Cryo, Hyper or Both? Investigating Combination Cryo/Hyperthermia in the Dorsal Skin Flap Chamber

Mapping Intimacies ◽

10.1115/imece2000-2239 ◽

2000 ◽

Author(s):

Nathan E. Hoffmann ◽

Bo H. Chao ◽

John C. Bischof

Keyword(s):

Combination Therapy ◽

Thermal History ◽

Standard Treatment ◽

Tissue Injury ◽

Skin Flap ◽

Dorsal Skin ◽

Combination Therapies ◽

Disease Treatment ◽

Copenhagen Rat

Abstract Combination therapies have been investigated as a mean to increase efficacy of disease treatment. For example, combinations such as radiation and chemotherapy, surgery and chemotherapy, and two different chemotherapies have become standard treatment for most cancers. Current theories suggest that vascular-mediated injury is an important mechanism of cryosurgical (reviewed in Gage and Baust (1998)) and hyperthermic destruction (Badylak et al., 1985; Dudar and Jain, 1984) in the treatment of solid tumors. These techniques appear complementary. Freezing creates vascular damage and promotes stasis within the vessels (Rabb et al., 1974), whereas hyperthermia creates cell and vascular destruction more effectively with a compromised vasculature (Shakil et al., 1999). Thus, in this study, we investigated the effect of combining these therapies on the vascular and tissue injury from the two therapies. We chose the dorsal skin flap chamber (DSFC) implanted in the Copenhagen rat as the cryosurgical model for this study. This in vivo freezing model allowed us to monitor thermal history and investigate both vascular and tissue injury in response to the combination therapy.

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Observation of Vascular Injury After Freezing: Investigating the Response of Normal Skin and Subcutaneous AT-1 Tumor Tissue to Cryosurgery in the Dorsal Skin Flap Chamber

10.1115/imece1999-0579 ◽

1999 ◽

Author(s):

Nathan E. Hoffmann ◽

David J. Swanlund ◽

John C. Bischof

Keyword(s):

Vascular Injury ◽

Thermal History ◽

Host Response ◽

Tissue Injury ◽

Skin Flap ◽

Tissue Type ◽

Crystal Formation ◽

Dorsal Skin ◽

Tissue Necrosis

Abstract Two main mechanisms have been explored in an attempt to explain injury to the cells of tissues due to freezing in vivo. The first is direct cellular injury caused by injurious osmotic changes and ice crystal formation that happens as a result of freezing (Mazur, 1984). The second is host response injury caused by the vascular damage and immunologic response in response to freezing (Gage and Baust, 1998). The amount of injury caused by freezing appears to vary with tissue type and thermal history of the freezing protocol. The hypothesis of this study was that host response injury, specifically vascular injury, causes the majority of tissue necrosis at the edge of a frozen region and therefore determines the size of the lesion seen after in vivo freezing. Many investigations have previously made a qualitative correlation between thermal history, vascular injury, and tissue necrosis (e.g. Greene. 1943 and Rabb et al., 1974). We chose the dorsal skin flap chamber (DSFC) implanted in the Copenhagen rat as the cryosurgical model for this study. This in vivo freezing model appears insensitive to the immunologic phenomenon (Hoffmann et al., 1999) and allows us to monitor thermal history and investigate both vascular and tissue injury in response to cryosurgery.

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The Evolving Reduction of Vancomycin and Daptomycin Susceptibility in MRSA—Salvaging the Gold Standards with Combination Therapy

Antibiotics ◽

10.3390/antibiotics9110762 ◽

2020 ◽

Vol 9 (11) ◽

pp. 762

Author(s):

Taylor Morrisette ◽

Sara Alosaimy ◽

Jacinda C. Abdul-Mutakabbir ◽

Razieh Kebriaei ◽

Michael J. Rybak

Keyword(s):

Combination Therapy ◽

Patient Outcomes ◽

Treatment Option ◽

Standard Treatment ◽

Primary Treatment ◽

Alternative Approach ◽

Improve Patient ◽

Substantial Morbidity

Methicillin-resistant Staphylococcus aureus (MRSA) is associated with substantial morbidity and mortality. Vancomycin (VAN) has been used as the gold standard treatment for invasive MRSA infections for decades but, unfortunately, the reliance of VAN as the primary treatment option against these infections has led to a reduction in VAN susceptibility in MRSA isolates. Although daptomycin (DAP) is another common treatment option against invasive MRSA infections, it has been shown that the development of VAN resistance can lead to DAP nonsusceptibility. VAN or DAP backbone regimens in combination with other antibiotics has been advocated as an alternative approach to improve patient outcomes in VAN/DAP-susceptible infections, enhance outcomes in infections caused by isolates with reduced VAN/DAP susceptibility, and/or prevent the emergence of VAN/DAP resistance or further resistance. A peer-reviewed literature search was conducted using Medline, Google Scholar and PubMed databases. The primary purpose of this review is to describe the mechanisms and epidemiology of MRSA isolates with a reduction in VAN and/or DAP susceptibility, evaluate in vitro and in vivo literature describing combination therapy (CT) against MRSA isolates with reduced VAN and/or DAP susceptibility and describe studies involving the clinical outcomes of patients treated with CT against invasive MRSA infections.

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Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochromebc1Inhibition Strategy for Malaria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00791-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4853-4859 ◽

Cited By ~ 27

Author(s):

Allison M. Stickles ◽

Martin J. Smilkstein ◽

Joanne M. Morrisey ◽

Yuexin Li ◽

Isaac P. Forquer ◽

...

Keyword(s):

Combination Therapy ◽

Acute Infection ◽

Quinone Reductase ◽

Infection Model ◽

Combination Therapies ◽

Content Type ◽

Infection Models ◽

Dual Site ◽

High Parasitemia

ABSTRACTAntimalarial combination therapies play a crucial role in preventing the emergence of drug-resistantPlasmodiumparasites. Although artemisinin-based combination therapies (ACTs) comprise the majority of these formulations, inhibitors of the mitochondrial cytochromebc1complex (cytbc1) are among the few compounds that are effective for both acute antimalarial treatment and prophylaxis. There are two known sites for inhibition within cytbc1: atovaquone (ATV) blocks the quinol oxidase (Qo) site of cytbc1, while some members of the endochin-like quinolone (ELQ) family, including preclinical candidate ELQ-300, inhibit the quinone reductase (Qi) site and retain full potency against ATV-resistantPlasmodium falciparumstrains with Qosite mutations. Here, we provide the firstin vivocomparison of ATV, ELQ-300, and combination therapy consisting of ATV plus ELQ-300 (ATV:ELQ-300), usingP. yoeliimurine models of malaria. In our monotherapy assessments, we found that ATV functioned as a single-dose curative compound in suppressive tests whereas ELQ-300 demonstrated a unique cumulative dosing effect that successfully blocked recrudescence even in a high-parasitemia acute infection model. ATV:ELQ-300 therapy was highly synergistic, and the combination was curative with a single combined dose of 1 mg/kg of body weight. Compared to the ATV:proguanil (Malarone) formulation, ATV:ELQ-300 was more efficacious in multiday, acute infection models and was equally effective at blocking the emergence of ATV-resistant parasites. Ultimately, our data suggest that dual-site inhibition of cytbc1is a valuable strategy for antimalarial combination therapy and that Qisite inhibitors such as ELQ-300 represent valuable partner drugs for the clinically successful Qosite inhibitor ATV.

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Cryosurgery of Normal and Tumor Tissue in the Dorsal Skin Flap Chamber: Part I—Thermal Response

Journal of Biomechanical Engineering ◽

10.1115/1.1385838 ◽

2001 ◽

Vol 123 (4) ◽

pp. 301-309 ◽

Cited By ~ 57

Author(s):

Nathan E. Hoffmann ◽

John C. Bischof

Keyword(s):

Blood Flow ◽

Thermal Properties ◽

Thermal History ◽

Tumor Tissue ◽

Normal Skin ◽

Skin Flap ◽

Companion Paper ◽

Two Dimensional ◽

Dorsal Skin ◽

Freezing And Thawing

Current research in cryosurgery is concerned with finding a thermal history that will definitively destroy tissue. In this study, we measured and predicted the thermal history obtained during freezing and thawing in a cryosurgical model. This thermal history was then compared to the injury observed in the tissue of the same cryosurgical model (reported in companion paper (Hoffmann and Bischof, 2001)). The dorsal skin flap chamber, implanted in the Copenhagen rat, was chosen as the cryosurgical model. Cryosurgery was performed in the chamber on either normal skin or tumor tissue propagated from an AT-1 Dunning rat prostate tumor. The freezing was performed by placing a ∼1 mm diameter liquid-nitrogen-cooled cryoprobe in the center of the chamber and activating it for approximately 1 minute, followed by a passive thaw. This created a 4.2 mm radius iceball. Thermocouples were placed in the tissue around the probe at three locations (r=2, 3, and 3.8 mm from the center of the window) in order to monitor the thermal history produced in the tissue. The conduction error introduced by the presence of the thermocouples was investigated using an in vitro simulation of the in vivo case and found to be <10°C for all cases. The corrected temperature measurements were used to investigate the validity of two models of freezing behavior within the iceball. The first model used to approximate the freezing and thawing behavior within the DSFC was a two-dimensional transient axisymmetric numerical solution using an enthalpy method and incorporating heating due to blood flow. The second model was a one-dimensional radial steady state analytical solution without blood flow. The models used constant thermal properties for the unfrozen region, and temperature-dependent thermal properties for the frozen region. The two-dimensional transient model presented here is one of the first attempts to model both the freezing and thawing of cryosurgery. The ability of the model to calculate freezing appeared to be superior to the ability to calculate thawing. After demonstrating that the two-dimensional model sufficiently captured the freezing and thawing parameters recorded by the thermocouples, it was used to estimate the thermal history throughout the iceball. This model was used as a basis to compare thermal history to injury assessment (reported in companion paper (Hoffmann and Bischof, 2001)).

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Systematic measurement of combination drug landscapes to predict in vivo treatment outcomes for tuberculosis

10.1101/2021.02.03.429579 ◽

2021 ◽

Author(s):

Jonah Larkins-Ford ◽

Talia Greenstein ◽

Nhi Van ◽

Yonatan N. Degefu ◽

Michaela C. Olson ◽

...

Keyword(s):

Combination Therapy ◽

Treatment Outcomes ◽

Mouse Models ◽

Drug Combination ◽

Combination Therapies ◽

Therapy Outcomes ◽

Combination Drug ◽

Shorten Treatment Duration

AbstractA lengthy multidrug chemotherapy is required to achieve a durable cure in tuberculosis. Variation in Mycobacterium tuberculosis drug response is created by the differing microenvironments in lesions, which generate different bacterial drug susceptibilities. To better realize the potential of combination therapy to shorten treatment duration, multidrug therapy design should deliberately explore the vast combination space. We face a significant scaling challenge in making systematic drug combination measurements because it is not practical to use animal models for comprehensive drug combination studies, nor are there well-validated high-throughput in vitro models that predict animal outcomes. We hypothesized that we could both prioritize combination therapies and quantify the predictive power of various in vitro models for drug development using a dataset of drug combination dose responses measured in multiple in vitro models. We systematically measured M. tuberculosis response to all 2- and 3-drug combinations among ten antibiotics in eight conditions that reproduce lesion microenvironments. Applying machine learning to this comprehensive dataset, we developed classifiers predictive of multidrug treatment outcome in a mouse model of disease relapse. We trained classifiers on multiple mouse models and identified ensembles of in vitro models that best describe in vivo treatment outcomes. Furthermore, we found that combination synergies are less important for predicting outcome than metrics of potency. Here, we map a path forward to rationally prioritize combinations for animal and clinical studies using systematic drug combination measurements with validated in vitro models. Our pipeline is generalizable to other difficult-to-treat diseases requiring combination therapies.One Sentence SummarySignatures of in vitro potency and drug interaction measurements predict combination therapy outcomes in mouse models of tuberculosis.

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Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2009620118 ◽

2021 ◽

Vol 118 (13) ◽

pp. e2009620118

Author(s):

Krista M. Dalton ◽

Timothy L. Lochmann ◽

Konstantinos V. Floros ◽

Marissa L. Calbert ◽

Richard Kurupi ◽

...

Keyword(s):

Combination Therapy ◽

Pediatric Cancer ◽

Complex I ◽

Cell Toxicity ◽

Combination Therapies ◽

Cell Systems ◽

Atp Production ◽

Lactate Transporter ◽

Highly Correlated

MYCN-amplified neuroblastoma is a lethal subset of pediatric cancer. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis. The understanding that both compensatory pathways and intrinsic redundancy in cell systems exists implies that the use of combination therapies for effective and durable responses is necessary. Additionally, the most effective targeted therapies exploit an “Achilles’ heel” and are tailored to the genetics of the cancer under study. We performed an unbiased screen on select metabolic targeted therapy combinations and correlated sensitivity with over 20 subsets of cancer. We found that MYCN-amplified neuroblastoma is hypersensitive to the combination of an inhibitor of the lactate transporter MCT1, AZD3965, and complex I of the mitochondrion, phenformin. Our data demonstrate that MCT4 is highly correlated with resistance to the combination in the screen and lowly expressed in MYCN-amplified neuroblastoma. Low MCT4 combines with high expression of the MCT2 and MCT1 chaperone CD147 in MYCN-amplified neuroblastoma, altogether conferring sensitivity to the AZD3965 and phenformin combination. The result is simultaneous disruption of glycolysis and oxidative phosphorylation, resulting in dramatic disruption of adenosine triphosphate (ATP) production, endoplasmic reticulum stress, and cell death. In mouse models of MYCN-amplified neuroblastoma, the combination was tolerable at concentrations where it shrank tumors and did not increase white-blood-cell toxicity compared to single drugs. Therefore, we demonstrate that a metabolic combination screen can identify vulnerabilities in subsets of cancer and put forth a metabolic combination therapy tailored for MYCN-amplified neuroblastoma that demonstrates efficacy and tolerability in vivo.

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Optimized Induction of Mitochondrial Apoptosis By Combination Therapies with Venetoclax for Chemotherapy-Free Treatment of BCR-ABL+ Acute Lymphoblastic Leukemia in Preclinical Models

Blood ◽

10.1182/blood-2018-99-114463 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4025-4025

Author(s):

Matthias Eder ◽

Hanna Kirchhoff ◽

Karin Battmer ◽

Katharina Wohlan ◽

Melanie Ricke-Hoch ◽

...

Keyword(s):

Combination Therapy ◽

Cell Lines ◽

Lymphoblastic Leukemia ◽

Mitochondrial Apoptosis ◽

Apoptosis Induction ◽

Triple Combination ◽

Combination Therapies ◽

Triple Combination Therapy ◽

Bh3 Mimetics

Abstract Background: BCR-ABL+ acute lymphoblastic leukemia (ALL) in adults has a poor prognosis with allogeneic stem cell transplantation (SCT) considered the best curative option for suitable patients. BH3 mimetics induce mitochondrial outer membrane permeabilization (MOMP) linked to apoptosis induction by releasing BH3-only proteins BIM and/or BID from the anti-apoptotic factors BCL2, BCL-XL, MCL1, BCLW and BFL1. The BCL2-specific BH3 mimetic venetoclax (ABT-199) may provide an opportunity to improve pharmacotherapy of BCR-ABL+ ALL in particular for elderly patients not suitable for SCT. Aim: We aimed to rationally design optimized combination therapies for BCR-ABL+ ALL based on the molecular mechanisms of apoptosis induction by BH3 mimetics. Methods: We first biochemically characterized binding of BIM, a BH3 only activator of mitochondrial apoptosis, to BCL2, BCLXL and MCL1 and its release by BH3 mimetics in two BCR-ABL+ ALL cell lines. We next visualized and quantitated MOMP-induction by BH3 mimetics in viable cells. We then characterized the effects of dexamethasone and tyrosine kinase inhibitors (TKI) imatinib and dasatinib on BIM expression and calculated dose-effect combination indices (CI) for combination therapies in cell lines and two BCR-ABL+ ALL primograft models co-cultured with mesenchymal stem cells ex vivo. We finally used in vivo bioluminescence and survival analyses in murine xenotransplantation models to evaluate therapeutic efficacy in vivo. Results: In BCR-ABL+ BV173 and SUPB15 cells BIM but not BID binds to BCL2. BIM is rapidly released from BCL2 by venetoclax in a time and dose dependent manner. Release of BIM induces both MOMP (as defined by a decrease in mitochondrial membrane potential) and apoptosis (as defined by PARP cleavage and propidium iodide staining). Furthermore, BIM is strongly required for cytotoxicity of venetoclax, dasatinib and dexamethasone. Primary BCR-ABL+ ALL cells are more resistant against MOMP induction by venetoclax than BCR-ABL-negative ones, and BIM expression is reduced in these cells. Both, TKIs and dexamethasone augment BIM expression in BV173 and SUPB15 cells and act synergistically with venetoclax in cell lines and two BCR-ABL+ primografts (CI for the triple combination therapy of venetoclax, dexamethasone and dasatinib between 0.1 and 0.15, CI< 1.0 considered synergistic). Triple combinations with venetoclax, dexamethasone and TKIs efficiently attenuate leukemia progression in xenotransplantation models and, notably, the dasatinib- but not the imatinib-containing combination led to treatment- and leukemia-free long-term survival in a BCR-ABL+ mouse model. Conclusions: These data demonstrate efficacy of venetoclax in ALL. Although BCR-ABL inhibits venetoclax cytotoxicity, this inhibition can be overcome by triple combination therapy with venetoclax, dexamethasone and dasatinib. Since the triple combination therapy can be curative in preclinical xenotranplatation models clinical studies with oral chemotherapy-free regimens may be considered in particular for elderly patients not suitable for allogeneic SCT. Disclosures Ganser: Novartis: Membership on an entity's Board of Directors or advisory committees.

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A Comparison of the Anti-Inflammatory Effects of Four Combined Statin and Antiplatelet Therapies on Tumor Necrosis Factor-Mediated Acute Inflammation in vivo

Pharmacology ◽

10.1159/000499335 ◽

2019 ◽

Vol 104 (1-2) ◽

pp. 21-27 ◽

Cited By ~ 2

Author(s):

Okki Cho ◽

Han-Sol Kim ◽

Kyung-Yeon Park ◽

Tae-Hwe Heo

Keyword(s):

Tumor Necrosis Factor ◽

Combination Therapy ◽

Tumor Necrosis ◽

Acute Inflammation ◽

Therapeutic Effects ◽

Combination Therapies ◽

Beneficial Effects ◽

Anti Inflammatory ◽

Necrosis Factor

Background: Combination therapy has been administered to patients with chronic or complex diseases due to its improved therapeutic effects compared with the results of monotherapy. Due to the pleiotropic effects of statins and antiplatelets, these drugs have been studied in combination with other drugs, but not all combinations exerted obvious beneficial effects compared with individual drugs. In this study, we aimed to compare the anti-inflammatory effects of 4 different combination therapies of statins and antiplatelets on the tumor necrosis factor (TNF)-mediated inflammation in vivo. Methods: Mice were orally administered cilostazol plus pravastatin (CILOP) or cilostazol plus rosuvastatin (CILOR), clopidogrel plus pravastatin (CLOP), or clopidogrel plus rosuvastatin (CLOR); then, acute inflammation was induced by the injection of lipopolysaccharide (LPS) or TNF. Serum TNF levels, macrophage accumulation in the lesioned aortas, and mouse mortality were observed to be comparable to the anti-inflammatory effects of the combination therapies. Results: In mice with LPS-induced inflammation, CILOP and CILOR substantially reduced macrophage infiltration of aortic lesions and the serum TNF levels compared with CLOP and CLOR. Moreover, among the 4 combinations, CILOP significantly improved the survival rate of mice with TNF-mediated acute lethal inflammation. Conclusions: The combination therapy comprising cilostazol and statins, particularly pravastatin, exerted the best anti-TNF effect compared with clopidogrel and statin therapy; thus, a suitable combination therapy, such as CILOP, can be a potential remedy to cure TNF-related diseases.

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