Static and dynamic imaging with indium-111 labelled Bleomycin in the localization of squamous cell neoplasia

Burton, Ian; Todd, Janet; Turner, R.

doi:10.1259/0007-1285-50-595-508

Cited by 9 publications

(7 citation statements)

References 3 publications

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“…3 In addition to its anti-tumor activity, bleomycin has been recognized for its ability to target tumors and has been demonstrated to act as a tumor-imaging agent. 4 Identification of the molecular elements in BLM responsible for tumor cell targeting would not only enable analogues with improved properties to be explored but might also allow for the selective delivery of other drugs to tumor cells.…”

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confidence: 99%

“…The bleomycins (BLMs) are a family of glycopeptide-derived antitumor antibiotics used clinically for the treatment of squamous cell carcinomas and malignant lymphomas (BLM A 5 is shown in Figure ). , Their antitumor activity is thought to result from selective oxidative cleavage of 5′-GC-3′ and 5′-GT-3′ sequences in DNA and possibly also from oxidative degradation of RNA . In addition to its antitumor activity, BLM has been recognized for its ability to target tumors and shown to act as a tumor-imaging agent . Identification of the molecular elements in BLM responsible for tumor cell targeting would not only enable analogues with improved properties to be explored but might also allow for the selective delivery of other drugs to tumor cells.…”

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Selective Tumor Cell Targeting by the Disaccharide Moiety of Bleomycin

et al. 2013

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In a recent study, the well documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been derivatized with multiple copies of BLM. It was shown that BLM selectively targeted MCF-7 human breast carcinoma cells, but not the “normal” breast cell line MCF-10A. Further, the BLM analogue deglycobleomycin, which lacks the disaccharide moiety of BLM, was found not to target either cell line, indicating that the BLM disaccharide moiety is necessary for tumor selectivity. Not resolved in the earlier study was the issue of whether the BLM disaccharide moiety alone is sufficient for tumor cell targeting, as well as the possible cellular uptake of the disaccharide. In the present study, we have conjugated BLM, deglycoBLM and BLM disaccharide to the cyanine dye Cy5**. It was found that the BLM and BLM disaccharide conjugates, but not the deglycoBLM conjugate, bound selectively to MCF-7 cells, and were internalized. The same was also true for the prostate cancer cell line DU-145 (but not for normal PZ-HPV-7 prostate cells) and for the pancreas cancer cell line BxPC-3 (but not for normal SVR A221a pancreas cells). The targeting efficiency of the disaccharide was only slightly less than that of BLM in MCF-7 and DU-145 cells, and comparable to BLM in BxPC-3 cells. These results establish that the BLM disaccharide is both necessary and sufficient for tumor cell targeting, a finding with obvious implications for the design of novel tumor imaging and therapeutic agents.

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Selective Tumor Cell Targeting by the Disaccharide Moiety of Bleomycin

et al. 2013

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“…The residue was purified by flash chromatography on a silica gel column (36 × 2 cm). Elution with 1:1 hexanes−ethyl acetate gave 13 as a colorless oil: yield 0.411 g (93%); silica gel TLC R f 0.23 (1:1 hexanes−ethyl acetate); [α] D 21 +11.0 (c 1.12, CHCl 3 ); 1 H NMR (CDCl 3 ) δ 0.85−0.89 (m, 6H), 0.92 (s, 9H), 0.99 (s, 9H), 1.28−1.41 (m, 4H), 1.56−1.66 (m, 4H), 2.08 (s, 3H), 3.81−4.11 (m, 8H), 5.00 (br s, 2H), 5.06−5.10 (dd, 1H, J = 6.3 and 3.3 Hz), 5.25 (dd, 1H, J = 1.8 and 1.8 Hz), and 5.46−5.49 (dd, 1H, J = 4.8 and 1.8 Hz); 13 4,6-Di-tert-butyl-O-silylene-2-O-acetyl-3-O-carbamoyl-1-phenylthio-α-D-mannopyranose (14). To a cooled (−78 °C) solution containing 2.62 g (4.38 mmol) of 13 and 4 Å molecular sieves in 15 mL of CH 2 Cl 2 were added sequentially 711 μL (723 mg, 6.57 mmol) of thiophenol and 1.98 mL (2.43 g, 10.9 mmol) of TMSOTf.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…The bleomycins (BLM) are a family of glycopeptide-derived antitumor antibiotics first isolated from Streptomyces verticillus. , Their antitumor activity derives from their ability to effect DNA cleavage in cancer cells − and probably reflects the propensity of the compounds to effect double-strand DNA cleavage. − The bleomycins are also tumor-seeking molecules, as demonstrated initially by the use of bleomycins derivatized with radionuclides − and more recently in cell culture experiments involving bleomycins and BLM carbohydrates conjugated to microbubbles and dyes …”

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confidence: 99%

The Disaccharide Moiety of Bleomycin Facilitates Uptake by Cancer Cells

et al. 2014

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The disaccharide moiety is responsible for the tumor cell targeting properties of bleomycin (BLM). While the aglycon (deglycobleomycin) mediates DNA cleavage in much the same fashion as bleomycin, it exhibits diminished cytotoxicity in comparison to BLM. These findings suggested that BLM might be modular in nature, composed of tumor-seeking and tumoricidal domains. To explore this possibility, BLM analogues were prepared in which the disaccharide moiety was attached to deglycobleomycin at novel positions, namely, via the threonine moiety or C-terminal substituent. The analogues were compared with BLM and deglycoBLM for DNA cleavage, cancer cell uptake, and cytotoxic activity. BLM is more potent than deglycoBLM in supercoiled plasmid DNA relaxation, while the analogue having the disaccharide on threonine was less active than deglycoBLM and the analogue containing the C-terminal disaccharide was slightly more potent. While having unexceptional DNA cleavage potencies, both glycosylated analogues were more cytotoxic to cultured DU145 prostate cancer cells than deglycoBLM. Dye-labeled conjugates of the cytotoxic BLM aglycons were used in imaging experiments to determine the extent of cell uptake. The rank order of internalization efficiencies was the same as their order of cytotoxicities toward DU145 cells. These findings establish a role for the BLM disaccharide in tumor targeting/uptake and suggest that the disaccharide moiety may be capable of delivering other cytotoxins to cancer cells. While the mechanism responsible for uptake of the BLM disaccharide selectively by tumor cells has not yet been established, data are presented which suggest that the metabolic shift to glycolysis in cancer cells may provide the vehicle for selective internalization.

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“…The bleomycins (Figure ) are glycopeptide-derived natural products, which were first identified as secondary metabolites from culture broths of Streptomyces verticillus following their isolation as Cu(II) chelates. , The bleomycins were shown to possess significant anticancer activity, , and some of the BLMs are now employed clinically as antitumor agents, both as single agents and in combination chemotherapy. , Interestingly, it has also been found that radionuclide complexes of the bleomycins bind selectively to a variety of tumor cells, − which likely contributes to their selectivity as antitumor agents. Redox-active metal complexes of the BLMs mediate oxidative degradation of DNA producing both single- and double-strand breaks, − and the double-strand DNA breaks are believed to form the basis for the antitumor activity of BLM …”

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Structural Features Facilitating Tumor Cell Targeting and Internalization by Bleomycin and Its Disaccharide

Rutgeerts

Bhattacharya

et al. 2015

Biochemistry

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We have shown previously that the bleomycin (BLM) carbohydrate moiety can recapitulate the tumor cell targeting effects of the entire BLM molecule, that BLM itself is modular in nature consisting of a DNA-cleaving aglycone which is delivered selectively to the interior of tumor cells by its carbohydrate moiety, and that there are disaccharides structurally related to the BLM disaccharide which are more efficient than the natural disaccharide at tumor cell targeting/uptake. Because BLM sugars can deliver molecular cargoes selectively to tumor cells, and thus potentially form the basis for a novel antitumor strategy, it seemed important to consider additional structural features capable of affecting the efficiency of tumor cell recognition and delivery. These included the effects of sugar polyvalency and net charge (at physiological pH) on tumor cell recognition, internalization, and trafficking. Since these parameters have been shown to affect cell surface recognition, internalization, and distribution in other contexts, this study has sought to define the effects of these structural features on tumor cell recognition by bleomycin and its disaccharide. We demonstrate that both can have a significant effect on tumor cell binding/internalization, and present data which suggests that the metal ions normally bound by bleomycin following clinical administration may significantly contribute to the efficiency of tumor cell uptake, in addition to their characterized function in DNA cleavage. A BLM disaccharide-Cy5** conjugate incorporating the positively charged dipeptide d-Lys-d-Lys was found to associate with both the mitochondria and the nuclear envelope of DU145 cells, suggesting possible cellular targets for BLM disaccharide–cytotoxin conjugates.

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Static and dynamic imaging with indium-111 labelled Bleomycin in the localization of squamous cell neoplasia

Cited by 9 publications

References 3 publications

Selective Tumor Cell Targeting by the Disaccharide Moiety of Bleomycin

Selective Tumor Cell Targeting by the Disaccharide Moiety of Bleomycin

The Disaccharide Moiety of Bleomycin Facilitates Uptake by Cancer Cells

Structural Features Facilitating Tumor Cell Targeting and Internalization by Bleomycin and Its Disaccharide

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