1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl] cytosine, an intracellular prodrug for (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine with improved therapeutic index in vivo.

Recombinant immunotoxins are extremely promising agents for the targeted therapy of tumors with a certain molecular profile. In this work, we studied the properties of a new recombinant HER2-specific immunotoxin composed of the scFv antibody and a fragment of Pseudomonas exotoxin A (4D5scFv-PE40). High affinity of the immunotoxin for the HER2 tumor marker, its selective cytotoxicity against HER2-overexpressing cells, and its storage stability were demonstrated. The 50% inhibitory concentration (IC50) of the 4D5scFv-PE40 immunotoxin for HER2-overexpressing cancer cells was 2.5-3 orders of magnitude lower compared to that for CHO cells not expressing this tumor marker and was 2.5-3 orders of magnitude lower than IC50 of free PE40 for HER2-overexpressing cancer cells. These findings provide a basis for expecting in the long run high therapeutic index values of the 4D5scFv-PE40 immunotoxin for its use in vivo.

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Nanoparticles Enable Efficient Delivery of Antimicrobial Peptides for the Treatment of Deep Infections

BIO Integration ◽

10.15212/bioi-2021-0003 ◽

2021 ◽

Author(s):

Yingxue Deng ◽

Rui Huang ◽

Songyin Huang ◽

Menghua Xiong

Keyword(s):

Antimicrobial Peptides ◽

Broad Spectrum ◽

Antimicrobial Properties ◽

Therapeutic Index ◽

Resistant Bacteria ◽

Drug Resistant ◽

Drug Resistant Bacteria ◽

Efficient Delivery ◽

Delivery Vehicles

Antimicrobial peptides (AMPs) have emerged as promising alternatives of traditional antibiotics against drug-resistant bacteria owing to their broad-spectrum antimicrobial properties and low tendency to drugresistance. However, their therapeutic efficacy in vivo, especially for infections in deep organs, is limited owing to their systemic toxicity and low bioavailability. Nanoparticles-based delivery systems offer a strategy to increase the therapeutic index of AMPs by preventing proteolysis, increasing the accumulation at infection sites, and reducing toxicity. Herein, we will discuss the current progress of using nanoparticles as delivery vehicles for AMPs for the treatment of deep infections.

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Antitumor activity of esorubicin in human tumor clonogenic assay with comparisons to doxorubicin.

Journal of Clinical Oncology ◽

10.1200/jco.1984.2.4.282 ◽

1984 ◽

Vol 2 (4) ◽

pp. 282-286 ◽

Cited By ~ 12

Author(s):

S E Salmon ◽

L Young ◽

B Soehnlen ◽

R Liu

Keyword(s):

Antitumor Activity ◽

Clonogenic Assay ◽

Human Tumor ◽

Therapeutic Index ◽

In Vivo Studies ◽

Early Results ◽

Colony Forming Units ◽

Human Solid Tumors

The new anthracycline analog, esorubicin (4'deoxy-doxorubicin, ESO), was tested against fresh biopsies of human solid tumors in vitro in clonogenic assay and the results were contrasted to those obtained with doxorubicin (DOX). ESO appeared to be significantly more potent on a weight basis than DOX in these studies, and exhibited a spectrum of antitumor activity in vitro that was in general qualitatively similar to that observed with DOX. In vitro antitumor activity was observed in a wide variety of human cancers including anthracycline-sensitive tumor types. ESO has previously been reported to have decreased cardiac toxicity in preclinical models as compared to DOX. Comparative testing of these anthracyclines on granulocyte-macrophage colony-forming units (GM-CFUs) and tumor colony forming units (TCFUs) indicated that the in vitro GM-CFU assay is more sensitive to these myelosuppressive drugs than are TCFUs, and underscores the need for in vivo studies to determine normal tissue toxicity and the therapeutic index of a drug. Early results of phase I studies suggest that with respect to myelosuppression, the maximally tolerated dose of ESO will be about half that of DOX. The increased in vitro antitumor potency observed for ESO and a spectrum of activity (even at one half the dose of DOX) supports the broad testing of ESO in the clinic to determine whether it will prove to be a more effective and less toxic anthracycline.

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Tumor Targeted Nanoparticles Improve Therapeutic Index of BCL2 and MCL1 dual inhibition

Blood ◽

10.1182/blood.2020008017 ◽

2020 ◽

Author(s):

Neeta Bala Tannan ◽

Mandana T Manzari ◽

Laurie Herviou ◽

Mariana da Silva Ferreira ◽

Connor J Hagen ◽

...

Keyword(s):

Ex Vivo ◽

Therapeutic Index ◽

Drug Dose ◽

Hematological Toxicity ◽

Bcl2 Family ◽

Fold Reduction ◽

Tumor Killing ◽

Toxic Drugs ◽

Ex Vivo Imaging

Cancer and normal cells utilize multiple anti-apoptotic BCL2 proteins to prevent cell death. Therapeutic targeting of multiple BCL2 family proteins enhances tumor killing, but is also associated with increased systemic toxicity. Here, we demonstrate that the dual targeting of MCL1 and BCL2 proteins, using the small molecules S63845 and venetoclax, induces durable remissions in mice harboring human DLBCL tumors but is accompanied by hematological toxicity and weight loss. To mitigate these toxicities, we encapsulated S63845 or venetoclax into nanoparticles targeting P-selectin that is enriched in tumor endothelial cells. In vivo and ex vivo imaging demonstrated preferential targeting of the nanoparticles to lymphoma tumors over vital organs. Mass-spectrometry analyses after nanoparticle drug administration confirmed tumor enrichment of the drug while reducing plasma levels. Furthermore, nanoparticle encapsulation allowed 3.5 to 6.5-fold reduction in drug dose, induced sustained remissions and minimized toxicity. Our results support the development of nanoparticles to deliver BH3 mimetic combinations in lymphoma and in general for toxic drugs in cancer therapy.

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Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors

Nature Communications ◽

10.1038/s41467-019-12409-w ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 11

Author(s):

Matthew J. Sale ◽

Emma Minihane ◽

Noel R. Monks ◽

Rebecca Gilley ◽

Frances M. Richards ◽

...

Keyword(s):

Cell Death ◽

Patient Outcomes ◽

Tumour Growth ◽

Therapeutic Index ◽

Synthetic Lethal ◽

Bcl2 Family ◽

Family Activity ◽

Pathway Inhibition ◽

Tumour Cell Death

AbstractBRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-XL expression in melanoma biases the pro-survival pool towards MCL1. Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, driving profound tumour cell death that requires BAK/BAX, BIM and BMF, and inhibiting tumour growth in vivo. Combination of ERK1/2 pathway inhibitors with BCL2/BCL-w/BCL-XL inhibitors is stronger in CRC, correlating with a low MCL1:BCL-XL ratio; indeed the MCL1:BCL-XL ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL2/BCL-w/BCL-XL inhibitors. Finally, AZD5991 delays acquired BRAFi/MEKi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi + MEKi resistance. Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes.

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Use of Magnetic Nanoparticles as Targeted Therapy: Theranostic Approach to Treat and Diagnose Cancer

Journal of Nanotechnology ◽

10.1155/2017/1098765 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Arif Malik ◽

Tariq Tahir Butt ◽

Sara Zahid ◽

Fatima Zahid ◽

Sulayman Waquar ◽

...

Keyword(s):

Magnetic Nanoparticles ◽

Cancer Imaging ◽

Metastatic Cancer ◽

Therapeutic Index ◽

Direct Access ◽

Human Beings ◽

Clinical Practices ◽

Proliferating Cells

The metastasis of cancer epitomizes the diagnostic and therapeutic challenge as a result of cancer heterogeneity. To overcome the uncontrolled growth of the proliferating cells, nanosystems have been developed and have undergone many preclinical trials both in vitro and in vivo and many practices have been further applied clinically on human beings. In practice, magnetic nanoparticles- (MNPs-) based systems following the application of Fe3O4 bound antitumor drug have shown an enhanced therapeutic index in comparison with conventional chemotherapy ensuring the significant decline in nanosystems’ toxicity. A number of improved strategies employing nanoparticle engineering have been in practice for upgrading selectivity of metastatic cells and to have direct access to poorly manageable tumor regions. Targeted nanoparticle therapy paving the way towards tumor biomarkers and tissue specific cancer stages provides effective strategies for nonaccessible tumor regions, thus leading to the tangible modification in the history of cancer world. An infinite number of targets have been exploited for surface receptor specificity to distinct types of nanoparticles and are presently enduring clinical practices both in vitro and in vivo. The aim of this review is to take into view current nanotechnology-based research in cancer imaging for diagnosis and treatment. Several commercially available magnetic nanoparticles-based systems applied as contrast agents for metastatic cancer imaging and treatment via hyperthermia have also been focused on.

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Molecular modification of a recombinant anti-CD3ε-directed immunotoxin by inducing terminal cysteine bridging enhances anti-GVHD efficacy and reduces organ toxicity in a lethal murine model

Blood ◽

10.1182/blood.v96.3.1157 ◽

2000 ◽

Vol 96 (3) ◽

pp. 1157-1165 ◽

Cited By ~ 7

Author(s):

Daniel A. Vallera ◽

David W. Kuroki ◽

Angela Panoskaltsis-Mortari ◽

Donald J. Buchsbaum ◽

Buck E. Rogers ◽

...

Keyword(s):

Therapeutic Index ◽

Maximum Tolerated Dose ◽

Cysteine Residue ◽

Genetically Engineered ◽

Therapeutic Window ◽

Single Chain ◽

Molecular Modification ◽

Organ Toxicity

Abstract Immunotoxin (IT) therapy shows potential for selectively eliminating GVHD-causing T cells in vivo, but the field has been hampered by toxicity. Previously, we showed that a genetically engineered IT consisting of a single-chain protein, including the anti-CD3sFv spliced to a portion of diphtheria-toxin (DT390) has anti-GVHD effects, but pronounced organ toxicity common to this class of agent. A recombinant DT390 anti-CD3sFv protein previously shown to have anti-GVHD activity was modified to reduce its filtration into kidney by genetically inserting a cysteine residue downstream of the sFv moiety at the c-terminus of the protein. This modification produced an intermolecular disulfide bridge, resulting in a bivalent, rather than a monovalent IT, termed SS2, that selectively inhibited T-cell proliferation in vitro. Although monomer and SS2 were similar in in vitro activity, SS2 had a superior therapeutic index in vivo with at least 8-fold more being tolerated with reduced kidney toxicity. Most importantly, in a lethal model of GVHD, 40 μg SS2 given for 1 day, protected 100% of the mice from lethal GVHD for 3 months, whereas the maximum tolerated dose (MTD) of monomer protected only 33%. To our knowledge, this is the first time disulfide bonded ITs have been created in this way and this simple molecular modification may address several problems in the IT field because it (1) markedly increased efficacy curing mice of GVHD after a single daily treatment, (2) markedly decreased organ toxicity, (3) increased the tolerated dosage, and (4) created a therapeutic window where none existed before.

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In Vivo Antimalarial Activities of Mono- and Bis Quaternary Ammonium Salts Interfering with Plasmodium Phospholipid Metabolism

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.8.2598-2605.2003 ◽

2003 ◽

Vol 47 (8) ◽

pp. 2598-2605 ◽

Cited By ~ 52

Author(s):

Marie L. Ancelin ◽

Michèle Calas ◽

Anne Bonhoure ◽

Serge Herbute ◽

Henri J. Vial

Keyword(s):

Quaternary Ammonium ◽

Lethal Dose ◽

Intraperitoneal Administration ◽

Therapeutic Index ◽

Phospholipid Metabolism ◽

Quaternary Ammonium Salts ◽

Ammonium Salts ◽

Once Daily ◽

Elimination Half

ABSTRACT We previously showed that quaternary ammonium salts have potent antimalarial activities against the blood stage of drug-resistant Plasmodium falciparum. In the present study, 13 compounds of this series were comparatively assessed in murine in vivo malarial models. Mice infected with Plasmodium berghei were successfully treated with 11 quaternary ammonium salts in a 4-day suppressive test with a once-daily intraperitoneal administration. The dose required to decrease parasitemia by 50% (ED50) ranged from 0.04 to 4.5 mg/kg of body weight. For six mono- and three bis-quaternary ammonium salts, the therapeutic indices (i.e., 50% lethal dose and ED50) were higher than 5, and at best, around 20 to 30 for five of them (E6, E8, F4, G5, and G25), which is comparable to that of chloroquine under the same conditions. Plasmodium chabaudi was significantly more susceptible to G5, G15, and G25 compounds than P. berghei. Similar therapeutic indices were obtained, regardless of the administration mode or initial parasitemia (up to 11.2%). Parasitemia clearance was complete without recrudescence. Subcutaneously administered radioactive compounds had a short elimination half-life in mice (3.5 h) with low bioavailability (17.3%), which was likely due to the permanent cationic charge of the molecule. The high in vivo therapeutic index in the P. chabaudi-infected mouse model and the absence of recrudescence highlight the enormous potential of these quaternary ammonium salts for clinical malarial treatment.

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Molecular modification of a recombinant anti-CD3ε-directed immunotoxin by inducing terminal cysteine bridging enhances anti-GVHD efficacy and reduces organ toxicity in a lethal murine model

Blood ◽

10.1182/blood.v96.3.1157.015k56_1157_1165 ◽

2000 ◽

Vol 96 (3) ◽

pp. 1157-1165 ◽

Cited By ~ 2

Author(s):

Daniel A. Vallera ◽

David W. Kuroki ◽

Angela Panoskaltsis-Mortari ◽

Donald J. Buchsbaum ◽

Buck E. Rogers ◽

...

Keyword(s):

Therapeutic Index ◽

Maximum Tolerated Dose ◽

Cysteine Residue ◽

Genetically Engineered ◽

Therapeutic Window ◽

Single Chain ◽

Molecular Modification ◽

Organ Toxicity

Immunotoxin (IT) therapy shows potential for selectively eliminating GVHD-causing T cells in vivo, but the field has been hampered by toxicity. Previously, we showed that a genetically engineered IT consisting of a single-chain protein, including the anti-CD3sFv spliced to a portion of diphtheria-toxin (DT390) has anti-GVHD effects, but pronounced organ toxicity common to this class of agent. A recombinant DT390 anti-CD3sFv protein previously shown to have anti-GVHD activity was modified to reduce its filtration into kidney by genetically inserting a cysteine residue downstream of the sFv moiety at the c-terminus of the protein. This modification produced an intermolecular disulfide bridge, resulting in a bivalent, rather than a monovalent IT, termed SS2, that selectively inhibited T-cell proliferation in vitro. Although monomer and SS2 were similar in in vitro activity, SS2 had a superior therapeutic index in vivo with at least 8-fold more being tolerated with reduced kidney toxicity. Most importantly, in a lethal model of GVHD, 40 μg SS2 given for 1 day, protected 100% of the mice from lethal GVHD for 3 months, whereas the maximum tolerated dose (MTD) of monomer protected only 33%. To our knowledge, this is the first time disulfide bonded ITs have been created in this way and this simple molecular modification may address several problems in the IT field because it (1) markedly increased efficacy curing mice of GVHD after a single daily treatment, (2) markedly decreased organ toxicity, (3) increased the tolerated dosage, and (4) created a therapeutic window where none existed before.

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Lowering S-Adenosylmethionine Levels inEscherichia coli Modulates C-to-T Transition Mutations

Journal of Bacteriology ◽

10.1128/jb.183.3.921-927.2001 ◽

2001 ◽

Vol 183 (3) ◽

pp. 921-927 ◽

Cited By ~ 14

Author(s):

Georgina Macintyre ◽

C. Victoria Atwood ◽

Claire G. Cupples

Keyword(s):

Escherichia Coli ◽

Dna Methylation ◽

Genomic Dna ◽

Synthetase Activity ◽

Inescherichia Coli ◽

Genome Methylation ◽

Sam Synthetase ◽

Methyl Cytosine

ABSTRACT Deoxycytosine methylase (Dcm) enzyme activity causes mutagenesis in vitro either directly by enzyme-induced deamination of cytosine to uracil in the absence of the methyl donor,S-adenosylmethionine (SAM), or indirectly through spontaneous deamination of [5-methyl]cytosine to thymine. Using a Lac reversion assay, we investigated the contribution of the first mechanism to Dcm mutagenesis in vivo by lowering the levels of SAM.Escherichia coli SAM levels were lowered by reducing SAM synthetase activity via the introduction of a metK84 allele or by hydrolyzing SAM using the bacteriophage T3 SAM hydrolase. ThemetK84 strains exhibited increased C-to-T mutagenesis. Expression of the T3 SAM hydrolase gene, under the control of the arabinose-inducible PBAD promoter, effectively reduced Dcm-mediated genomic DNA methylation. However, increased mutagenesis was not observed until extremely high arabinose concentrations were used, and genome methylation at Dcm sites was negligible.

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