scholarly journals Experimental Validation of a Mathematical Model to Describe the Drug Cytotoxicity of Leukemic Cells

Symmetry ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1760
Author(s):  
Ekaterina Guzev ◽  
Galia Luboshits ◽  
Svetlana Bunimovich-Mendrazitsky ◽  
Michael A. Firer
Keyword(s):  
Mathematical Model ◽  
Drug Efficacy ◽  
In Vitro Cytotoxicity ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Logistic Growth ◽  
Treatment Schedule ◽  
Cytotoxicity Studies

Chlorambucil (Chl), Melphalan (Mel), and Cytarabine (Cyt) are recognized drugs used in the chemotherapy of patients with advanced Chronic Lymphocytic Leukemia (CLL). The optimal treatment schedule and timing of Chl, Mel, and Cyt administration remains unknown and has traditionally been decided empirically and independently of preclinical in vitro efficacy studies. As a first step toward mathematical prediction of in vivo drug efficacy from in vitro cytotoxicity studies, we used murine A20 leukemic cells as a test case of CLL. We first found that logistic growth best described the proliferation of the cells in vitro. Then, we tested in vitro the cytotoxic efficacy of Chl, Mel, and Cyt against A20 cells. On the basis of these experimental data, we found the parameters for cancer cell death rates that were dependent on the concentration of the respective drugs and developed a mathematical model involving nonlinear ordinary differential equations. For the proposed mathematical model, three equilibrium states were analyzed using the general method of Lyapunov, with only one equilibrium being stable. We obtained a very good symmetry between the experimental results and numerical simulations of the model. Our novel model can be used as a general tool to study the cytotoxic activity of various drugs with different doses and modes of action by appropriate adjustment of the values for the selected parameters.

Polymeric/Inorganic Multifunctional Nanoparticles for Simultaneous Drug Delivery and Visualization

2010 ◽  
Vol 1257 ◽  
Author(s):  
Andrea Fornara ◽  
Alberto Recalenda ◽  
Jian Qin ◽  
Abhilash Sugunan ◽  
Fei Ye ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Fluorescence Microscopy ◽  
Contrast Agents ◽  
Gold Nanorods ◽  
In Vitro Cytotoxicity ◽  
In Vivo Studies ◽  
Multifunctional Nanoparticles ◽  
Cytotoxicity Studies

AbstractNanoparticles consisting of different biocompatible materials are attracting a lot of interest in the biomedical area as useful tools for drug delivery, photo-therapy and contrast enhancement agents in MRI, fluorescence and confocal microscopy. This work mainly focuses on the synthesis of polymeric/inorganic multifunctional nanoparticles (PIMN) based on biocompatible di-block copolymer poly(L,L-lactide-co-ethylene glycol) (PLLA-PEG) via an emulsion-evaporation method. Besides containing a hydrophobic drug (Indomethacin), these polymeric nanoparticles incorporate different visualization agents such as superparamagnetic iron oxide nanoparticles (SPION) and fluorescent Quantum Dots (QDs) that are used as contrast agents for Magnetic Resonance Imaging (MRI) and fluorescence microscopy together. Gold Nanorods are also incorporated in such nanostructures to allow simultaneous visualization and photodynamic therapy. MRI studies are performed with different loading of SPION into PIMN, showing an enhancement in T2 contrast superior to commercial contrast agents. Core-shell QDs absorption and emission spectra are recorded before and after their loading into PIMN. With these polymeric/inorganic multifunctional nanoparticles, both MRI visualization and confocal fluorescence microscopy studies can be performed. Gold nanorods are also synthesized and incorporated into PIMN without changing their longitudinal absorption peak usable for lased excitation and phototherapy. In-vitro cytotoxicity studies have also been performed to confirm the low cytotoxicity of PIMN for further in-vivo studies.

scholarly journals Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: a phase I trial of daily bolus infusion

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 576-585 ◽  
Author(s):  
ML Grossbard ◽  
AS Freedman ◽  
J Ritz ◽  
F Coral ◽  
VS Goldmacher ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Maximum Tolerated Dose ◽  
In Vitro Cytotoxicity ◽  
Bolus Infusion ◽  
Protein Toxin ◽  
Cytotoxicity Studies ◽  
Ricin A

Anti-B4-blocked Ricin (Anti-B4-bR) is an immunotoxin comprised of the anti-B4 monoclonal antibody (MoAb) and the protein toxin “blocked ricin.” The anti-B4 MoAb is directed against the B-lineage-restricted CD19 antigen expressed on more than 95% of normal and neoplastic B cells. Blocked ricin is an altered ricin derivative that has its nonspecific binding eliminated by chemically blocking the galactose binding domains of the B chain. In vitro cytotoxicity studies demonstrate that the IC37 of Anti-B4-bR is 2 x 10(-11) mol/L compared with 4 x 10(-12) mol/L for native ricin. A phase I dose escalation clinical trial was conducted in 25 patients with refractory B-cell malignancies. Anti-B4-bR was administered by daily 1-hour bolus infusion for 5 consecutive days at doses ranging from 1 microgram/kg/d to 60 micrograms/kg/d. Serum levels above 1 nmol/L were achieved transiently in the majority of patients treated at the maximum tolerated dose of 50 micrograms/kg/d for 5 days for a total dose of 250 micrograms/kg. The dose-limiting toxicity was defined by transient, reversible grade 3 elevations in hepatic transaminases, without impaired hepatic synthetic function. Minor toxicities included transient hypoalbuminemia, thrombocytopenia, and fevers. Human antimouse antibody and human anti-ricin antibody were detected in nine patients. One complete response, two partial responses, and eight mixed or transient responses were observed. These results show the in vitro and in vivo cytotoxicity of Anti-B4-bR and indicate that this immunotoxin can be administered as a daily bolus infusion for 5 days with tolerable, reversible toxicity.

scholarly journals Preparation, Cytotoxicity, and In Vitro Bioimaging of Water Soluble and Highly Fluorescent Palladium Nanoclusters

2020 ◽  
Vol 7 (1) ◽  
pp. 20 ◽  
Author(s):  
Suresh Thangudu ◽  
Poliraju Kalluru ◽  
Raviraj Vankayala
Keyword(s):  
In Vitro Cytotoxicity ◽  
Molecular Probes ◽  
Water Soluble ◽  
Quantum Yields ◽  
Cell Labelling ◽  
Metal Nanoclusters ◽  
Extinction Coefficients ◽  
Cytotoxicity Studies

Fluorescent probes offer great potential to identify and treat surgical tumors by clinicians. To this end, several molecular probes were examined as in vitro and in vivo bioimaging probes. However, due to their ultra-low extinction coefficients as well as photobleaching problems, conventional molecular probes limit its practical utility. To address the above mentioned challenges, metal nanoclusters (MNCs) can serve as an excellent alternative with many unique features such as higher molar extinction coefficients/light absorbing capabilities, good photostability and appreciable fluorescence quantum yields. Herein, we reported a green synthesis of water soluble palladium nanoclusters (Pd NCs) and characterized them by using various spectroscopic and microscopic characterization techniques. These nanoclusters showed excellent photophysical properties with the characteristic emission peak centered at 500 nm under 420 nm photoexcitation wavelength. In vitro cytotoxicity studies in human cervical cancer cells (HeLa) cells reveal that Pd NCs exhibited good biocompatibility with an IC50 value of >100 µg/mL and also showed excellent co-localization and distribution throughout the cytoplasm region with a significant fraction translocating into cell nucleus. We foresee that Pd NCs will carry huge potential to serve as a new generation bioimaging nanoprobe owing to its smaller size, minimal cytotoxicity, nucleus translocation capability and good cell labelling properties.

scholarly journals Immunologic and Cytogenetic Studies of Chronic Lymphocytic Leukemic Cells

Blood ◽  
1965 ◽  
Vol 26 (2) ◽  
pp. 121-132 ◽  
Author(s):  
JOOST J. OPPENHEIM ◽  
JACQUELINE WHANG ◽  
EMIL FREI
Keyword(s):  
Tritiated Thymidine ◽  
Lymphocyte Transformation ◽  
Normal Subjects ◽  
Peripheral Circulation ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Serum Factors ◽  
Cytogenetic Studies

Abstract The lymphocyte transformation response of 17 chronic lymphocytic leukemia patients when tested in the short-term tissue culture with PHA-M, and PPD was found to be significantly decreased when compared to normal subjects. Serum factors were not found to be responsible for this cellular hyporesponsiveness. The proportions of immunoresponsive lymphocytes found in the patients’ peripheral circulation decreased as their white blood cell count increased. The transformation response to PHA-M was generally better than to PPD. Neither the PPD negative patients nor the normal PPD negative subjects’ cells responded to PPD stimulation in vitro. Monocytes usually would phagocytize particles added to the cultures and could thus be distinguished from the nonphagocytic proliferating lymphocytes which were the only cells that incorporated thymidine H3. Radioautographs of tritiated thymidine also revealed the rate of PPD lymphocyte transformation to be slower than with PHA-M. There were no significant differences in the proportions or the degree of leukemic and normal transformed lymphocyte labeling with tritiated thymidine. Cytogenetic studies revealed that the patients’ mitotic indices both in vivo and in vitro were markedly depressed. The modal chromosome number was 46 in each patient, and no cytogenetic abnormalities other than those due to exposure to radiation were found.

scholarly journals Complement alternative pathway activation by chronic lymphocytic leukemia cells: its role in their hepatosplenic localization

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 463-467 ◽  
Author(s):  
F Praz ◽  
G Karsenty ◽  
JL Binet ◽  
P Lesavre
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Alternative Pathway ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Complement Alternative Pathway ◽  
Acetylneuraminic Acid ◽  
Pathway Activation ◽  
Do So

Abstract Using affinity-purified 125I-F(ab')2 anti-human C3, we have investigated the ability of various leukemic cells to activate complement. Lymphocytes from patients with chronic lymphocytic leukemia (CLL) activated the alternative pathway, but cells from patients with other forms of leukemia or normal lymphocytes did not do so. The amount of C3 deposited on the CLL cells was significantly higher in patients with organomegaly (i.e., splenomegaly and/or hepatomegaly). Activation of complement by CLL cells as assessed by C3 deposition on the membrane occurred both in vivo and in vitro and was not related to the N- acetylneuraminic acid content of the membrane.

Preclinical Testing of a Novel Axl-Kinase Inhibitor in Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1799-1799
Author(s):  
Maria Göbel ◽  
Michael Möllmann ◽  
Andre Görgens ◽  
Ulrich Dührsen ◽  
Andreas Hüttmann ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Cell Polarization ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Blue Staining ◽  
Nsg Mice

Abstract Abstract 1799 The receptor tyrosine kinase Axl belongs to the TAM (Tyro-3, Axl and Mer) family and is involved in the progression of several human malignancies including chronic lymphocytic leukemia (CLL), where it is has been found to be overexpressed in comparison to normal B-cells. An increasing body of evidence suggests that Axl acts as an oncogene which increases the survival, proliferation, metastatic potential and chemotherapy resistance of tumor cells. Hence, it has been recently identified as a potential therapeutic target in a wide range of tumor entities with deregulated Axl expression including prostate cancer, glioma, lung cancer and CLL. Here, we investigated two different Axl inhibitors for their potential to inhibit the migratory capacity and survival of leukemic cells in preclinical CLL models. In vitro studies: Freshly isolated PBMC (>90% CD5+CD19+) from CLL patients were incubated in serum free medium for 48h containing concentrations series of 2 different Axl inhibitors: BMS777607, a previously published inhibitor of the MET kinase family, and LDC2636, a novel inhibitor of the TAM receptor tyrosine kinase (RTK) family with high affinity to Axl. Viability of CLL cells was assessed by trypan blue staining and flow cytometry employing annexin V staining. Since a polarized phenotype is required for migration, cell polarization was analyzed by time-lapse video-microscopy. We detected cytotoxic effects in a patient dependent manner that were more prevalent in LDC2636 as compared to BMS777607 treated cells (LD50= 1.4 μM vs. 5.2 μM, p<0.004, n=5). Cell polarization of the remaining viable cells was significantly reduced in a dose dependent fashion in comparison to vehicle only controls (LDC2636 IC50 = 7.2 μM, p<0.00001; BMS777607: IC50=6.2μM; p=0.0004). Of note, both Axl inhibitors exhibited significantly weaker effects on both, the viability and cell polarization of normal PBMC over the whole concentration range tested (p<0.05, n=5). In vivo studies: To verify our hypothesis that reduced cell polarization results in decreased homing of leukemic cells in vivo we employed a recently developed adoptive transfer model of CLL. In this model NOD/SCID/gcnull(NSG) mice were pre-treated with a single intraperitoneal bolus of LDC2636 or BMS777607 (20 mg/kg) and subsequently transplanted with primary CLL cells. Both Axl inhibitors significantly reduced the homing capacity of CLL cells to the bone marrow of NSG mice by 43% and 59%, respectively, compared to vehicle treated controls (LDC2636: p=0.046, BMS777607 p=0.0077; n=3). These data demonstrate that Axl inhibitors exert potent in vitro and in vivo activity against human CLL cells, which is caused at least in part by the suppression of CLL homing to their supportive stromal niches. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Induction of in vitro differentiation and immunoglobulin synthesis of human leukemic B lymphocytes.

1978 ◽  
Vol 148 (6) ◽  
pp. 1570-1578 ◽  
Author(s):  
S M Fu ◽  
N Chiorazzi ◽  
H G Kunkel ◽  
J P Halper ◽  
S R Harris
Keyword(s):  
T Cells ◽  
B Cells ◽  
Plasma Cells ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Pokeweed Mitogen ◽  
In Vitro Differentiation ◽  
Immunoglobulin Synthesis

Successful induction of in vitro differentiation and immunoglobulin synthesis of the leukemic lymphocytes was carried out in two cases of chronic lymphocytic leukemia. Few plasma cells and little specific Ig secretion were detected in the cultures of isolated leukemic B cells in either the presence or the absence of autologous T cells. Up to 30% of the leukemic B cells matured to plasma cells, and a 32-fold increase in specific Ig synthesis was observed when T cells from normal individuals were added to the cultures of these leukemic B cells. In one of the two cases, autologous T cells were able to induce greater than 50% of the leukemic B cells to differentiate further to plasma cells in the presence of pokeweed mitogen. This markedly accelerated in vitro differentiation was only achieved with leukemic cells from cases in which there was evidence of slight differentiation in vivo. No evidence could be obtained for excessive suppressor T cells in these patients. However, a T-cell defect in the generation of allogeneic effect helper factors was identified. This defect may be responsible for the reduced rate of leukemic maturation in vivo.

scholarly journals CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism

2021 ◽  
Vol 5 (14) ◽  
pp. 2817-2828
Author(s):  
Matteo Grioni ◽  
Arianna Brevi ◽  
Elena Cattaneo ◽  
Alessandra Rovida ◽  
Jessica Bordini ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Antigen Specificity

Abstract Chronic lymphocytic leukemia (CLL) is caused by the progressive accumulation of mature CD5+ B cells in secondary lymphoid organs. In vitro data suggest that CD4+ T lymphocytes also sustain survival and proliferation of CLL clones through CD40L/CD40 interactions. In vivo data in animal models are conflicting. To clarify this clinically relevant biological issue, we generated genetically modified Eμ-TCL1 mice lacking CD4+ T cells (TCL1+/+AB0), CD40 (TCL1+/+CD40−/−), or CD8+ T cells (TCL1+/+TAP−/−), and we monitored the appearance and progression of a disease that mimics aggressive human CLL by flow cytometry and immunohistochemical analyses. Findings were confirmed by adoptive transfer of leukemic cells into mice lacking CD4+ T cells or CD40L or mice treated with antibodies depleting CD4 T cells or blocking CD40L/CD40 interactions. CLL clones did not proliferate in mice lacking or depleted of CD4+ T cells, thus confirming that CD4+ T cells are essential for CLL development. By contrast, CD8+ T cells exerted an antitumor activity, as indicated by the accelerated disease progression in TCL1+/+TAP−/− mice. Antigen specificity of CD4+ T cells was marginal for CLL development, because CLL clones efficiently proliferated in transgenic mice whose CD4 T cells had a T-cell receptor with CLL-unrelated specificities. Leukemic clones also proliferated when transferred into wild-type mice treated with monoclonal antibodies blocking CD40 or into CD40L−/− mice, and TCL1+/+CD40−/− mice developed frank CLL. Our data demonstrate that CD8+ T cells restrain CLL progression, whereas CD4+ T cells support the growth of leukemic clones in TCL1 mice through CD40-independent and apparently noncognate mechanisms.

scholarly journals Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: a phase I trial of daily bolus infusion

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 576-585 ◽  
Author(s):  
ML Grossbard ◽  
AS Freedman ◽  
J Ritz ◽  
F Coral ◽  
VS Goldmacher ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Maximum Tolerated Dose ◽  
In Vitro Cytotoxicity ◽  
Bolus Infusion ◽  
Protein Toxin ◽  
Cytotoxicity Studies ◽  
Ricin A

Abstract Anti-B4-blocked Ricin (Anti-B4-bR) is an immunotoxin comprised of the anti-B4 monoclonal antibody (MoAb) and the protein toxin “blocked ricin.” The anti-B4 MoAb is directed against the B-lineage-restricted CD19 antigen expressed on more than 95% of normal and neoplastic B cells. Blocked ricin is an altered ricin derivative that has its nonspecific binding eliminated by chemically blocking the galactose binding domains of the B chain. In vitro cytotoxicity studies demonstrate that the IC37 of Anti-B4-bR is 2 x 10(-11) mol/L compared with 4 x 10(-12) mol/L for native ricin. A phase I dose escalation clinical trial was conducted in 25 patients with refractory B-cell malignancies. Anti-B4-bR was administered by daily 1-hour bolus infusion for 5 consecutive days at doses ranging from 1 microgram/kg/d to 60 micrograms/kg/d. Serum levels above 1 nmol/L were achieved transiently in the majority of patients treated at the maximum tolerated dose of 50 micrograms/kg/d for 5 days for a total dose of 250 micrograms/kg. The dose-limiting toxicity was defined by transient, reversible grade 3 elevations in hepatic transaminases, without impaired hepatic synthetic function. Minor toxicities included transient hypoalbuminemia, thrombocytopenia, and fevers. Human antimouse antibody and human anti-ricin antibody were detected in nine patients. One complete response, two partial responses, and eight mixed or transient responses were observed. These results show the in vitro and in vivo cytotoxicity of Anti-B4-bR and indicate that this immunotoxin can be administered as a daily bolus infusion for 5 days with tolerable, reversible toxicity.

In Vitro and in Vivo Studies of Poly-L-Lysine as Inducer of Friend Leukemic Cells Differentiation

1987 ◽  
Vol 73 (5) ◽  
pp. 431-436
Author(s):  
Rosanna Supino ◽  
Nadia Gibelli ◽  
Rosanna Nano ◽  
Gabriella Pezzoni ◽  
Franco Zunino
Keyword(s):  
Bone Marrow Cells ◽  
Therapeutic Potential ◽  
Leukemic Cells ◽  
In Vivo Studies ◽  
In Vivo Model ◽  
Treatment Schedule ◽  
Potent Inducer ◽  
Multiple Treatment

Poly-L-lysine, a synthetic cationic polypeptide known for its ability to bind to cell membranes, was found to induce differentiation of Friend leukemia cells « in vitro ». Studies were extended to the same « in vivo » model, in order to examine the therapeutic potential of this new differentiating agent. The i.p. administration of the polymer (Mw 2700) at the maximal tolerated dose resulted in major alterations of disease-related parameters. In particular, a multiple treatment schedule on the advanced disease resulted in a successful reduction of target organ weight and peripheral white blood cell count and appreciable differentiation of spleen and bone marrow cells. Apparently, the effects of poly-L-lysine were superior to those produced by N-methyl-acetamide, a potent inducer of differentiation « in vitro ».

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