid scintillation analyzer. Objectives were to determine the biodistribution of 14C-5-FU in the absence and presence of D in plasma, tumor and tissues. Results: 14C-5-FU disappeared in a bi-phasic manner after i.v. injection both in the presence and absence of D. Addition of D increased the amount of 5-FU exposure as measured by area under the curve (AUC) from 1.5 to 24 hours post-dose. This finding confirms results from a Phase I study where administering escalating doses 30 to 280 mg/m2 D with fixed 500 mg/m2 5-FU also demonstrated an increase in 5-FU systemic exposure as the D dose increased to 280 mg/m2 Conclusions: In mice, 14C-5-FU dosed with D increased the overall exposure of 14C-5-FU during the 1.5 to 24 hr sampling time duration in plasma, tumor and kidneys, when compared to 14C-5-FU dosed alone. These results, and the results obtained from a Phase I study where D was co-administered with 5-, warrants further testing in a Phase II/III clinical trial. [Table: see text]
Gemcitabine (G) given as a prolonged infusion in patients (pts) with advanced solid tumors: A phase I study with intra-pt dose escalation (DE) and pharmacokinetic (PK) / pharmacodynamic (PD) analysis
Authors: Soulié P. , Luet D. , Dupuis S. , Boisdron-Celle M. , Guérin-Meyer V. , Abadie S. , Leproust B. , Maillart P. , Delva R. , Gamelin E. 
Published: March 2020

12029 Background: Optimizing drug delivery based on pharmacokinetic data is an important research issue. Previous studies have demonstrated a pharmacological advantage for infusions of G with a fixed dose rate to maximize cellular accumulation of G active metabolite (GTP), despite high interindividual PK variability. Methods: To develop a PK-guided G dosing schedule, we conducted an intra-pt G DE trial to determine: (1) maximum tolerated dose level (MTD) and dose-limiting toxicity (DLT), (2) plasma G and peripheral mononuclear cell GTP post-infusion levels. G was administered over 150 min on day 1, 8 and 15, q4w. The initial dose level (DL) was 1000 mg/m2, escalated by 250 mg/m2 every cycle (cy) if no limiting toxicity occurred. Results: From 09/2003, 30 pts entered the study. Pts’ characteristics: 16 men/14 women; median age 66 years (49–81); tumor type: pancreas (10 pts), lung (7 pts), others (13 pts); prior chemotherapy (15 pts). A total of 109 cy were given (median: 3 cy/pt). Tolerance: Number of pts/DL: DL1 = 7 pts, DL2 = 5 pts, DL3 = 11 pts, DL4 = 5 pts, DL5 = 2 pts. Main reasons for stopping DE were: disease progression/early death (15 pts), DLT (4 pts), investigator’s decision (8 pts). DLT were: haematological (1 pt), asthenia (2 pts) and infection (1 pt). Most common grade (gr) 1–2/3–4 toxicities (% cy) included: nausea/vomiting (38%/2%), asthenia (56%/11%), neutropenia (29%/27%) and thrombocytopenia (42%/1%). Activity: 26 pts are evaluable (radiological assessment every 3 cycles) showing 5 partial response (2 unconfirmed), 7 stabilization and 14 progression. Conclusions: The main reason for DE failure was early progression, stressing the importance of an early individual dose adjustment. PK and PK/PD correlation analyses are ongoing to confirm our hypothesis. No significant financial relationships to disclose.
Recombinant arginase as a novel anti-melanoma agent
Authors: Hsueh E. C. , Knebel S. , Collier I. , Kadze M. , Hsueh C. , Lo T. , Cheng P. , Leung T. 
Published: March 2020

12032 Background: BCT-100 is a recombinant arginase comprised of 329 amino acid residues. Arginase converts arginine to urea and ornithine. Previous studies suggested that melanoma cells were auxotrophic for arginine due to absence of argininosuccinate synthetase (ASS) expression. Thus, we hypothesized that recombinant arginase, BCT-100, is cytotoxic to human melanoma cells and its cytotoxicity correlates with absence of ASS expression. Methods: BCT-100 pegylated recombinant human arginase was manufactured by large scale fermentation of a recombinant B. subtilis strain LLC101 encoded with a human arginase gene. Following fermentation, the recombinant protein was extracted, purified, pegylated, and ultra-dialyzed. Ten established human melanoma cell lines were used. Cells were grown to 90% confluence, harvested, and plated at 104 cells per well in a 96-well plate and co-cultured with increasing concentrations of pegylated BCT-100 for 72 hours. CellTiter 96 Aqueous Non-radioactive Cell Proliferation Assay (Promega, Madison, WI) was used to measure percent viability, with absorbances measured at 490 nm. Total cellular RNA was isolated from established melanoma cell lines converted to cDNA at a concentration of 5 ng/ul. Quantitative real time polymerase chain reaction was performed on a 7300 Real Time PCR System, using Gene Expression Assays for ASS and GAPDH (Applied Biosystems). 10,000 fold standard curves were generated for all samples using GAPDH expression. Results: All ten cell lines demonstrated decreased viability as concentrations of BCT-100 increased. Average IC50 value was 0.11 IU/ml. Eight of the 10 cells lines have IC50 values < 0.1 IU/ml. Of the 8 cell lines with IC50< 0.1 IU/ml, all of them have low or undetectable ASS expression using quantitative RT-PCR. Of the 2cell lines with IC50 > 0.1 IU/ml, ASS expression was detected in 1 of 2. Conclusions: Arginine depletion with recombinant arginase, BCT-100, was cytotoxic to melanoma cells in vitro. The cytotoxic effect of BCT-100 on melanoma cells correlated with expression of argininosuccinate synthetase. BCT-100 is a promising novel agent for treatment of melanoma. Further in vivo experiment with BCT-100 is ongoing. [Table: see text]
Prostate cancer: Autologous immunotherapy optimized by indoleamine-2,3-dioxygenase (IDO)-inhibitor as immune-tolerance breaker
Authors: Lasalvia-Prisco E. M. , Garcia-Giralt E. , Cucchi S. , Larrañaga J. , Wagner D. 
Published: March 2020

12509 Background: In several peer review publications (Cancer Biol Ther 2003) our team has reported a procedure of cancer immunotherapy using an autologous thermostable hemoderivative vaccine (ATHV) with anti-progressive tumor effect in metastatic malignant disease from different primary tumors including prostate cancer. Last year (ASCO Meeting 2005) we have reported that the tolerance break for tumor associated antigens through the interference with CD4+CD25+ regulatory cells is a component of the mechanism of action of the ATHV antitumoral effect. Therefore, we have intended to optimize this autologous immunotherapy adding to the procedure different steps of immune-tolerance blockage selected due to their proven efficacy in pre-clinical models and their feasibility in the frame of ATHV technology. In this study we report the results in prostate cancer when the adjuvant step added was the translational knowledge the tolerance blockage by IDO-inhibition through 1-Methyl-Tryptophane or 1-MT (Munn DH et al J Exp Med 1999). Methods: Thirty metastasic prostate cancer patients, hormone and chemotherapy resistant, Performance Status ≤ 2 and PSA progressing serum level, were included in this institutional-IRB approved phase I/II trial. The patients were randomized in 3 groups submitted to 3 different treatments: I, only sympthomatic; II, the previously reported ATHV and III, ATHV + simultaneous s.c. 1-MT. Tumor size increase (tumor growth) measured according RECIST was registered in each case. Mean difference in the 3 groups was statistically assessed (Student’s t-test). Tryptophane to Kynurenine conversion was tested to assess IDO inhibition. Results: Tumor growth was significantly slower in Group II and III than in Group I (p<0.01 and p<0.005). Tumor growth was also significantly slower in Group III than in Group II (p<0.02). IDO-inhibition was confirmed only in Group III. No relevant toxicities were detected. Conclusions: These results support that additional tolerance break by IDO-inhibition optimizes the tumor growth inhibition through immunotherapy with an autologous thermostable hemoderivative vaccine. No significant financial relationships to disclose.
Poly TLR agonist polyantigenic vaccine (Mycobacterium w) in palliative therapy of head and neck cancer
Authors: Dave R. I. , Tripathi U. , Shah S. , Patel K. M. 
Published: March 2020

12512 Background: Poly TLR poly-antigenic vaccine containing Mycobacterium w (Mw) is found useful in the management of lung cancer and bladder cancer when used along with standard therapy1,2 but not in Head and Neck cancer3–4. This study was carried out to evaluate its efficacy as a single agent in advanced head & neck cancer. Methods: In a prospective study consecutive 75 symptomatic patients with advanced head & neck cancer (squamous cell) attending hospital for palliative care following failure of standard therapy were administered Mw once a week for 8 weeks. Results: Of 75 patients 43 were male & 32 females with 76% between the ages of 31 to 60). 18 had buccal mucosa tumor, 12 alveolar and 11 at base of the tongue. Partial response was seen in 27. It was associated with Pain relief (27/27), Healing of ulcer/fistula (4/5), improvement in dysphagia (7/15), improvement in voice(5/19). All 27 showed improvement in constitutional symptoms also. No systemic side effects were seen. Conclusions: Mw vaccine is useful in palliative care of head & neck cancer. Reference 1Sur PK, Dastidar AG. Role of mycobacterium w as adjuvant treatment of lung cancer. J Indian Med Assoc. 2003;101:118, 120. 2Chaudhuri P, Mukhopadhyay S. Bladder preserving approach for muscle invasive bladder cancer–role of mycobacterium w. J Indian Med Assoc. 2003;101:559–60 3M. C. Pant, R. Hadi, R. Prasad, D. Dalela, et al. Role of immuno-therapy as a adjuvant treatment in advance head & neck cancer, patient receiving chemo radiotherapy. Journal of Clinical Oncology 2005; 23, (16S Part 1): 190S 4S. K. Sarkar, C. Dasgupta. Role of Mycobacterium W as an adjuvant treatment of Head & Neck Cancer_A Randomised trial. Journal of Clinical Oncology 2005; 23, (16S Part 1): 521 s. No significant financial relationships to disclose.
Effect of bevacizumab (BV) and chemotherapy (CT) on serum levels of vascular endothelial growth factor receptor-2 (sVEGFR-2) in patients with inflammatory and locally advanced breast cancer
Authors: Walshe J. M. , Denduluri N. , Berman A. W. , Nguyen D. , Yang S. Y. , Liewehr D. J. , Steinberg S. M. , De Sauvage F. , Chen H. , Swain S. M. 
Published: March 2020

13003 Background: VEGFR-2 is a principal mediator of angiogenesis. The effects on sVEGFR-2 after anti-angiogenesis therapy are unknown. Methods: Twenty-one patients (pts) with breast cancer underwent neoadjuvant treatment with BV for 1 cycle (C1) followed by 6 cycles of BV, CT and filgrastim. Blood was collected at baseline (BL), post-cycles 1, 4 and 7. Objectives were to correlate sVEGFR-2 changes after treatment with response, assess wound healing complications, and evaluate for tumor VEGFR-2 mutations. sVEGFR-2 levels were measured by ELISA. Exons 17–26 were sequenced on tissue samples from 20 pts at BL and post C1 to evaluate for VEGFR-2 mutations. Statistical testing is non-parametric. All p-values are two-tailed, with a p < 0.01 interpreted as a statistically significant difference. Results: Thirteen pts had a partial response (PR), 1 unconfirmed PR, 5 stable disease (SD), and 2 progressive disease (PD). Median sVEGFR-2 levels increased by 16% from BL to post C1 (p = 0.0003) and decreased by 19% post C1 to post C4 (p = 0.048). sVEGFR-2 levels were not associated with clinical response. sVEGFR-2 levels at BL did not correlate with other BL parameters: Ki67, microvessel density, VEGF-A, pVEGFR-2, VEGFR-2 or TUNEL (apoptosis). A moderate-weak correlation was seen between post C1 levels of sVEGFR-2 and pVEGFR-2 (r = 0.43). A moderate inverse correlation was seen in the relative difference of sVEGFR-2 and TUNEL from BL to post C1 (r = −0.59). Comparing pts with (n = 5) and without (n = 16) wound healing problems, median sVEGFR-2 levels were 11322 ng/ml and 7524 ng/ml at BL (p = 0.019), 13928 ng/ml and 10148 ng/ml post C1 (p = 0.029), and 10965 ng/ml and 7932 ng/ml post C4 (p = 0.042). In 40 samples where tumor VEGFR-2 sequencing was obtained, no mutations were seen compared to the reference sequence. Conclusion: sVEGFR-2 levels rose significantly following BV alone but were not associated with response. There is a suggestion that sVEGFR-2 may correlate with activated VEGFR2 and a decrease in apoptosis. sVEGFR-2 levels were higher in pts with wound healing problems and may predict pts at higher risk of this complication. There were no mutations of VEGFR2. [Table: see text]