Enhancement of the Specific Cytotoxicity of Anti-Carcinoembryonic Antigen Immunotoxins by Adenovirus and Carboxylic Ionophores

Griffin, Thomas W.; Childs, Linda R.; Levin, Larissa V.

doi:10.1016/b978-0-08-031739-7.50113-0

Cited by 7 publications

(8 citation statements)

References 11 publications

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“…Monensin has been shown to potentiate the effects of immunotoxins against leukaemia (Raso & Lawrence 1984), breast carcinoma (Griffin et al 1987), colorectal carcinoma (Griffin et al 1988) and small cell lung carcinoma (Derbyshire et al 1992) cell lines in-vitro. However, monensin, being lipophilic in nature, has a short half-life in-vivo and therefore needs to be formulated in a suitable drug delivery system.…”

Section: Introductionmentioning

confidence: 99%

Long-circulating monensin nanoparticles for the potentiation of immunotoxin and anticancer drugs

Shaik

Ikediobi

Turnage

et al. 2001

Journal of Pharmacy and Pharmacology

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The carboxylic ionophore monensin was formulated into long-circulating nanoparticles with the help of polyethylene glycol/poly (DL-lactide-co-glycolide) diblock copolymers, in an attempt to enhance the cytotoxicity of a ricin-based immunotoxin, anti-My9, and anticancer drugs like adriamycin and tamoxifen. This study looked into various aspects involving the preparation (using a homogenizer and an EmulsiFlex homogenizer-extrusion device) and lyophilization of long-circulating monensin nanoparticles (LMNP) of particle size < 200 nm in diameter. The particle size of LMNP was reduced from 194 nm to 160 nm by passing the nanoparticles through an EmulsiFlex, before freeze-drying. There was a 4.8-83.7% increase in the particle size of LMNP after freeze-drying, which was dependent upon the manufacturing conditions such as use of the EmulsiFlex for size reduction before freeze-drying, the freezing method (rapid/slow) and the concentration of lyoprotectant (mannitol or trehalose) employed for freeze-drying. LMNP freeze-dried with 2.4% of trehalose showed minimal size change (< 9%) after freeze-drying. Further, the freezing method was found to have negligible effect on the particle size of LMNP freeze-dried with trehalose in comparison with mannitol. The entrapment efficiency of monensin in LMNP was found to be 14.2 +/- 0.3%. The LMNP were found to be spherical in shape and smooth in surface texture as observed by atomic force microscopy. In-vitro release of monensin from LMNP in phosphate buffered saline (PBS) pH 7.4 or PBS supplemented with 10% human serum indicated that there was an initial rapid release of about 40% in the first 8 h followed by a fairly slow release (about 20%) in the next 88 h. In-vivo studies conducted with Sprague-Dawley rats showed that 20% of monensin remained in circulation 4-8 h after the intravenous administration of LMNP. An in-vitro dye-based cytotoxicity assay (MTS/PMS method) showed that there was 500 times and 5 times potentiation of the cytotoxicity of anti-My9 immunotoxin by LMNP (5 x 10(-8) M of monensin) in HL-60 sensitive and resistant human tumour cell lines, respectively. Further, LMNP (5 x 10(-8) M of monensin) potentiated the cytotoxicity of adriamycin in MCF 7 and SW 620 cell lines by 100 fold and 10 fold, respectively, and that of tamoxifen by 44 fold in MCF 7 cell line as assessed by crystal violet dye uptake assay. Our results suggest that it is possible to prepare LMNP possessing appropriate particle size (< 200 nm), monensin content and in-vitro and in-vivo release characteristics with the help of a homogenizer and an EmulsiFlex homogenizer-extrusion device. LMNP can be freeze-dried with minimal increase in particle size by using a suitable concentration of a lyoprotectant like trehalose. Furthermore, LMNP could potentiate the cytotoxicity of immunotoxin, adriamycin and tamoxifen by 5-500 fold in-vitro, which will be further investigated in-vivo in a suitable animal model.

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Section: Introductionmentioning

confidence: 99%

Long-circulating monensin nanoparticles for the potentiation of immunotoxin and anticancer drugs

Shaik

Ikediobi

Turnage

et al. 2001

Journal of Pharmacy and Pharmacology

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“…A tumor compartment could be added to the model and the kinetics of the antibody in this compartment would be important in determining the effectiveness of the antibody in the immunodetection of tumors that may vary in size and location. In addition, the 260F9 antibody, when conjugated to ricin A chain, is a highly effective and specific cytotoxin for human breast [1,2,9] and ovarian cancer cells [16]. Understanding the pharmacokinetics and metabolic processing of this antibody may aid the development of immunoconjugates for cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…The l t 1 In-labeled monoclonal anti-(breast cancer) antibody (260F9) (an IgG0 [6,9,16] was administered to seven patients. The antibody was generated by immunizing a mouse with a liver metastasis of a human breast tumor.…”

Section: Introductionmentioning

confidence: 99%

A preliminary pharmacokinetic study of 111In-labeled 260F9 anti-(breast cancer) antibody in patients

Bokhari

Collins

et al. 1989

Cancer Immunol Immunother

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The pharmacokinetics of 111In-labeled 260F9, a murine monoclonal antibody directed against a breast-cancer-associated antigen, was determined in seven patients with advanced breast cancer. Six patients were administered 1 mg antibody containing 1 mCi 111In. The seventh patient was administered 20 mg unlabeled antibody followed by 1 mg 111In-labeled antibody all via a peripheral vein. Immunoprecipitation, HPLC and SDS-PAGE gels demonstrated the stability of radiolabel on the antibody. The serum clearance of the radiolabel closely fits (r2 greater than 0.95) a two-compartment model for the first six patients. The apparent volume of distribution of the radiolabel approximated to the plasma volume (31) and its mean residence time was 23.7 h. The radiolabel had an average t 1/2 beta of 22.9 +/- 12.21 h at the 1-mg dose. At the 20-mg dose one-compartment elimination kinetics were observed with the radiolabel and antibody showing similar mean residence times (36-41 h) and a t 1/2 beta of 26-28 h. Whole-body imaging showed that the blood-pool: liver ratio of radioactivity increased fourfold (at 48 h postinfusion) at the higher dose and the percentage of the injected dose of radioactivity in the liver decreased from 25% to 8% (24 h postinfusion). In one patient 7-14 times more radioactivity was localized in a breast tumor than in fat (normal breast). Over the first 25 h an average (cumulative) 7.5% of the total dose was excreted in urine. A study of 260F9 in CDF-1 mice demonstrated that the radiolabel remained associated with the antibody in serum. The antibody, however, cleared 60-fold slower in mice than in patients and showed an increased mean residence time of 191 h. The disparity in the pharmacokinetics of the antibody seen in the mouse and in the clinic, points to the different behavior shown by murine monoclonal antibodies in humans. This points to the need for preliminary studies of antibodies in patients for preclinical evaluations of their effectiveness as drug-targeting agents.

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“…Fitzgerald et al [77] also showed that inactivated human adenovirus type 2 infection of target cells augmented the cytotoxicity of an anti-transferrin-PE conjugate by 100 to 300-fold. Griffin et al [78] were able to show that inactivated human adenovirus was able to specifically potentiate a targeted toxin comprised of carcinoembryonic antigen conjugated to ricin A chain for the human colorectal adenocarcinoma cell line LoVo shortening the length of time taken to reduce protein synthesis to fifty percent control cell levels from 10 h without virus to 0.5 h with virus, representing a twenty-fold increase in intoxification kinetics. Some years later Satyamoorthy et al [79] were able to show that the potency of an fibroblast growth factor-saporin conjugate for a melanoma cell line expressing the cognate receptor was enhanced ten-fold by target melanoma cells infected with a replication deficient adenovirus.…”

Section: Figurementioning

confidence: 99%

Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins

Fuchs

Bachran²,

Flavell

et al. 2013

Antibodies

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Membranes are vital barriers by which cells control the flux of molecules and energy between their exterior and interior and also between their various intracellular compartments. While numerous transport systems exist for ions and small molecules, the cytosolic uptake of larger biological molecules and in particular antibody-targeted drugs, is a big challenge. Inducing leakage of the plasma membrane is unfavorable since the target cell specificity mediated by the antibody would likely be lost in this case. After binding and internalization, the antibody drug conjugates reach the endosomes. Thus, enforcing the endosomal escape of anti-tumor toxins without affecting the integrity of other cellular membranes is of paramount importance. Different strategies have been developed in the last decades to overcome endosomal accumulation and subsequent lysosomal degradation of targeted protein-based drugs. In this review we summarize the various efforts made to establish efficient techniques to disrupt the endosomal membrane barrier including the use of molecular ferries such as cell penetrating peptides or viral membrane fusion proteins, endosomal leakage inducing molecules such as saponins or monensin and physicochemical methods as represented by photochemical internalization.

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Enhancement of the Specific Cytotoxicity of Anti-Carcinoembryonic Antigen Immunotoxins by Adenovirus and Carboxylic Ionophores

Cited by 7 publications

References 11 publications

Long-circulating monensin nanoparticles for the potentiation of immunotoxin and anticancer drugs

Long-circulating monensin nanoparticles for the potentiation of immunotoxin and anticancer drugs

A preliminary pharmacokinetic study of 111In-labeled 260F9 anti-(breast cancer) antibody in patients

Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins

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