methylcellulose and Neoplasms

BFL-1 is an understudied pro-survival BCL-2 protein. The expression of BFL-1 is reported in many cancers, but it is yet to be clarified whether high transcript expression also always correlates with a pro-survival function. However, recent applications of BH3-mimetics for the treatment of blood cancers identified BFL-1 as a potential resistance factor in this type of cancer. Hence, understanding the role of BFL-1 in human cancers and how its up-regulation leads to therapy resistance has become an area of great clinical relevance. In addition, deletion of the murine homologue of BFL-1, called A1, in mice showed only minimal impacts on the well-being of these animals, suggesting drugs targeting BFL-1 would exhibit limited on-target toxicities. BFL-1 therefore represents a good clinical cancer target. Currently, no effective BFL-1 inhibitors exist, which is likely due to the underappreciation of BFL-1 as a potential target in the clinic and lack of understanding of the BFL-1 protein. In this review, the roles of BFL-1 in the development of different types of cancers and drug resistant mechanisms are discussed and some recent advances in the generation of BFL-1 inhibitors highlighted.

Topics: Animals; Apoptosis; Humans; Methylcellulose; Mice; Minor Histocompatibility Antigens; Neoplasms; Proto-Oncogene Proteins c-bcl-2

Topics: Adolescent; Adult; Aged; Carboxymethylcellulose Sodium; Child; Child, Preschool; Clinical Trials as Topic; Drug Evaluation; Female; Fever; Humans; Hypotension; Infant; Interferons; Leukemia; Male; Methylcellulose; Middle Aged; Neoplasms; Peptides; Poly I-C; Polylysine

Induction of apoptosis by the FDA-approved drug Venetoclax in cancer cells mainly derives from blocking the interactions between BCL-2 and BH3-only proteins. Anti-apoptotic BFL-1, a homolog of BCL-2, also competitively binds to the BH3-only proteins and is responsible for Venetoclax-induced drug resistance. Compared to BCL-2, small-molecule inhibitors of BFL-1 are relatively underexplored. In order to tackle this issue, in-house compound library was screened and a hit compound was identified and optimized to obtain 12 (ZH97) functioning as a covalent and selective inhibitor of BFL-1. 12 modifies BFL-1 at the C55 residue, blocks BFL-1/BID interaction in vitro, promotes cellular cytochrome c release from mitochondria, and induced apoptosis in BFL-1 overexpressing cancer cells. Mechanistic studies show that 12 inhibited BFL-1/PUMA interaction in cell lysate and is effective in cancer cells that harboring high expression level of BFL-1. In summary, blockade of BFL-1/BH3-only proteins interactions with a covalent small-molecule inhibitor induced apoptosis and elicited antitumor activity. Thus, our study demonstrates an appealing strategy for selective modulation of cellular BFL-1 for cancer therapy.

Topics: Apoptosis; Methylcellulose; Minor Histocompatibility Antigens; Mitochondria; Neoplasms; Proto-Oncogene Proteins c-bcl-2

To develop low-molecular-weight methylcellulose (LMw MC)-based gel/Pluronic F127 micelle combination system for local and sustained delivery of docetaxel (DTX).. LMw MC and Pluronic F127 were used to formulate an injectable thermo-reversible gel/micelle combination system containing DTX. The DTX-loaded combination system was characterized and its therapeutic efficacy evaluated in a subcutaneous tumor model.. Mixtures of LMw MC, AS, and Pluronic F127 formed gel at ~15-40°C depending on AS concentration. The combination system released DTX for >30 days with a biphasic and sustained release pattern, and DTX stability was maintained during release. The combination system significantly enhanced anti-cancer effects of DTX and prolonged survival of the model mouse in comparison with free DTX.. The LMw MC gel/Pluronic F127 micelle combination system constitutes a promising tool for reducing tumor size and eradicating remaining tumor cells before and after surgery.

Topics: Animals; Antineoplastic Agents; Delayed-Action Preparations; Docetaxel; Male; Methylcellulose; Mice; Mice, Inbred C57BL; Micelles; Neoplasms; Poloxamer; Taxoids

Immunoselected CD34+ peripheral blood progenitor cell (PBPC) transplantation is now frequently used to support autologous hematopoiesis after myeloablative therapy, its feasability having been proved by several groups. However, we and others observed delayed platelet recovery. We hypothesized that immunoselection processing might induce selective loss of megakaryocyte progenitors, or a decrease in their proliferation. We used a colony-forming units megakaryocyte (CFU-Mk) assay to evaluate these consequences and predict platelet recovery in patients. In CD34+ PBPCs from 10 children with solid tumors, we observed no selective loss in CFU-Mk numbers during immunoselection processing and no impairment of clonogenicity. The CFU-Mk yield (59.2 +/- 11.3%) was at least similar to the CD34+ yield (44.2 +/- 3.8%). We assessed the predictive value of CFU-Mk numbers infused for recovery of platelet lineage. We found an inverse correlation between the time taken to reach a platelet count greater than 50 x 10(9)/L and only the CFU-Mk dose (r = -0.71; p = 0.022) among the different type of progenitors, including colony-forming units granulocyte-macrophage (CFU-GM), burst-forming units erythrocyte (BFU-E) and colony-forming units-mixed (CFU-Mix). These findings suggest that CFU-Mk number could be used as sole predictive functional parameter for platelet reconstitution in children after immunoselection of CD34+ cells, in particular for low CD34+ cell dose, and thus as an indicator for initial quality of hematopoietic cells before in vitro expansion.

Topics: Adolescent; Antigens, CD34; Blood Platelets; Cell Lineage; Child; Child, Preschool; Colony-Forming Units Assay; Culture Media, Serum-Free; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Infant; Megakaryocytes; Methylcellulose; Neoplasms; Platelet Count

Topics: Analgesia; Carboxymethylcellulose Sodium; Catheters, Indwelling; Drug Combinations; Gelatin; Humans; Injections, Epidural; Methylcellulose; Morphine; Neoplasms; Pain; Pectins; Polyenes; Tissue Adhesives

We have performed Phase I trials of two synthetic double-stranded polyribonucleotide complexes--poly(I,C)-LC, a complex of polyinosinic-polycytidylic acid with poly-L-lysine and carboxymethylcellulose, and poly(I,C)-L, which lacks carboxymethylcellulose--in patients with advanced cancer. With poly(I,C)-LC, several treatment schedules were investigated in an attempt to decrease toxicity and maximize interferon (IFN) induction. The best tolerated was an alternate-day schedule, with gradual dose escalation. Daily short infusions and continuous (24-h) infusions were tolerated less well. Maximum tolerated doses varied over a several hundredfold dose range. Toxicity consisted of fever, rigors, hypotension, and blood count depression. Two patients treated with poly(I,C)-L developed systemic allergic reactions, and antibodies to poly(I,C)-L and its components were detected in the serum of some patients treated with both compounds. IFN-alpha was induced in most patients at serum levels similar to those achieved after intramuscular administration of human IFN-alpha. Of 32 patients, one with renal cell carcinoma showed partial tumor regression. Poly(I,C) complexes are effective IFN inducers in humans, but their toxicity limits their use in cancer patients.

Topics: Adult; Aged; Antibody Formation; Carboxymethylcellulose Sodium; Carcinoma, Renal Cell; Drug Evaluation; Drug Tolerance; Female; Humans; Hypotension; Interferons; Kidney Neoplasms; Killer Cells, Natural; Leukopenia; Male; Methylcellulose; Middle Aged; Neoplasms; Poly I-C; Polylysine

Twenty-five patients with metastatic carcinoma were entered into a Phase I clinical trial using poly(I,C)-LC at either 1 mg/m2 or 4 mg/m2 intravenous, twice weekly, for 4 weeks. None of the 15 patients entered at the 1 mg/m2 dose had an objective response; three had progressive disease. Similarly, no objective responses were observed among the 10 patients treated at the 4 mg/m2 dose of poly(I,C)-LC; one patient was removed from the study due to progressive disease. Toxicities observed at the 1 mg/m2 dose were mild hypotension, fever, nausea, vomiting, fatigue, and headache. The first patient treated at the 4 mg/m2 dose was taken off of the study for severe hypotension. In the subsequent nine patients treated at this dose, a pretreatment with one dose at 1 mg/m2 was given, and no further problems with hypotension were encountered. The other toxicities at 4 mg/m2 were similar to those seen at 1 mg/m2.

Topics: Carboxymethylcellulose Sodium; Drug Evaluation; Fever; Humans; Hypotension; Interferons; Kinetics; Methylcellulose; Nausea; Neoplasms; Poly I-C; Polylysine

Poly(I,C)-LC was administered in low (1 mg/m2) and intermediate (4 mg/m2) doses to cancer patients by intramuscular injection or intravenous infusion to evaluate the immunomodulatory effects. Natural killer cell (NK) activity was elevated slightly at the low dose and remained unchanged overall, but some depression was observed at the 4 mg/m2 intravenous dose. Monocyte function was elevated in all groups of patients, as was the interferon-induced enzyme 2'5'-oligo-A synthetase. These increases were observed at the 1 mg/m2 intramuscular dose, despite a lack of detectable circulating serum interferon (IFN). In regard to cell surface markers, poly(I,C)-LC induced an increase in OKT10-positive cells and a small but consistent trend toward increases in the ratio of Leu-3/Leu-2-positive cells. Lymphocyte proliferation in response to concanavalin A was depressed by poly(I,C)-LC administration. Although an optimum immunomodulatory dose and schedule was not determined, the data indicate that low doses produce significant changes in immune function and that induction of detectable levels of circulating interferon is not required for poly(I,C)-LC to have biological effects.

Topics: 2',5'-Oligoadenylate Synthetase; Adjuvants, Immunologic; Carboxymethylcellulose Sodium; Drug Evaluation; Humans; In Vitro Techniques; Killer Cells, Natural; Leukocytes; Lymphocyte Activation; Methylcellulose; Monocytes; Neoplasms; Poly I-C; Polylysine

A methylcellulose monolayer system is described that facilitates the "in vitro" cultures of human spontaneous tumor cells. The tumor samples were disaggregated mechanically and cultured in 0.9% methylcellulose with 30% fetal calf serum in Iscove's modified Dulbecco's medium. Eighty-five individual tumor samples with different histological types were seeded, 45 gave rise to tumor cell colonies. The plating efficiency ranged from 0.02% to 0.22%. Cytologic and cytochemical staining from aspirated cells revealed the same morphology of cells as the cells in the suspension. A flattening of colonies, as it has been described by others using methylcellulose monolayer, was not observed.

Topics: Clone Cells; Culture Media; Humans; Methylcellulose; Neoplasms; Neoplastic Stem Cells; Stem Cells

Topics: Agar; Biopsy; Breast Neoplasms; Cell Survival; Clone Cells; Culture Techniques; Female; Humans; Lung Neoplasms; Male; Melanoma; Methylcellulose; Microscopy, Electron; Neoplasms; Pleural Effusion

Human tumor cell lines, derived from cancers of the colon, ovary, and cervix, were grown in liquid tissue culture media and media made semisolid with agar (Bacto + deoxycholate lactose agar), agarose [LE, ME, Sea Plaque and Sea Prep (15/45)], and methyl cellulose. The effects of each agent on overall cell proliferation and rate of overall cell proliferation were examined. The agents, used to make media semisolid, were observed to inhibit or, in some cases, enhance cell growth in a fashion that was characteristic of individual cell lines. These phenomena may be of consequence to the optimization of nutrient media for primary tumor cell preparations.

Topics: Agar; Cell Division; Cells, Cultured; Culture Media; Humans; Methylcellulose; Neoplasms; Sepharose

Lymphocyte transformation to phytohaemagglutinin (PHA) was measured simultaneously by two methods (heparin and methyl cellulose) in 16 patients with non-lymphoid cancer and 21 normal subjects. Twelve cancer patients showed transformation levels below the normal heparin range, but only two patients showed levels below the normal methyl cellulose range. These findings suggest that in interpreting lymphocyte transformation studies close attention should be given to the methods employed.

Topics: Adolescent; Adult; Aged; Heparin; Humans; Lectins; Lymphocyte Activation; Methods; Methylcellulose; Middle Aged; Neoplasms

Topics: Adult; Aged; Arsenicals; Cells, Cultured; Culture Media; Female; Humans; Hydrocortisone; Immunity, Cellular; Insulin; Lectins; Lymphocyte Activation; Lymphocytes; Male; Methotrexate; Methylcellulose; Neoplasms; Penicillins; Plasma; Streptomycin; Thymidine; Tritium

Topics: Animals; Antineoplastic Agents; Female; Methylcellulose; Mice; Mice, Inbred Strains; Naphthalenes; Neoplasms; Plant Extracts; Quinoxalines

Sodium carboxymethyl cellulose and hydroxyethyl starch were found to support rapid growth of two hematopoietic cell lines. The polymers were not metabolized by the cells. In the presence of these compounds, lower rates of glucose utilization and lactic acid production were observed. The uptake of glucose by the cells decreased as the concentration of the polymer in the medium was increased. These results indicate that sodium carboxymethyl cellulose and hydroxyethyl starch probably protect the cells against physical stress in suspended cultures.

Topics: Autoradiography; Carbon Isotopes; Cell Line; Culture Techniques; Glucose; Humans; Lactates; Lymphocytes; Methylcellulose; Neoplasms; Starch

Several synthetic polymers (hydroxyethyl starch, sodium carboxymethyl cellulose, polyvinylpyrrolidone) markedly improved the growth of three human lymphocyte cell lines [Roswell Park Memorial Institute (RPMI) 1348, 1788, and 8098]. Growth was stimulated when each of these polymers was added to RPMI 1640 medium supplemented with only 2% fetal bovine serum. Dextran T-40, T-70, and T-110 varied in their effect on the growth of these cell lines. Dextran T-250 and Haemaccel did not improve cell yields when partially substituted for the serum. The successful partial substitution of polymers for serum was specific for individual cell lines.

Topics: Blood; Cell Count; Cell Line; Culture Media; Culture Techniques; Dextrans; Gelatin; Glucose; Humans; Lymphocytes; Methylcellulose; Neoplasms; Polymers; Povidone; Species Specificity; Starch; Viscosity

Topics: Adenoma; Animals; Body Weight; Carcinoma; Carcinoma, Hepatocellular; Diet; Female; Food Additives; Genital Neoplasms, Female; Liver Neoplasms; Lung Neoplasms; Male; Methylcellulose; Neoplasms; Rats; Skin Neoplasms; Urogenital Neoplasms

Topics: Animals; Estradiol; Friends; Leukemia; Leukemia Virus, Murine; Leukemia, Experimental; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mercaptopurine; Methylcellulose; Mice; Mitomycin; Mitomycins; Neoplasm Transplantation; Neoplasms; Pharmacology; Research; Sarcoma; Triethylenemelamine; Urethane

Topics: Animals; Cold Temperature; Dimethyl Sulfoxide; Freezing; Histological Techniques; Immune Sera; Leukocytes; Methylcellulose; Mice; Neoplasms; Neoplasms, Experimental; Nitrogen; Preservation, Biological; Rabbits; Research; Swine; Tissue Culture Techniques

Topics: Blood Chemical Analysis; Carboxymethylcellulose Sodium; Catalase; Chromatography; Chromatography, Ion Exchange; Endotoxins; Humans; Iron; Liver; Metabolism; Methylcellulose; Neoplasm Proteins; Neoplasms; Oxygenases; Research; Sarcoma; Sarcoma, Experimental; Tryptophan

Topics: Asbestosis; Beryllium; Carcinogens; Cholesterol; Glycogen; Lipoproteins; Macromolecular Substances; Methylcellulose; Neoplasms; Neoplasms, Experimental; Polyvinyls; Pyrrolidinones; Research; Resins, Plant; Resins, Synthetic; Silicon Dioxide

Topics: Blood Pressure Determination; Blood Proteins; Lymphoma; Lymphoma, Non-Hodgkin; Methylcellulose; Neoplasms; Neoplasms, Experimental

Topics: Lymphoma; Lymphoma, Non-Hodgkin; Methylcellulose; Neoplasm Regression, Spontaneous; Neoplasms; Rats; Research

Topics: Blood Proteins; Cell Death; Hemolysis; Humans; Lymphoid Tissue; Methylcellulose; Neoplasms; Peptide Nucleic Acids