scholarly journals Monofunctional platinum(ii) anticancer complexes based on multidentate phenanthridine-containing ligand frameworks

2020 ◽  
Vol 49 (20) ◽  
pp. 6557-6560 ◽  
Author(s):  
Issiah B. Lozada ◽  
Bin Huang ◽  
Morgan Stilgenbauer ◽  
Travis Beach ◽  
Zihan Qiu ◽  
...  
Keyword(s):  
Therapeutic Index ◽  
Multidentate Ligands ◽  
Anticancer Complexes

Pt(ii) complexes supported by chelating, multidentate ligands containing phenanthridine heterocycles are reported and shown to exhibit a superior in vitro therapeutic index compared with phenanthriplatin and cisplatin.

Biochemical and Pharmacological Properties of SANORG 34006, a Potent and Long-Acting Synthetic Pentasaccharide

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4197-4205 ◽  
Author(s):  
J.M. Herbert ◽  
J.P. Hérault ◽  
A. Bernat ◽  
R.G.M. van Amsterdam ◽  
J.C. Lormeau ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Therapeutic Index ◽  
Inhibitory Effect ◽  
Experimental Models ◽  
Treatment And Prevention ◽  
Long Acting

Abstract SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the “synthetic pentasaccharide” (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 ± 0.3 v 48 ± 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 ± 15 anti–factor Xa U/mg v850 ± 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti–factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti–factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50values = 40.0 ± 3.4 and 105.0 ± 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti–factor Xa activity. SANORG 34006 enhanced rt-PA–induced thrombolysis and inhibited accretion of125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.

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

1984 ◽  
Vol 2 (4) ◽  
pp. 282-286 ◽  
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.

A phase II study of combined methotrexate and teniposide infusions prior to reinduction therapy in relapsed childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study.

1991 ◽  
Vol 9 (1) ◽  
pp. 139-144 ◽  
Author(s):  
J Ochs ◽  
J Rodman ◽  
M Abromowitch ◽  
R Kavanagh ◽  
M Harris ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Lymphoblastic Leukemia ◽  
Therapeutic Index ◽  
Small Sample ◽  
Therapeutic Window ◽  
Infusion Schedule ◽  
Small Sample Sizes

Teniposide (VM-26) can increase intracellular methotrexate (MTX) and its polyglutamate derivatives in vitro and thus has the potential to improve the therapeutic index of regimens containing MTX. In this phase II study, children and adolescents with acute lymphoblastic leukemia (ALL) in first or second marrow relapse were randomly assigned to receive either simultaneous (n = 11) or sequential (n = 12) continuous infusions of MTX and VM-26 prior to reinduction. Infusions of VM-26 were begun 12 hours after completion of MTX infusion in the sequential group. Dosages were individually adjusted to maintain plasma concentration levels of 10 microns for MTX and 15 microns for VM-26; total infusion times were 24 and 72 hours, respectively. Significant toxicity in the first six patients who received the scheduled 72-hour VM-26 infusion (including one drug-related death) prompted a 50% reduction in infusion duration. The reduced dose was associated with similar but more manageable toxicity. Examination of bone marrow aspirates 10 days after therapy was begun showed one complete and two partial marrow remissions; a fourth patient who had an aplastic marrow on day 10 received no further chemotherapy and had a complete remission (CR) documented on day 31. There was no obvious clinical advantage associated with either infusion schedule, although small sample sizes preclude definitive conclusions. The 17% response rate to the MTX/VM-26 therapeutic window in patients with refractory disease suggests the need for further investigation to evaluate alternative schedules and concomitant therapy for this drug combination.

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

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
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.

scholarly journals Synthesis and Evaluation of Anti-Rhinovirus 1B Activity of Oxazolinyl-Isoflavans and -3(2H)-Isoflavenes

1992 ◽  
Vol 3 (4) ◽  
pp. 195-202 ◽  
Author(s):  
N. Desideri ◽  
C. Conti ◽  
I. Sestili ◽  
P. Tomao ◽  
M. L. Stein ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Antiviral Activity ◽  
Cytopathic Effect ◽  
Potent Inhibitor ◽  
Therapeutic Index ◽  
Intermediate Compound ◽  
Plaque Formation ◽  
Interesting Compound ◽  
Viral Cytopathic Effect

Oxazolinyl-isoflavans and −3(2H)-isoflavenes, substituted or not with a chlorine atom, were synthesized in order to compare their anti-rhinovirus activity with that of previously studied analogous compounds. The activity of the oxazolines and of the esters and acids, which are intermediates in the synthesis, was studied in vitro against rhinovirus serotype 1B infection in HeLa cells. The ability of various non cytotoxic concentrations to interfere with the development of the viral cytopathic effect and plaque formation was examined. All the tested compounds exerted a significant antiviral activity, and most of them were as active as some representative compounds of the oxazolinyl-phenoxyalkylisoxazole (WIN) series. 6-Oxazolinylisoflavan (VI) appeared to be the most interesting compound due to its high activity and therapeutic index. Among the substituted isoflavans and isoflavenes tested so far, the intermediate compound 6-chloro-3 (2H)-isoflavene-4′-carboxylic acid (XIX) was unexpectedly the most potent inhibitor of rhinovirus 1B plaque formation.

scholarly journals In vitro anti-influenza virus effect of total flavonoid from Trollius ledebouri Reichb

2018 ◽  
Vol 46 (4) ◽  
pp. 1380-1390 ◽  
Author(s):  
Yongping Liu ◽  
Jiming Tong ◽  
Ying Tong ◽  
Ping Li ◽  
Xiaolan Cui ◽  
...  
Keyword(s):  
Virus Type ◽  
Influenza A ◽  
North China ◽  
Therapeutic Index ◽  
Total Flavonoid ◽  
Syncytial Virus ◽  
Group B ◽  
Pathway Analyses

Objective To investigate the in vitro antivirus effect of total flavonoid from Trollius ledebouri Reichb (TFTLR). Methods Madin-Darby canine kidney (MDCK) and Human epithelial type 2 (HEp-2) cell lines were used to test the antivirus effect of TFTLR on nine virus subtypes: four H1N1, one H3N2, and four other subtypes prevalent in North China. Tamiflu, Ribavirin and Lianhua Qingwen were used as active comparators. Comprehensive molecular pathway analyses of TFTLR-H1N1 and TFTLR-H3N2 relationships were also conducted. Results TFTLR inhibited MDCK cell lesions induced by H1N1 subtypes (A/FM1/1/47, A/Puerto Rico/8/1934 H1N1, A1/Tianjin Jinnan/15/2009, and A/Brisbane/59/2007) and by the H3N2 Brisbane/10/2009 strain. TFTLR inhibitory concentration (IC)50 values against these viruses were 0.13, 0.07, 0.06, 0.14, and 0.07 mg/ml, respectively; and therapeutic index (TI) values were 8.62, 16.0, 18.67, 8.0, and 16.0, respectively. TFTLR showed no effect on parainfluenza virus type 1, herpes simplex virus type 1, respiratory syncytial virus, and coxsackie group B virus type 4. Pathway analysis revealed possible functional therapeutic mechanisms for TFTLR against H1N1 and H3N2 infections. Conclusion TFTLR may represent a potential therapeutic agent against influenza A subtypes H1N1 and H3N2 that are prevalent in North China, and should be investigated further.

scholarly journals Modulation of nitrosourea resistance in myeloid leukemias

Blood ◽  
1988 ◽  
Vol 71 (5) ◽  
pp. 1487-1494 ◽  
Author(s):  
SL Gerson ◽  
JE Trey
Keyword(s):  
Dna Repair ◽  
Therapeutic Index ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Biochemical Modulation ◽  
Repair Protein ◽  
Myeloid Leukemias ◽  
Dna Repair Protein ◽  
Dna Alkyltransferase

Abstract Drug resistance in myeloid leukemias may be mediated by an increased capacity to repair chemotherapy-induced DNA damage. Some tumor cell lines that are resistant to nitrosoureas contain the DNA repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase). This protects cells by removing cytotoxic, nitrosourea-induced O6-alkylguanine adducts. We measured the level of alkyltransferase activity in myeloid leukemic cells freshly obtained from patients to determine whether the alkyltransferase was an important factor in nitrosourea resistance in these cells and whether inactivation of this protein could sensitize leukemic cells to nitrosoureas. Myeloid leukemic cells from patients with acute nonlymphocytic leukemia and chronic myelogenous leukemia had higher levels of alkyltransferase than did myeloid precursors from normal donors (P less than .01). This difference did not appear to be due to the state of differentiation of the leukemic or normal cells. To show that this repair protein mediated nitrosourea resistance in leukemic cells, cells were treated with the modified base O6- methylguanine to selectively and irreversibly inactivate the alkyltransferase and then exposed to 1,3-bis (2-chloroethyl)-1- nitrosourea (BCNU). An 18-hour incubation in 0.5 mmol/L O6- methylguanine caused an 87% +/- 3.6% decrease in alkyltransferase activity in leukemic cells and a 73% +/- 8.6% decrease in normal myeloid precursors. After treatment with O6-methylguanine, clonogenic leukemic cells from ten different donors became much more sensitive to BCNU, with a decrease in the dose needed to reduce colony survival by 50% (LD50) of 6.3 +/- 1.4-fold. A lesser effect was seen on CFU-GM, BFU- E, and CFU-GEM where the LD50 decreased two- to threefold. These studies show that nitrosourea resistance in myeloid leukemic cells can be abrogated by inactivation of the DNA repair protein O6-alkylguanine- DNA alkyltransferase. This method of biochemical modulation of DNA repair will sensitize leukemic cells to nitrosoureas in vitro and has the potential of increasing the therapeutic index of nitrosoureas in this disease.

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 ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1157-1165 ◽  
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.

In Vitro Biological Activity of Adriamycin

1970 ◽  
Vol 56 (3) ◽  
pp. 137-148 ◽  
Author(s):  
Rosella Silvestrini ◽  
Carmela Gambarucci ◽  
Teresa Dasdia
Keyword(s):  
Biological Activity ◽  
Cellular Proliferation ◽  
Therapeutic Index ◽  
Dna And Rna ◽  
Total Inhibition ◽  
A Cell ◽  
Nuclear Structures ◽  
Higher Doses

Adriamycin is an antibiotic, isolated from cultures of a mutant of Streptomyces peucetius, var. caesius, with a chemical structure very similar to daunomycin but with a higher therapeutic index in experimental tumors. The biological activity of this antibiotic has been studied in vitro on the HeLa cell strain. Adriamycin quickly penetrates into the cells and fixes to the nuclear structures with a marked localization at the level of the perinucleolar chromatin. It causes a marked and immediate disturbance of the mitotic process, viz. pre-prophasic inhibition at the low doses and mitotic block at the higher doses. Even the synthesis of DNA and RNA, evaluated autoradiographically as incorporation of 3H-thymidine and 3H-uridine, appear markedly inhibited. The viability of the cells, tested both as regards capacity to give rise to colonies and as regards proliferative activity of a cell population, was seriously reduced, in a degree proportional to the period of treatment and to the concentration of the antibiotic, until total inhibition. In comparison with daunomycin, adriamycin exerts an immediate antimitotic and anti-metabolic effect which, at equivalent doses, is slightly lower than that of daunomycin. The long-term antiproliferative activity on cellular proliferation is however, identical for the two antibiotics.

scholarly journals The HEPT Analogue WPR-6 Is Active against a Broad Spectrum of Nonnucleoside Reverse Transcriptase Drug-Resistant HIV-1 Strains of Different Serotypes

2015 ◽  
Vol 59 (8) ◽  
pp. 4882-4888 ◽  
Author(s):  
Weisi Xu ◽  
Jianxiong Zhao ◽  
Jianping Sun ◽  
Qianqian Yin ◽  
Yan Wang ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Therapeutic Index ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
Highly Active ◽  
Hiv Drugs ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACTNonnucleoside reverse transcriptase inhibitors (NNRTIs) are important components of the highly active antiretroviral therapy (HAART) used to treat human immunodeficiency type 1 virus (HIV-1). However, because of the emergence of drug resistance and the adverse effects of current anti-HIV drugs, it is essential to develop novel NNRTIs with an excellent safety profile, improved activity against NNRTI-resistant viruses, and enhanced activity against clinical isolates of different subtypes. Here, we have identified 1-[(benzyloxy)methyl]-6-(3,5-dimethylbenzyl)-5-iodopyrimidine-2,4(1H,3H)-dione (WPR-6), a novel NNRTI with a 50% effective concentration (EC50) of 2 to 4 nM against laboratory-adapted HIV-1 strain SF33 and an EC50of 7 to 14 nM against nucleoside reverse transcriptase inhibitor-resistant HIV-1 strain 7391 with a therapeutic index of >1 × 104. A panel of five representative clinical virus isolates of different subtypes circulating predominantly in China was highly sensitive to WPR-6, with EC50s ranging from 1 to 6 nM. In addition, WPR-6 showed excellent antiviral potency against the most prevalent NNRTI-resistant viruses containing the K103N and Y181C mutations. To determine whether WPR-6 selects for novel resistant mutants,in vitroresistance selection was conducted with laboratory-adapted HIV-1 strain SF33 on MT-4 cells. The results demonstrated that V106I and Y188L were the two dominant NNRTI-associated resistance mutations detected in the breakthrough viruses. Taken together, thesein vitrodata indicate that WPR-6 has greater efficacy than the reference HEPT analogue TNK651 and the marketed drug nevirapine against HIV-1. However, to develop it as a new NNRTI, further improvement of its pharmacological properties is warranted.

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