scholarly journals Chemotherapeutic dose scheduling based on tumor growth rates: the case for low dose metronomic high entropy therapies

2017 ◽  
Author(s):  
Jeffrey West ◽  
Paul K. Newton
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Growth Rates ◽  
Process Model ◽  
Low Dose ◽  
Maximum Tolerated Dose ◽  
High Density ◽  
High Dose ◽  
Single Cycle ◽  
Chemotherapy Drugs

AbstractWe extend classical tumor regression models, such as the Norton-Simon hypothesis, from instantaneous regression rates (i.e. the derivative) to the cumulative effect (i.e. the integral) over one (or many) cycles of chemotherapy. To achieve this end, we use a stochastic Moran process model of tumor cell kinetics, coupled with a prisoner’s dilemma game-theoretic cell-cell interaction model to design chemotherapeutic strategies tailored to different tumor growth characteristics. Using the Shannon entropy as a novel tool to quantify the success of dosing strategies, we contrast maximum tolerated dose (MTD) strategies as compared with low dose, high density metronomic strategies (LDM) for tumors with different growth rates. Our results show that LDM strategies can outperform MTD strategies in total tumor cell reduction (TCR). The advantage is magnified for fast growing tumors that thrive on long periods of unhindered growth without chemotherapy drugs present and is not evident after a single cycle of chemotherapy, but grows after each subsequent cycle of repeated chemotherapy. The model supports the concept of designing different chemotherapeutic schedules for tumors with different growth rates and develops quantitative tools to optimize these schedules for maintaining low volume tumors. The evolutionary model we introduce in this paper is compared with regression data from murine models and shown to be in good agreement.Major FindingsModel simulations show that metronomic (low dose, high density) therapies can outperform maximum tolerated dose (high dose, low density) therapies. This is due to the fact that tumor cell reduction is more sensitive to changes in dose density than changes in dose concentration, especially for faster growing tumors. This effect is negligible after a single cycle of chemotherapy, but magnified after many cycles. The model also allows for novel chemotherapeutic schedules and quantifies their performance according to tumor growth rate.

miR-15a regulation of endothelial radiation sensitivity in colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 709-709
Author(s):  
Shushan Rajesh Rana ◽  
Cristina Espinosa ◽  
Rebecca Ruhl ◽  
Latroy Robinson ◽  
Charles R. Thomas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Background Radiation ◽  
Acid Sphingomyelinase ◽  
High Dose ◽  
Tumor Cell Death ◽  
Caspase 1

709 Background: Radiation dose escalation causes significant changes within the tumor microenvironment (TME) to enhance tumor cell death including altered microRNA (miR) levels. Among endothelial miRs, we identified miR-15a exhibits dose dependent differential regulation. miR-15a targets a key determinant of endothelial cell (EC) radiosensitivity, acid sphingomyelinase (SMPD1), an enzyme that drives rapid EC apoptosis via enhanced ceramide production. In colorectal cancer (CRC) (n = 182 patients), high miR-15a is associated with worse 5-year progression free and overall survival. miR-15a also affects immune function by promoting a pro-inflammatory TME milieu. We hypothesized miR-15a inhibition will increase tumor cell death through preservation of EC SMPD1, enhancing endothelial apoptosis and inflammatory cytokine upregulation. Methods: Using TaqMan Human miR panels, miRs were profiled in human umbilical vein ECs (HUVECs) after single 2 vs 20 Gy treatment. miR-target prediction programs identified miRs targeting SMPD1. In vitro gain and loss of function studies were performed with miR transfections in HUVECs and CT26 CRC cells. CXCL10 expression was measured by qRT-PCR. Caspase 1 activation was measured by a luminescence based assay. A CT26 syngeneic CRC flank murine model was used for in vivo miR-15a inhibitor assessment administered via tail vein injection unencapsulated or encapsulated in vascular-targeted 7C1 nanoparticles. Results: Among miRs targeting SMPD1, miR-15a exhibited the greatest differential change in HUVECs 6h post-IR between low and high dose radiation. Lower dose was associated with higher miR-15a and vice versa. Further, miR-15a levels inversely correlated with SMPD1. Exogenous miR-15a significantly decreased SMPD1 mRNA and protein. miR-15a inhibition decreased proliferation in both HUVECs and CT26 cells and increased apoptosis when combined with radiation. miR-15a inhibition increased endothelial CXCL10 expression and caspase-1 activation. Both systemic and vascular-targeted miR-15a inhibitor significantly diminished tumor growth in vivo. Conclusions: Our data suggests inhibition of vascular miR-15a is sufficient to decrease tumor growth likely due to rescue of endothelial SMPD1.

scholarly journals Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma

2020 ◽  
Vol 8 (2) ◽  
pp. e000537
Author(s):  
Hampartsoum B Barsoumian ◽  
Rishab Ramapriyan ◽  
Ahmed I Younes ◽  
Mauricio S Caetano ◽  
Hari Menon ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Antitumor Effect ◽  
Low Dose ◽  
Checkpoint Inhibitors ◽  
Macrophage Polarization ◽  
High Dose ◽  
Primary Tumor Site ◽  
Secondary Tumors ◽  
M1 Macrophage

BackgroundDespite some successes with checkpoint inhibitors for treating cancer, most patients remain refractory to treatment, possibly due to the inhibitory nature of the tumor stroma that impedes the function and entry of effector cells. We devised a new technique of combining immunotherapy with radiotherapy (XRT), more specifically low-dose XRT, to overcome the stroma and maximize systemic outcomes.MethodsWe bilaterally established 344SQ lung adenocarcinoma tumors in 129Sv/Ev mice. Primary and secondary tumors were irradiated with either high-dose or low-dose of XRT with systemic anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte associated protein 4 administration. Survival and tumor growth were monitored for the various groups, and secondary tumors were phenotyped by flow cytometry for immune populations. Tumor growth factor-beta (TGF-β) cytokine levels were assessed locally after low-dose XRT, and specific immune-cell depletion experiments were conducted to identify the major contributors to the observed systemic antitumor effect.ResultsThrough our preclinical and clinical studies, we observed that when tumor burden was high, there was a necessity of combining high-dose XRT to ‘prime’ T cells at the primary tumor site, with low-dose XRT directed to secondary (metastatic) tumors to ‘modulate the stroma’. Low-dose XRT improved the antitumor outcomes of checkpoint inhibitors by favoring M1 macrophage polarization, enhancing natural killer (NK) cell infiltration, and reducing TGF-β levels. Depletion of CD4+ T cells and NK cells abrogated the observed antitumor effect.ConclusionOur data extend the benefits of low-dose XRT to reprogram the tumor environment and improve the infiltration and function of effector immune cells into secondary tumors.

Immunotherapy with Recombinant Xenogeneic Vascular Endothelial Growth Factor as a Vaccine Combined Low-Dose Adriamycin Induces Synergistic Antitumor Efficacy in EL4 Lymphoma Model.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4811-4811
Author(s):  
Ting Niu ◽  
Ting Liu ◽  
Yong-qian Jia ◽  
Yan-jun Wen ◽  
Ling Tian ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Cell Apoptosis ◽  
Low Dose ◽  
Combination Group ◽  
Vascular Endothelial ◽  
Tumor Cell Apoptosis ◽  
Anti Vegf ◽  
Endothelial Growth Factor

Abstract We explored the antitumor efficacy of a strategy using recombinant Xenopus laevis vascular endothelial growth factor (xVEGF) as a xenogeneic protein vaccine, which we have demonstrated to have effective antiangiogenic activities in several tumor models, in combination with low-dose adriamycin in lymphoma model. EL4 lymphoma model was established in C57BL/6 mice. Mice were randomly divided into four groups: combination therapy (xVEGF plus adriamycin), xVEGF treatment alone, adriamycin treatment alone, and normal saline (NS) groups, and received relevant treatments. Tumor growth, survival rate of tumor-bearing mice, and potential toxicity of regimens above were investigated. Anti-VEGF antibodies and anti-VEGF antibody-producing B cells (APBCs) were detected by Western blot analysis and enzyme-linked immunospot (ELISPOT) assay, respectively. In addition, microvessel density (MVD) within tumor tissues and tumor cell apoptosis were determined by immunohistochemistry and TUNEL staining, respectively. Our data showed that combination therapy inhibited tumor growth and improved survival of tumor-bearing mice significantly, and complete regression of tumor was observed in 3 of 10 mice in combination group in EL4 lymphoma model.Survival rate of mice was significantly higher in combination group than that in xVEGF alone group,in adriamycin alone group (P<0.05),or that in NS group (P<0.01). Remarkably, the combination treatment resulted in not only significant antiangiogenic effects but also promotion of tumor cell apoptosis. The calculated indexes of combination therapy showed synergistic relationship in terms of inhibition of tumor growth, antiangiogenesis, induction of tumor cell apoptosis. In addition, anti-VEGF antibodies and APBCs were found in mice treated with either xVEGF vaccine alone or combination treatment. No marked toxicities were found in the treated mice. In summary, these findings may provide an effective combination approach for lymphoma therapy in the future.

Effect on tumor growth by TGF-β1/COX-2 siRNA combination product (STP705) in a human cholangiocarcinoma (HuCCT-1) xenograft tumor model in nude mice.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14652-e14652
Author(s):  
Michael Molyneaux ◽  
John Xu ◽  
David M. Evans ◽  
Patrick Lu
Keyword(s):  
Tumor Growth ◽  
Nude Mice ◽  
Low Dose ◽  
Tumor Volume ◽  
Tumor Model ◽  
Control Group ◽  
High Dose ◽  
Combination Product ◽  
Cox 2 ◽  
Tgf Β1

e14652 Background: Cholangiocarcinoma (CCA) is a hepatobiliary cancer and although there have been advances recently there is a need for additional treatment methods for patients. Over expressions of TGF-β1 and COX-2 have been reported to play key roles in tumorigenesis of CCA. We studied the effect of STP705 on the growth of HuCCT-1 xenograft tumors in nude mice. STP705 is a TGF-β1/COX-2 specific siRNA combination product formulated in Histidine-Lysine co-Polymer nanoparticle delivery system. Methods: HuCCT-1 xenograft tumors were implanted subcutaneously into 24 BALB/c nude female mice (n = 8/group). Group 1 received vehicle control, group 2 (low-dose) received 8µg of STP705, and group 3 (high-dose) received 16µg of STP705. Intratumoral test article administration and tumor volume measurements were conducted twice a week for 3-weeks. Qualitative analysis was performed on H&E, Picrosirius red (PSR) and immunohistochemistry (IHC) stained sections of tumor tissues. Results: High- and low- dose groups of STP705 reported significantly lower mean tumor volume at day 21 (p = 0.005 & p = 0.036, respectively) as compared to control group. High-dose group reported significantly lower tumor volume at days 11 (p = 0.042), 15 (p = 0.003), and 18 (p = 0.007) as compared to the control group. IHC assessment demonstrated that STP705-treated animals had significantly lower (H-score ± SEM) TGF-β1, COX-2, HSP70, Bcl-xL and MMP-9 staining (52±9, 39±4, 178±8, 25±7 & 7±1, respectively) as compared to control animals (94±11, 66±8, 213±7, 59±8 & 11±2, respectively – with p < 0.05). Assessment of Caspase-3 and H&E (necrosis and inflammation) slides reported higher mean score for STP705-treated animals, while PSR staining reported lower fibroplasia for STP705-treated animals as compared to the control animals. Conclusions: The data suggests that STP705-treatment suppresses TGF-β1 and COX-2 expression resulting in inhibition of (i) tumor cell survival, (ii) fibrosis, (iii) promotes apoptosis, and (iv)decreased invasiveness of tumor cells. Overall, STP705 is an innovative siRNA-based treatment that results in significant suppression of tumor growth in a HuCCT-1 xenograft mouse tumor model.

scholarly journals Optimizing chemo-scheduling based on tumor growth rates

2018 ◽  
Author(s):  
Jeffrey West ◽  
Paul Newton
Keyword(s):  
Tumor Growth ◽  
Low Dose ◽  
Cell Kinetics ◽  
Evolutionary Game ◽  
Maximum Tolerated Dose ◽  
General Concept ◽  
Theory Model ◽  
Moran Process ◽  
Evolutionary Features ◽  
Gompertzian Growth

AbstractWe review the classic tumor growth and regression laws of Skipper and Schable based on fixed exponential growth assumptions, and Norton and Simon’s law based on a Gompertzian growth assumption. We then discuss ways to optimize chemotherapeutic scheduling using a Moran process evolutionary game-theory model of tumor growth that incorporates more general dynamical and evolutionary features of tumor cell kinetics. Using this model, and employing the quantitative notion of Shannon entropy which assigns high values to low-dose metronomic (LDM) therapies, and low values to maximum tolerated dose (MTD) therapies, we show that low-dose metronomic strategies can outperform maximum tolerated dose strategies, particularly for faster growing tumors. The general concept of designing different chemotherapeutic strategies for tumors with different growth characteristics is discussed.

Estimation of maximum tolerated dose and minimum efficient dose of BP-C1 in the treatment of stage IV breast cancer patients: A phase I response surface pathway designed study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11022-e11022
Author(s):  
Stig Einride Larsen ◽  
Sagita Dewi ◽  
Vichien Srimuninnimit ◽  
Yen-Shen Lu ◽  
Tjakra Manuaba ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cumulative Dose ◽  
Dose Group ◽  
Low Dose ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
High Dose Group ◽  
High Dose ◽  
Breast Cancer Patients ◽  
Stage Iv Breast Cancer

e11022 Background: The aims were to establish a treatment routine and to estimate the Maximum Tolerated Dose (MTD) and the Minimum Efficient Dose (MED) of a novel anti-cancer agent named BP-C1. Methods: The material consists of 15 Stage IV breast cancer patients with a mean age of 51 years. The study was performed as a non-randomized multi-centre trial with between patient 3-level Response Surface Pathway design. BP-C1 was given intramuscularly once daily during 32 days. The given cumulative dose window was 0.16 to 1.12 mg/kg bw, resulting in a starting dose of 0.64 mg/kg bw. The main variable was the National Cancer Institute common toxicity criteria (NCI-CTC) Bethesda. If the increase in toxicity was classified as moderate or less, the next patient in the sequence was allocated to an increased dose. In case of severe toxicity increase, the dose was reduced. Patients receiving cumulative dose of 0.96 mg/kg bw or higher was defines as the high-dose group. Results: Three of the five patients on the first design level recorded unchanged toxicity, one mild and one moderate increased Max NCI-CTC. Of the four patients receiving 0.96 mg/kg bw, three obtained no change and one a mild toxicity increase. The four patients on the third design level received the maximal dose of 1.12 mg/kg bw without any change in Max NCI-CTC. The Sum NCI-CTC increased (p= 0.07) in the low-dose group, but reduced (p=0.09) in the high-dose group. The cumulative dose of BP-C1 was found significantly (p=0.048) and negatively correlated (r = - 0.52) to the increase in toxicity. Only mild to moderate Adverse Events were reported and the prevalence was found largest in the high dose group (p=0.06). In the high-dose group 62.5% of the patients were classified as responders compared to 28.6% in the low-dose group. One of the patients in the high-dose group was classified as complete responder. The development in both Karnofsky Scale of Performance Status and patient wellbeing was found obviously better in the high-dose group. Conclusions: BP-C1 can safely be administrated continuously during a period of 32 days. The MTD seem to be at least 1.12 mg/kg bw and the MED to be 0.96 mg/kg bw.

scholarly journals Evaluation of Anti-Tumor Effects of Whole-Body Low-Dose Irradiation in Metastatic Mouse Models

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1126
Author(s):  
Kyung-Hee Song ◽  
Seung-Youn Jung ◽  
Jeong-In Park ◽  
Jiyeon Ahn ◽  
Jong-Kuk Park ◽  
...  
Keyword(s):  
T Cells ◽  
Radiation Therapy ◽  
Tumor Growth ◽  
Mouse Models ◽  
Low Dose ◽  
Whole Body ◽  
High Dose ◽  
Mesenchymal Transition ◽  
Dose Irradiation ◽  
Dose Radiation

Low-dose irradiation (LDI) has recently been shown to have various beneficial effects on human health, such as on cellular metabolic activities, DNA repair, antioxidant activity, homeostasis potency, and immune activation. Although studies on the immunogenic effects of LDI are rapidly accumulating, clinical trials for cancer treatment are considered premature owing to the lack of available preclinical results and protocols. Here, we aim to investigate anti-tumor and anti-metastatic effects of whole-body LDI in several tumor-bearing mouse models. Mice were exposed to single or fractionated whole-body LDI prior to tumor transplantation, and tumor growth and metastatic potential were determined, along with analysis of immune cell populations and expression of epithelial–mesenchymal transition (EMT) markers. Whole-body fractionated-LDI decreased tumor development and lung metastasis not only by infiltration of CD4+, CD8+ T-cells, and dendritic cells (DCs) but also by attenuating EMT. Moreover, a combination of whole-body LDI with localized high-dose radiation therapy reduced the non-irradiated abscopal tumor growth and increased infiltration of effector T cells and DCs. Therefore, whole-body LDI in combination with high-dose radiation therapy could be a potential therapeutic strategy for treating cancer.

scholarly journals Chemotherapeutic Dose Scheduling Based on Tumor Growth Rates Provides a Case for Low-Dose Metronomic High-Entropy Therapies

2017 ◽  
Vol 77 (23) ◽  
pp. 6717-6728 ◽  
Author(s):  
Jeffrey West ◽  
Paul K. Newton
Keyword(s):  
Tumor Growth ◽  
Growth Rates ◽  
Low Dose ◽  
High Entropy

Acetaminophen: Neonatal hepatotoxicity due to late pregnancy exposure

1987 ◽  
Vol 45 ◽  
pp. 718-719
Author(s):  
G.A. Miranda ◽  
M.A. Arroyo ◽  
C.A. Lucio ◽  
M. Mongeotti ◽  
S.S. Poolsawat
Keyword(s):  
Low Dose ◽  
Fetal Liver ◽  
Late Pregnancy ◽  
Toxic Chemicals ◽  
Control Group ◽  
High Dose ◽  
Over The Counter ◽  
Liver And Kidney ◽  
Neonatal Liver ◽  
Childbearing Women

Exposure to drugs and toxic chemicals, during late pregnancy, is a common occurrence in childbearing women. Some studies have reported that more than 90% of pregnant women use at least 1 prescription; of this, 60% used more than one. Another study indicated that 80% of the consumed drugs were not prescribed, and of this figure, 95% were “over-the-counter” drugs. Acetaminophen, the safest of all over-the-counter drugs, has been reported to induce fetal liver necrosis in man and animals and to have abortifacient and embryocidal action in mice. This study examines the degree to which acetaminophen affects the neonatal liver and kidney, when a fatty diet is simultaneously fed to the mother during late pregnancy.Timed Swiss Webster female mice were gavaged during late pregnancy (days 16-19) with fat suspended acetaminophen at a high dose, HD = 84.50 mg/kg, and a low dose, LD = 42.25 mg/kg; a control group received fat alone.

Evaluation of hippocampus in rhesus monkeys after chronic (1-year) inhalation exposure to marijuana: I. Electron microscopy

1990 ◽  
Vol 48 (3) ◽  
pp. 398-399
Author(s):  
A.M. Andrews ◽  
S.W. Wilson ◽  
A.C. Scallet ◽  
S.F. Ali ◽  
J. Bailey ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Rhesus Monkeys ◽  
Low Dose ◽  
Inhalation Exposure ◽  
Synaptic Cleft ◽  
High Dose ◽  
Withdrawal Time ◽  
Treatment Groups ◽  
Ultrastructural Evidence ◽  
Male Rhesus

Exposure of rhesus monkeys (Macaca mulatta) to marijuana via inhalation or to intravenous delta-9-tetrahydrocannabinol (THC), reportedly caused ultrastructural evidence of increased synaptic width. Chronic marijuana smoke in a single rhesus monkey examined after a six month withdrawal time caused ultrastructure changes in the septal, hippocampal and amygdala regions; the synaptic cleft was widened, electron opaque material was found in the cleft and in the pre- and postsynaptic regions, with some clumping of the synaptic vesicles. The objective of our study was to assess neuropathological alterations produced by chronic inhalation of marijuana smoke.Nineteen male rhesus monkeys, 3-5 years of age and weighing 3-8 kg, were divided into four treatment groups: a) sham control, b) placebo smoke (7 days/ week) c) low dose marijuana (2 times/week with 5 days/week sham) and d) high dose marijuana (7 times/week). A smoke exposure consisted of smoke from one cigarette (2.6% THC) burned down to 10 mm butt length. Smoke was administered via smoke generator (ADL II, Arthur D. Little, Inc. Cambridge, MA) and nose-mouth only masks (local production) equipped with one-way valves.

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