Purpose Exposing human tumor cells to sublethal doses of external beam radiation up-regulates expression of tumor antigen and accessory molecules, rendering tumor cells more susceptible to killing by antigen-specific CTLs. This study explored the possibility that exposure to palliative doses of a radiopharmaceutical agent could alter the phenotype of tumor cells to render them more susceptible to T cell – mediated killing. Experimental Design Here, 10 human tumor cell lines (4 prostate, 2 breast, and 4 lung) were exposed to increasing doses of the radiopharmaceutical samarium-153-ethylenediaminetetrame-thylenephosphonate (153Sm-EDTMP) used in cancer patients to treat pain due to bone metastasis. Fluorescence-activated cell sorting analysis and quantitative real-time PCR analysis for expression of five surface molecules and several tumor-associated antigens involved in prostate cancer were done. LNCaP human prostate cancer cells were exposed to153Sm-EDTMP and incubated with tumor-associated antigen-specific CTL in a CTL killing assay to determine whether exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to T cell – mediated killing. Results Tumor cells up-regulated the surface molecules Fas (100% of cell lines up-regulated Fas), carcinoembryonic antigen (90%), mucin-1 (60%), MHC class I (50%), and intercellular adhesion molecule-1 (40%) in response to 153Sm-EDTMP. Quantitative real-time PCR analysis revealed additional up-regulated tumor antigens. Exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to killing by CTLs specific for prostate-specific antigen, carcinoembryonic antigen, and mucin-1. Conclusions Doses of 153Sm-EDTMP equivalent to palliative doses delivered to bone alter the phenotype of tumor cells, suggesting that153Sm-EDTMP may work synergistically with immuno-therapy to increase the susceptibility of tumor cells to CTL killing.
The objective of this retrospective study was to describe the responses to treatment with intravenous lipid emulsion (ILE) and the outcomes for a variety of severe intoxications. This case series includes 10 client-owned animals, 9 dogs and 1 cat, that underwent treatment with ILE for a variety of severe intoxications over a 4-year period. History, physical examination findings, clinical signs, clinicopathological test results, treatment, response to treatment, and outcome were recorded. Eight of the 10 patients survived to discharge. The toxicities included in this case series were baclofen, ivermectin and spinosad plus milbemycin oxime, baclofen and tadalafil, carbamate, methamphetamine, dextroamphetamine sulfate, amlodipine, bromethalin, and organophosphate. The two patients who died were intoxicated with bromethalin and an organophosphate. Six of the 10 patients developed lipemia secondary to ILE administration, and there were no other known adverse effects. Overall, ILE was a safe therapeutic option. This case series provides clinical evidence of successful treatment with ILE as an antidote for previously unpublished toxicities (amlodipine, carbamate, methamphetamine, and dextroamphetamine sulfate), additional evidence of success in treating baclofen and ivermectin toxicosis, as well as unsuccessful treatment of bromethalin and organophosphate toxicities.
In contrast to differences in periurethral collagen content found between pre- and postmenopausal women, such differences may not occur in dogs. This implies that changes in pelvic organ support structures may not play an important role in urinary incontinence in neutered female dogs. Further evaluation is needed to determine the role of age on collagen and pelvic organ support structures in the pathogenesis of canine urinary incontinence.
Background: Akt is a key serine/threonine protein kinase commonly activated in hematologic malignancies that promotes cell survival through phosphorylation and activation of pathways such as IKKa-NFkB. In AML, constitutive Akt activation is associated with poor prognosis and may contribute to chemotherapy resistance. In vitro inhibition of Akt suppresses tumor cell growth, angiogenesis and metastasis, and induces apoptosis. Triciribine Phosphate Monohydrate (TCN-PM) is a small molecule inhibitor of Akt. Herein, we report results of a phase I dose-escalation clinical and pharmacodynamic (PD) study of TCN-PM in patients with advanced hematological malignancy. Objectives: The primary objective of this dose escalation Phase I study is to determine safety, tolerability, and pharmacokinetic profile of TCN-PM in patients with advanced hematological cancers. Secondary objectives included assessment of TCN-PM on p-AKT status within leukemic blasts and clinical activity. Eligibility: Patients with relapsed or refractory AML, ALL, CML-BC, MDS, and CLL were eligible. Methods: TCN-PM was administered as a 1 hour IV infusion on days 1, 8, and 15 of each cycle. Cycles were repeated every 21 days. Patients were permitted to receive subsequent cycles, barring unacceptable toxicity or disease progression. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC). A dose limiting toxicity (DLT) was defined as any significant grade 3 or grade 4 toxicity during cycle 1. Peripheral blood (PB) for PK analysis was collected during cycle 1. In patients with circulating blasts, PB for PD studies (i.e. p-AKT status) was collected pre- and post-treatment with TCN-PM. Results: 39 patients (27 M/12 F) were enrolled to date. Median age was 68 years (range, 30 – 79). Diagnoses included AML=31, MDS=4, CMML=2. Median number of prior therapies was 3 (range, 1 – 7). At the highest dose of 65 mg/m2, one patient experienced DLT (grade 3 lipase and triglyceride elevation). Another patient treated at this dose developed hepatotoxicity (grade 3 bilirubin elevation) after 2 cycles. More common non dose-limiting non-hematologic toxicities included: dyspnea (n=4), fatigue (n=3); febrile neutropenia (n=3), hyperglycemia (n=3); others (n=6). Due to concerns for hepatic and metabolic toxicity, the MTD was declared at 55 mg/m2. Pharmacokinetic studies indicated a dose dependent accumulation of TCN-P within leukemia blasts. In a xenograft nude mice model, TCN-PM significantly inhibits tumor growth in Akt-overexpressing cells, but not in tumors with low levels of Akt. In this regard, pharmacodynamic studies showed that 5/8 patients had a ratio of phosphorylated Akt/Akt indicating high Akt expression prior to therapy. Two of these patients treated at 35mg/m2 demonstrated decreases in the ratio of phosphorylated Akt/Akt and phosphorylated Bad/Bad, consistent with an inhibition of this survival pathway and activity of triciribine in this patient population. Four patients treated at the 25 mg/m2 or 35 mg/m2 dose level experienced up to 50 percent reductions in peripheral blast cells. Additional hematological improvements included two patients achieving major improvements in platelet count lasting 7 and 36 days, respectively, and four patients achieving major improvements in neutrophil count lasting a median of 19 days. Another patient with CMML experienced a decrease in the WBC from > 100 × 109/L to the normal range by cycle 3. There were no complete or partial responses. Conclusions: Results from this dose escalation Phase I trial evaluating TCN-PM administered on a weekly schedule are encouraging and demonstrate at doses up to MTD is well-tolerated, with preliminary evidence of PD activity as measured by decreased blast p-AKT. Accrual at the MTD of 55 mg/m2 is continuing. Future TCN-PM studies in hematological malignancies could enrich for patient populations where Akt is overexpressed.
1783 Background: The PI3K/Akt/mTOR signaling pathway is an attractive target to inhibit for cancer therapy because it is altered in many cancers and is vital to essential biological processes. While inhibition of specific PI3K isoforms, such as δ, has demonstrated efficacy in B-cell malignancies, recent studies suggest that inhibition of all Class IA isoforms (α, β, and δ) is essential to produce maximal inhibition of cell proliferation and to induce apoptosis. For example, the pan PI3K inhibitor LY294002 has been shown to inhibit both the viability and chemotaxis of chronic lymphocytic leukemia (CLL) B-cells, whereas a PI3K δ inhibitor did not. Dual PI3K and mTOR inhibition is also expected to offer a therapeutic advantage, as several mTOR inhibitors have demonstrated promising activity in B-cell malignancies, including the mobilization of CLL cells from tissue sites into the circulation that could enhance the cytotoxicity of other agents. Objectives: The role of PI3K in a wide range of normal biologic processes raises potential safety concerns about dual inhibition of mTOR and all PI3K Class I isoforms. The objective of this Phase I study is to demonstrate that SF1126 can overcome these concerns by accumulating preferentially in tumor tissue to both maximize efficacy and minimize toxicity. SF1126 is a peptidic prodrug that converts to LY294002, one of the most widely studied dual PI3K/mTOR inhibitors. LY294002 is conjugated to an Arg-Gly-Asp (RGD) peptide via a cleavable linker to form SF1126, which has improved properties for clinical use. As a prodrug with improved solubility and site selectivity due to targeting of RGD-recognizing integrin receptors, SF1126 opened up a new avenue for the clinical development of LY294002. Furthermore, the fact that proliferation of CLL cells requires stromal support mediated through cytokines and adhesion molecules (eg, integrins) provides additional biological rationale for testing a RGD-targeted agent as a treatment for CLL. Methods: Based on translational studies demonstrating that LY294002 induces apoptosis in CLL cells and sensitize CLL cells to cytotoxic drugs, patients with CLL and other B-cell malignancies will be enrolled on this expanded Phase I trial at the maximum administered dose of SF1126 (1110 mg/m2) as determined by 47 patients treated to date in dose-escalation studies. SF1126 will be administered intravenously over 90-minutes on days 1 and 4 weekly in cycles of 4 weeks. Patients with CLL will be assessed using the International Workshop on CLL (IWCLL) criteria and patients with indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL) will be assessed using the International Workshop Group (IWG) criteria. Correlative pharmacodynamic studies will also be conducted to evaluate the potential inhibition of PI3K in tumor cells from patients enrolled in this trial. Results: At the maximum administered dose of 1110 mg/m2, SF1126 appears to be well tolerated and demonstrates activity in relapsed and refractory CLL patients treated to date in this ongoing Phase I study. Similar to the tumor flare reaction (TFR) demonstrated in CLL patients treated with immune-modulating agents, such as lenalidomide, two patients treated with SF1126 experienced TFR during the cycle one, day 1–4 time period. TFR has been postulated to be associated with a drug-induced, immune-mediated anti-tumor response and is manifested as an acute onset of swelling of involved lymph nodes that is not associated with disease progression. Time course analysis by flow cytometry of isolated lymphocytes from the first two CLL patients treated demonstrate consistent increases in late apoptosis over time relative to baseline following the first dose of SF1126. Western blot analyses of isolated lymphocytes from the first CLL patient treated demonstrate decreased pAKT (473) signaling and increased PARP cleavage over time relative to baseline. One CLL patient with a 17p deletion genotype demonstrated clinical activity as indicated by stable disease and significant lymph node decreases accompanied by an increases in absolute lymphocyte count (ALC) as seen with the mTOR inhibitor everolimus. The trial continues to enroll patients and updated results from this study will be presented. In view of SF1126's ability to mobilize CLL cells into the circulation, combination studies with synergistic agents that are effective against circulating CLL cells are also being planned. Disclosures: Garlich: Semafore Pharmaceuticals: Employment, Patents & Royalties. Becker:Semafore Pharmaceuticals: Consultancy, Patents & Royalties. Shelton:Semafore Pharmaceuticals: Consultancy. Qi:Seamfore Pharmaceuticals: Research Funding. Liu:Semafore Pharmaceuticals: Research Funding. Cooke:Semafore Pharmaceuticals: Research Funding. Mahadevan:semafore pharmaceuticals: Research Funding.
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