orabase and Neoplasms

Immunotherapies have become the first line of treatment for many cancer types. Unfortunately, only a small fraction of patients benefits from these therapies. This low rate of success can be attributed to 3 main barriers: 1) low frequency of anti-tumor specific T cells; 2) lack of infiltration of the anti-tumor specific T cells into the tumor parenchyma and 3) accumulation of highly suppressive cells in the tumor mass that inhibit the effector function of the anti-tumor specific T cells. Thus, the identification of immunomodulators that can increase the frequency and/or the infiltration of antitumor specific T cells while reducing the suppressive capacity of the tumor microenvironment is necessary to ensure the effectiveness of T cell immunotherapies. In this review, we discuss the potential of poly-ICLC as a multi-functional immune modulator for treating cancer and its impact on the 3 above mentioned barriers. We describe the unique capacity of poly-ICLC in stimulating 2 separate pattern recognition receptors, TLR3 and cytosolic MDA5 and the consequences of these activations on cytokines and chemokines production. We emphasize the role of poly-ICLC as an adjuvant in the setting of peptide-based cancer vaccines and in situ tumor vaccination by mimicking natural immune responses to infections. Finally, we summarize the impact of poly-ICLC in enhancing T infiltration into the tumor parenchyma and address the implication of this finding in the clinic.

Topics: Animals; Antineoplastic Agents; Carboxymethylcellulose Sodium; Cytokines; Humans; Immunity, Innate; Immunologic Factors; Immunomodulation; Interferon-Induced Helicase, IFIH1; Lymphocytes, Tumor-Infiltrating; Neoplasms; Poly I-C; Polylysine; Receptors, Pattern Recognition; Toll-Like Receptor 3

Topics: Adjuvants, Immunologic; Antibodies; Antineoplastic Agents; Carboxymethylcellulose Sodium; Clinical Trials as Topic; Combined Modality Therapy; Drug Administration Schedule; Drug Evaluation; Interferon Inducers; Interferons; Killer Cells, Natural; Neoplasms; Poly I-C; Polylysine; Recombinant Proteins; Terminology as Topic

Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects.. In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing.. Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD.. This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

Topics: Adult; Aged; Antigens, Neoplasm; Cancer Vaccines; Carboxymethylcellulose Sodium; Combined Modality Therapy; Cyclophosphamide; Cytokines; Dendritic Cells; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Injections, Intralesional; Leukocytes, Mononuclear; Male; Middle Aged; Neoplasms; Poly I-C; Polylysine; Radiosurgery; Response Evaluation Criteria in Solid Tumors

We have performed a phase IB study of polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose (poly-ICLC) in combination with interleukin 2 (IL-2) in 25 patients with a variety of cancers. Patients received weekly or biweekly poly-ICLC by i.m. injection, at doses ranging from 0.01 to 1.0 mg/m2, for 1 month. This was followed by 2 months of outpatient therapy with biweekly i.m. poly-ICLC in combination with IL-2 (3 x 10(6) units/m2) given i.v. by 24-h continuous infusion twice weekly, using a portable infusion pump. No objective tumor responses were observed. Toxicity was moderate at all poly-ICLC doses tested and increased only slightly following the addition of IL-2. No increases in peripheral blood natural killer (NK) activity were observed after treatment with poly-ICLC alone. However, high dose poly-ICLC (greater than or equal to 0.3 mg/m2) in combination with IL-2 resulted in NK activity greater than that seen using the same dose of IL-2 in combination with lower poly-ICLC doses. Increases in the number and percentage of CD56+ cells were evident only after initiation of IL-2 therapy and were unaffected by the poly-ICLC dose. In the majority of patients, these increases were preferentially associated with the subset of CD56+ cells coexpressing CD8, while the CD56+/CD16+ population was elevated to a lesser extent. Moderate increases in serum neopterin levels and 2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells were noted at 72 h following initial treatment with 1.0 mg/m2 poly-ICLC. No induction of alpha or gamma interferon was detected. This study shows that the addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity without increases in the dose and, therefore, the toxicity of IL-2 treatment.

Topics: Antigens, CD; Biopterins; Carboxymethylcellulose Sodium; Cytotoxicity, Immunologic; Drug Evaluation; Female; Humans; Interleukin-2; Killer Cells, Natural; Male; Middle Aged; Neoplasms; Neopterin; Poly I-C; Polylysine

Topics: Adjuvants, Immunologic; Antibodies; Antineoplastic Agents; Carboxymethylcellulose Sodium; Clinical Trials as Topic; Combined Modality Therapy; Drug Administration Schedule; Drug Evaluation; Interferon Inducers; Interferons; Killer Cells, Natural; Neoplasms; Poly I-C; Polylysine; Recombinant Proteins; Terminology as Topic

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

Topics: Carboxymethylcellulose Sodium; Fibroins; HEK293 Cells; Humans; Hydrogels; Hyperthermia, Induced; Magnetic Phenomena; Neoplasms; Spectroscopy, Fourier Transform Infrared

In this work, novel biocompatible and reduction-responsive soft hydrogels were formulated from norbornene (Nb)-functionalized carboxymethyl cellulose (CMCNb). To cross-link the CMC-Nb via a highly bioorthogonal inverse electron demand Diels-Alder (IEDDA) reaction, we employed a water-soluble and reduction-responsive diselenide-based cross-linker possessing two terminal tetrazine (Tz) groups with varying molar concentrations (Nb/Tz molar ratios of 10/10, 10/05, and 10/2.5). The N

Topics: Carboxymethylcellulose Sodium; Click Chemistry; Doxorubicin; Electrons; Glutathione; Hydrogels; Neoplasms; Norbornanes; Water

Thermo-sensitive hydrogels change their properties through phase transition, which could be used to regulate various behaviors by changing the temperature. In this study, degradable hydrogels with thermo-response were designed by reaction of oxidized carboxymethyl cellulose (CMC-CHO) with functional P(NIPAM-co-AH). The hydrogels showed biocompatibility and thermo-response with lower critical solution temperature (LCST) regulated by weight ratio of P(NIPAM-co-AH)/CMC-CHO. The photo-thermal property of gold nanorod was triggered by the near-infrared (NIR) to enhance the DOX release for in vivo anti-tumor therapy of model mice. The results showed good biocompatibility and biodegradability of the hydrogel both in vitro and in vivo, and the DOX with hydrogel loading reduced the toxicity through sustained release behavior. The anti-tumor performance further enhanced with NIR triggered drug release regulated by photo-thermal property. In conclusion, the injectable P(NIPAM-co-AH)/CMC-CHO based self-healing hydrogels could act as promising drug delivery vehicle for potential localized anti-tumor therapy.

Topics: Animals; Carboxymethylcellulose Sodium; Cellulose; Delayed-Action Preparations; Doxorubicin; Drug Liberation; Gold; Hydrogels; Mice; Neoplasms

The preparation of modified Mohs paste, commonly used for malignant wounds, requires time and effort. Moreover, metal-containing liquid waste is generated when malignant wounds are scrubbed. Therefore, we previously changed the base material of the modified Mohs paste from zinc oxide starch powder to carboxymethyl cellulose (CMC). The novel modified Mohs paste based on CMC (moM-CMC sol) may reduce these disadvantages. In the present study, the moM-CMC sol was applied to malignant tumors in three dogs to manage bleeding and malodor. The moM-CMC sol transitioned into a gel on the tumors within an hour of application and could be easily removed. The symptoms resolved in all cases. The moM-CMC sol could be beneficial for dogs with malignant wounds.

Topics: Animals; Carboxymethylcellulose Sodium; Dog Diseases; Dogs; Neoplasms; Starch

In this research, a hydrogel that combined the tumor photodynamic therapy (PDT) and photothermal therapy (PTT) ability was designed, using dopamine-modified sodium carboxymethyl cellulose (CMC-DA) as the matrix and Chlorin e6 (Ce6) as the photosensitizer. The gel formation was initiated by adding the oxidizing agent sodium periodate (NaIO

Topics: Carboxymethylcellulose Sodium; Cell Line, Tumor; Humans; Hydrogels; Indoles; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Polymers; Porphyrins

In this study, we produced curcumin loaded gelatine microparticles, through spray-drying method, with dialdehyde carboxymethyl cellulose (DCMC) which is introduced as a new cross-linking agent for drug delivery systems and examined toxicities by comparison of traditional cross-linking agents. We employed various parameters in the production and tried to develop the most efficient drug delivery system through Taguchi method by examining efficiencies on gastric cancer under

Topics: Antineoplastic Agents; Carboxymethylcellulose Sodium; Cell Line; Cell Line, Tumor; Cross-Linking Reagents; Curcumin; Delayed-Action Preparations; Drug Liberation; Gelatin; Humans; Neoplasms

Polymer-drug conjugation is an attractive approach for target delivering insoluble and highly toxic drugs to tumor sites to overcome the side-effects caused by cancer chemotherapy. In this study we designed and synthesized novel polymer-drug-peptide conjugates for improved specificity on targeting cancer cells. Chemically modified polysaccharide, carboxymethylcellulose (CMC), was conjugated with doxorubicin (DOX) anticancer drug by amide bonds and dually biofunctionalized with integrin-target receptor tripeptide (RGD) and l-arginine (R) as cell-penetrating amino acid for synergistic targeting and enhancing internalization by cancer cells. These bioconjugates were tested as prodrugs against bone, breast, and brain cancer cell lines (SAOS, MCF7, and U87) and a normal cell line (HEK 293T, reference). The physicochemical characterization showed the formation of amide bonds between carboxylates (-RCOO

Topics: Animals; Antibiotics, Antineoplastic; Arginine; Carboxymethylcellulose Sodium; Cell Line, Tumor; Cell-Penetrating Peptides; Chickens; Doxorubicin; Drug Carriers; Drug Delivery Systems; HEK293 Cells; Humans; Integrins; Neoplasms; Oligopeptides

Topics: Aged; Biopsy; Carboxymethylcellulose Sodium; Drug Administration Schedule; Female; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Immunologic Factors; Immunomodulation; Injections, Intralesional; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Pilot Projects; Poly I-C; Polylysine; Prognosis; Tomography, X-Ray Computed; Treatment Outcome

Multidrug resistance is a major therapeutic challenge faced in the conventional chemotherapy. Nanocarriers are beneficial in the transport of chemotherapeutics by their ability to bypass the P-gp efflux in cancers. Most of the P-gp inhibitors under phase II clinical trial are facing failures and hence there is a need to develop a suitable carrier to address P-gp efflux in cancer therapy. Herein, we prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin against highly drug resistant HeLa cells. The experimental results revealed that improved cellular uptake, enhanced drug intensity profile with greater percentage of apoptotic cells was attained when doxorubicin loaded magnetic nanocapsules were used in the presence of external magnetic field. Hence, we conclude that this magnetic field assisted nanocapsule system can be used for delivery of chemotherapeutics for potential therapeutic efficacy at minimal dose in multidrug resistant cancers.. Many cancer drugs fail when cancer cells become drug resistant. Indeed, multidrug resistance (MDR) is a major therapeutic challenge. One way that tumor cells attain MDR is by over expression of molecular pumps comprising of P-glycoprotein (P-gp) and multidrug resistant proteins (MRP), which can expel chemotherapeutic drugs out of the cells. In this study, the authors prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin. The results show that there was better drug delivery and efficacy even against MDR tumor cells.

Topics: Carboxymethylcellulose Sodium; Doxorubicin; Drug Resistance, Neoplasm; HeLa Cells; Humans; Magnetite Nanoparticles; Nanocapsules; Neoplasms; Protamines

We have developed a polymer conjugate (Cellax) composed of acetylated carboxymethylcellulose (CMC), docetaxel (DTX), and PEG, designed to enhance the pharmacokinetics (PK) and antitumor efficacy of DTX. Our design placed an emphasis on nanoparticle self-assembly to protect DTX during blood transport, stability of the nanoparticle, and PEGylation to enhance PK. Compared to Taxotere, Cellax exhibited a 38.6 times greater area under the curve (AUC), and significantly lower clearance (2.5%) in PK. Less than 10% of DTX was released from Cellax in the blood circulation, indicating that Cellax were stable during blood transport. Cellax reduced non-specific distribution of DTX to the heart, lung and kidney by 48, 90, and 90%, respectively, at 3 h, compared to Taxotere. The uptake of Cellax at 3 h in the liver and spleen was high (15-45 μg DTX/g) but declined rapidly to <10 μg DTX/g in 24 h, and induced no measurable toxicity at 170 mg DTX/kg. Taxotere, on the other hand, displayed non-specific uptake in all the examined normal tissues and induced significant apoptosis in the lung and kidney at 40 mg DTX/kg. The tumor uptake of Cellax was 5.5-fold more than that by Taxotere and the uptake occurred within 3 h after injection and persisted for 10 days. The conjugate exhibited enhanced efficacy in a panel of primary and metastatic mouse tumor models. These results clearly demonstrated that Cellax improved the pharmacokinetics, biodistribution and efficacy of DTX compared to Taxotere with reduced toxicity.

Topics: Animals; Antineoplastic Agents; Carboxymethylcellulose Sodium; Disease Models, Animal; Docetaxel; Drug Screening Assays, Antitumor; Intracellular Space; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasm Metastasis; Neoplasms; Polyethylene Glycols; Polymers; Taxoids; Tissue Distribution; Treatment Outcome

A carboxymethylcellulose-based polymer conjugate with nanoparticle forming properties (Cellax) has been shown to enhance the pharmacokinetics, specificity of biodistribution, anti-tumor efficacy and safety of docetaxel (DTX) in comparison to the Taxotere™ formulation. We examined Cellax and Taxotere efficacy in four tumor models (EMT-6, B16F10, PC3, and MDA-MB-231), and observed variances in efficacy. To explore whether differences in tumor uptake of Cellax were responsible for these effects, we incorporated superparamagnetic iron oxide nanoparticles (SPIONs) into Cellax particles to enable magnetic resonance (MR) imaging (Cellax-MR). In the EMT-6 tumor model, Cellax-MR nanoparticles exhibited peak tumor accumulation 3-24 h post intravenous injection, and 3 days post-treatment, significant MR contrast was still detected. The amount of Cellax-MR deposited in the EMT-6 tumors was quantifiable as a hypointense volume fraction, a value positively correlated with drug content as determined by LC/MS analysis (R(2) = 0.97). In the four tumor models, Cellax-MR uptake was linearly associated with anti-tumor efficacy (R(2) > 0.9), and was correlated with blood vessel density (R(2) > 0.9). We have affirmed that nanoparticle uptake is variable in tumor physiology, and that this efficacy-predictive parameter can be non-invasively estimated in real-time using a theranostic variant of Cellax.

Topics: Animals; Carboxymethylcellulose Sodium; Cell Line, Tumor; Contrast Media; Disease Models, Animal; Docetaxel; Dose-Response Relationship, Drug; Drug Delivery Systems; Female; Humans; Magnetic Resonance Imaging; Male; Mice; Nanoparticles; Neoplasms; Neovascularization, Pathologic; Platelet Endothelial Cell Adhesion Molecule-1; Staining and Labeling; Subcutaneous Tissue; Taxoids; Tissue Distribution; Treatment Outcome

Cellax is a PEGylated carboxymethylcellulose conjugate of docetaxel (DTX) which condenses into a 120-nm nanoparticle, and was compared against the approved clinical taxane nanoformulation (Abraxane®) in mouse models. Cellax increased the systemic exposure of taxanes by 37× compared to Abraxane, and improved the delivery specificity: Cellax uptake was selective to the tumor, liver and spleen, with a 203× increase in tumor accumulation compared to Abraxane. The concentration of released DTX in Cellax treated tumors was well above the IC50 for at least 10 d, while paclitaxel released from Abraxane was undetectable after 24h. In s.c. PC3 (prostate) and B16F10 (melanoma) models, Cellax exhibited enhanced efficacy and was better tolerated compared to Abraxane. In an orthotopic 4T1 breast tumor model, Cellax reduced the incidence of lung metastasis to 40% with no metastasic incidence in other tissues. Mice treated with Abraxane displayed increased lung metastasic incidence (>85%) with metastases detected in the bone, liver, spleen and kidney. These results confirm that Cellax is a more effective drug delivery strategy compared to the approved taxane nanomedicine.

Topics: Albumin-Bound Paclitaxel; Albumins; Animals; Antineoplastic Agents; Carboxymethylcellulose Sodium; Cell Line, Tumor; Delayed-Action Preparations; Docetaxel; Female; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, SCID; Nanoparticles; Neoplasms; Paclitaxel; Taxoids; Tumor Burden; Xenograft Model Antitumor Assays

Hybrid magnetic hydrogels are of interest for applications in biomedical science as controlled drug-delivery systems. We have developed a strategy to obtain novel hybrid hydrogels with magnetic nanoparticles (NPs) of CoFe(2)O(3) and Fe(3)O(4) as crosslinker agents of carboxymethylcellulose (CMC) or hyaluronic acid (HYAL) polymers and we have tested these systems for controlled doxorubicin release. The magnetic NPs are functionalized with (3-aminopropyl)trimethoxysilane (APTMS) in order to introduce amino groups on the surface. The amino coating is determined and quantified by standard Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy methods, and by cyclic voltammetry, a novel approach that permits us to look at the solution properties of the functionalized NPs. The gel formation involves the creation of an amide bond between the carboxylic groups of CMC or HYAL and the amine groups of functionalized NPs, which work as crosslinking agents of the polymer chains. The hybrid hydrogels are chemically and morphologically characterized. The rheological and the water uptake properties of the hydrogels are also investigated. Under the application of an alternating magnetic field, the CMC-HYAL hybrid hydrogel previously loaded with doxorubicin shows a drug release greater than that showed by the CMC-HYAL hydrogel crosslinked with 1,3-diaminopropane. In conclusion, the presence of magnetic NPs makes the synthesized hybrid hydrogels suitable for application as a drug-delivery system by means of alternating magnetic fields.

Topics: Animals; Antineoplastic Agents; Carboxymethylcellulose Sodium; Cross-Linking Reagents; Delayed-Action Preparations; Diamines; Humans; Hyaluronic Acid; Hydrogels; Magnetic Fields; Magnetite Nanoparticles; Neoplasms

A nanoparticle formulation of docetaxel (DTX) was designed to address the strengths and limitations of current taxane delivery systems: PEGylation, high drug conjugation efficiency (>30 wt %), a slow-release mechanism, and a well-defined and stable nanoparticle identity were identified as critical design parameters. The polymer conjugate was synthesized with carboxymethylcellulose (CMC), an established pharmaceutical excipient characterized by a high density of carboxylate groups permitting increased conjugation of a drug. CMC was chemically modified through acetylation to eliminate its gelling properties and to improve solvent solubility, enabling high yield and reproducible conjugation of DTX and poly(ethylene glycol) (PEG). The optimal conjugate formulation (Cellax) contained 37.1 ± 1.5 wt % DTX and 4.7 ± 0.8 wt % PEG, exhibited a low critical aggregation concentration of 0.6 μg/mL, and formed 118-134 nm spherical nanoparticles stable against dilution. Conjugate compositions with a DTX degree of substitution (DS) outside the 12.3-20.8 mol % range failed to form discrete nanoparticles, emphasizing the importance of hydrophobic and hydrophilic balance in molecular design. Cellax nanoparticles released DTX in serum with near zero order kinetics (100% in 3 weeks), was internalized in murine and human cancer cells, and induced significantly higher toxic effects against a panel of tumor cell lines (2- to 40-fold lower IC50 values) compared to free DTX.

Topics: Animals; Antineoplastic Agents; Carboxymethylcellulose Sodium; Cell Line, Tumor; Docetaxel; Drug Carriers; Humans; Inhibitory Concentration 50; Mice; Nanoparticles; Neoplasms; Polyethylene Glycols; Taxoids

Magnetic particles for medical applications have been developed by many researchers. Since magnetic particles have unique magnetic features not present in other materials, they can be applied to special medical techniques. Separation, immunoassay, magnetic resonance imaging (MRI), drug delivery, and hyperthermia are enhanced by the use of magnetic particles. Magnetite cationic liposomes (MCLs), one of the groups of cationic magnetic particles, can be used as carriers to introduce DNA into cells since their positively charged surface associates with the negatively charged DNA. MCLs can also be used as heat mediators for cancer therapy. Magnetic particles conjugated with tumor-specific antibodies have enabled tumor-specific contrast enhancement in MRI. In addition, antibody-conjugated magnetic particles were shown to target renal cell carcinoma cells, and are applicable to the hyperthermic treatment of carcinomas. It was also found that the hyperthermic treatment using magnetic particles induced an antitumor immunity. Thus, the use of magnetic particles with their unique features will further improve medical techniques.

Topics: Animals; Biomedical Technology; Carboxymethylcellulose Sodium; Cell Separation; Combined Modality Therapy; Drug Delivery Systems; Ferrosoferric Oxide; Gene Transfer Techniques; Genetic Therapy; Hyperthermia, Induced; Immunoassay; Immunomagnetic Separation; Immunotherapy; Iron; Liposomes; Magnetic Resonance Imaging; Magnetics; Mice; Microspheres; Models, Immunological; Neoplasms; Oxides; Particle Size; Rats

An analysis of recently conducted phase I trials of biological response modifiers (BRM), performed mainly under the sponsorship of the BRM Program of the National Cancer Institute, has led to the development of a format for performing such trials with these agents in the future. The evolution of this format and its use in ongoing phase I trials of recombinant beta and gamma interferons is discussed. An evaluation of the method will be undertaken at the conclusion of these studies.

Topics: Biological Products; Carboxymethylcellulose Sodium; Drug Evaluation; Humans; Interferon Type I; Interferon-gamma; Neoplasms; Poly I-C; Polylysine; Thymosin

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

Administration of several biological response modifiers (BRMs) to mice strongly augmented natural killer (NK) activity of leukocytes isolated from the liver. This augmentation of NK activity was induced by two synthetic molecules (MVE-2 and poly ICLC), by two BRMs of bacterial origin (formalin-fixed Propionibacterium acnes: P. acnes and a streptococcal cell wall preparation designated OK-432), as well as a single injection of human recombinant interleukin-2 (hrIL 2). All of these BRMs augmented NK activity in the liver to a greater degree than in the spleen. In addition, adherent leukocytes (greater than 90% macrophages) isolated from the liver following P. acnes administration also exhibited augmented macrophage-mediated cytotoxicity. This cytotoxicity was characterized as macrophage mediated and distinguished from NK activity, on the basis of adherence purification, kinetics of cytotoxicity, and target cell selectivity. The results demonstrate that a variety of BRMs induce augmented natural immunity in the liver and suggest that such organ-associated immune responses may play an important role in the antimetastatic effects of BRMs.

Topics: Adjuvants, Immunologic; Animals; Carboxymethylcellulose Sodium; Cytotoxicity, Immunologic; Female; Humans; Interleukin-2; Killer Cells, Natural; Liver; Macrophages; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms; Picibanil; Poly I-C; Polylysine; Propionibacterium acnes; Pyran Copolymer; Recombinant Proteins; Spleen

A search for effective inducers of interferon lead to the discovery of polyinosinic-polycytidylic acid [poly(I,C)], which was effective in rodents but not primates. Stabilization of poly(I,C) with poly-L-lysine and carboxymethyl-cellulose produced a derivative that is much more effective as an inducer in humans, but also more toxic. The ability of modified poly(I,C) to induce interferon in primates appears to be at least partly related to its ability to resist hydrolysis by nucleases. As the ability to induce interferon in primates increases, so does the toxicity. Several investigations have emphasized increasing the ease of hydrolysis in order to minimize toxicity. The inducers should not be considered just as a readily available source of interferon, as there are a number of differences between the biologic effects of the inducers and exogenous interferon.

Topics: Animals; Carboxymethylcellulose Sodium; Female; Humans; Interferon Inducers; Interferons; Macaca mulatta; Male; Neoplasms; Pan troglodytes; Poly I-C; Polylysine; Ribonucleases; Sex Factors; Species Specificity

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

Topics: Adjuvants, Immunologic; Animals; Biological Products; Carboxymethylcellulose Sodium; Humans; Immunotherapy; Interferon Inducers; Neoplasms; Neoplasms, Experimental; Poly I-C; Polylysine; T-Lymphocytes

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

Topics: Animals; Antineoplastic Agents; Carboxymethylcellulose Sodium; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Mice; Neoplasms; Poly I-C; Polylysine; Polyribonucleotides; Research Design

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