These results suggest that polymorphic variation in or near the 3' end of the VDR gene influences breast cancer risk in Latina women.
A simple, 10-min immunoassay system has been developed that simultaneously screens for five different classes of drugs of abuse in a urine sample. This system tests for amphetamines, cannabinoids, cocaine metabolites, opiates, and phencyclidine, and each assay has a specific preset cutoff concentration. Accuracy is > 99% for reporting positive or negative results for samples with 200% or 50%, respectively, of the cutoff concentrations of the drugs. Tests of a panel of 96 compounds yielded only three cases of nonspecific reactivity (at a drug concentration of 100 mg/L). Another panel of 12 compounds that could normally be found in urine samples was also evaluated and no interferences were observed. Concordance was > 95% between this system and the comparable automated immunoassays for detecting drugs of abuse. Greater than 98% of GC/MS-confirmed positive samples gave positive results with this assay system.
Metronomic chemotherapy has shown promising antitumor activity in a number of malignancies. For example, we previously reported (Allegrini et al., Angiogenesis (2012) 15(2):275-86) a phase II clinical trial of metronomic UFT (a 5-fluorouracil prodrug; 100 mg/twice per day p.o.) and cyclophosphamide (CTX; 500 mg/mq2 i.v. bolus on day 1 and then 50 mg/day p.o.) plus celecoxib (200 mg/twice a day p.o.) in 38 patients with advanced refractory gastrointestinal tumors. The mechanisms of action of metronomic chemotherapy include upregulation of the angiogenesis inhibitor Thrombospondin-1, the suppression of bone marrow derived endothelial progenitor cells and, at least for drugs such as CTX, activation of the immune system. To further evaluate the latter, we carried out an immune system multiplex 14-cytokine profiling of plasma samples that were available (for day 0, day 28, and day 56) from 31 of the 38 patients in the above noted (Allegrini et al) clinical trial. Our results show that pre-treatment plasma level cut-offs of interferon-gamma (>12.84pg/ml), sCD40L (<2168pg/ml), interferon-alpha2 (>55.11pg/ml), and IL-17a (<15.1pg/ml) were predictive markers for those patients with better progression-free survival (p<.05 for each cytokine). After 28 days of metronomic therapy, the plasma levels of sCD40L, IL-17a, and of IL-6 (<130pg/ml) could serve as predictors of improved progression-free survival, as could levels interferon-gamma and sCD40L after 56 days of therapy. We observed minimal changes in cytokine profiles, from baseline, as a consequence of the metronomic therapy, with the exception of an elevation of IL-6 and IL-8 levels 28 days (and 56 days) after treatment started (p<0.05). Our results indicate that a selective cytokine elevation, involving IL-6 and IL-8, following metronomic chemotherapy administration. In addition, interferon-gamma and sCD40L may be potential biomarkers for gastrointestinal cancer patients that are likely to benefit from metronomic chemotherapy. Our study contributes to our understanding of the mechanisms of action of metronomic chemotherapy, and may guide future patient selection criteria for metronomic chemotherapy for gastrointestinal cancers. Citation Format: Paloma Valenzuela, Karla Parra, Derrick Oaxaca, Luis Reza, Jose Lopez, Montserrat Garcia Arreguin, Diana Garcia, Georgialina Rodriguez, Alfredo Falcone, Giacomo Allegrini, Teresa Di Desidero, Guido Bocci, Robert Kirken, Giulio Francia. Pharmacodynamic biomarkers in metronomic chemotherapy: Multiplex cytokine measurements in gastrointestinal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 784. doi:10.1158/1538-7445.AM2017-784
Recent advances for the treatment of late stage colon cancer include a metronomic capecitabine plus bevacizumab maintenance regimen as reported for the CAIRO3 phase 3 clinical trial (Simkens et al, Lancet: 2015; 385: 1843-52) . We previously reported a phase 2 trial evaluating metronomic cyclophosphamide (CTX) plus UFT (a 5-fluorouracil prodrug) and celecoxib in gastrointestinal cancer patients (Allegrini et al, Angiogenesis: 2012; 15, 275-286). We also reported the preclinical evaluation of metronomic oral topotecan in mouse models of colon cancer (Hackl et al, Gut: 2013; 62, 259-71). Here we report our studies using orthotopic (intracecal) implantation of human HT29/luc/hCG colon cancer cells in SCID mice. Disease progression was noninvasively assessed using the transfected human chorionic gonadotropin (hCG), whose levels in the mouse urine correlate with tumor burden - and this was coupled with luciferase (luc) bioimaging of the mice. These implanted tumor models were used together with patient derived xenografts (PDX), to evaluate metronomic regimens of etoposide (80mg/kg/day, p.o.), gemcitabine (given i.p.; at either 120mg/kg every 3 days, or at the much lower 1mg/kg/day), or CTX given as a monotherapy (20mg/kg/day given via the drinking water) or combined with neutralizing antibodies against VEGF or EGFR. Our results indicate; 1) effective anti-tumor activity of daily etoposide, and of 2) daily gemcitabine (as well as when the gemcitabine was given every 3 days), and that 3) orthotopic HT29/luc/hCG colon tumors are weakly responsive to CTX or CTX plus targeted agents compared to the same tumors implanted subcutaneously or intraperitoneally. The effectiveness of metronomic etoposide was confirmed in a colon PDX model in NSG mice (n=5 mice/group; p<.05) - obtained from Jackson labs. Notably ovarian cancer and breast cancer PDX models did not respond to etoposide therapy (n=5/group), indicating the response may be tumor specific. Collectively, these results highlight the importance of advanced disease models to confirm sometime overly optimistic experimental therapeutic results from subcutaneously or intraperitoneally implanted tumor models. They also demonstrate the promising anti-tumor activity of metronomic etoposide and gemcitabine regimens for colon cancer, and they lead us to advocate the concerted use of both implanted xenografts and PDX for the testing of new therapeutic strategies for the treatment of colon cancer. Citation Format: Jose Lopez, Paloma Valenzuela, Valerie Gallegos, Karla Parra, Valeria Rolih, Diana Gonzalez Garcia, Joel Martinez, Urban Emmenegger, Guido Bocci, Robert S. Kerbel, Giulio Francia. Evaluation of metronomic chemotherapy regimens in preclinical orthotopically implanted colon cancer models, and in patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 10.
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