Intracellular Disposition and Cytotoxicity of Transferrin-Mitomycin C Conjugate in HL60 Cells as a Receptor-Mediated Drug Targeting System.

Tanaka, Tetsuro; Kaneo, Yoshiharu; Miyashita, Masahide

doi:10.1248/bpb.21.147

Cited by 8 publications

(7 citation statements)

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“…4) We demonstrated that TF-MMC internalized into the HL60 cell, and a part of the internalized TF-MMC degraded and exposed cytotoxicity against the HL60 cell.…”

mentioning

confidence: 77%

“…22,23) We have previously described the covalent attachment of MMC to give TF-MMC, which aided the delivery of MMC to the tumor cells. 3,4) In this study, we examined the intracellular disposition of TF-MMC, such as binding to the TF receptor and internalization in both the HepG2 cell and the cultured rat hepatocyte. By the calculation with MULTI, the number of the binding site (n) and the association constant (K a ) for TF-MMC were estimated to be 3.96ϫ10 5 molecules/cell and 3.24ϫ10…”

Section: Discussionmentioning

confidence: 99%

“…TF-MMC and MMC have a cytotoxicity against the human leukemia cell line HL60 cell. 4) The values of IC 50 of MMC against the HepG2 cell and the HL60 cell were almost similar. However, TF-MMC was more cytotoxic against the HepG2 cell (IC 50 ϭ0.9 mg MMC/ml) than the HL60 cell (IC 50 ϭ1.6 mg MMC/ml).…”

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confidence: 80%

“…4) A curve fitting was done using a nonlinear least-squares program, MULTI. 125 I]TF reached the maximum value at 10 min and 20 min, respectively.…”

Section: )mentioning

confidence: 99%

“…These values in the HepG2 cell and the hepatocyte were almost identical to those in the HL60 cell (0.188Ϯ0.015 min Ϫ1 for TF-MMC and 0.231Ϯ 0.019 min Ϫ1 for TF). 4) On the other hand, the rates of release of TF from the HL60 cell was 0.0768Ϯ0.0082 min…”

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confidence: 97%

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Receptor Mediated Endocytosis and Cytotoxicity of Transferrin-Mitomycin C Conjugate in the HepG2 Cell and Primary Cultured Rat Hepatocyte.

Tanaka

Fujishima

Kaneo

2001

Biological & Pharmaceutical Bulletin

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Intracellular disposition and cytotoxicity of macromolecular conjugate of mitomycin C (MMC) with transferrin (TF) were examined in the human hepatoma cell line HepG2 cell and normal cultured rat hepatocyte. The conjugate (TF-MMC) was specifically bound to the HepG2 cell as well as TF. The number of the binding site and the association constant of TF-MMC in the HepG2 cell were 396000؎31000 molecules/cell and 3.24؋10 7 ؎0.58 ؋10 M ؊1, respectively. No difference in the binding parameters of TF-MMC and TF can be detected in the HepG2 cell. The association constant for the TF receptor was almost identical between HepG2 cell and hepatocyte, however, the numbers of the binding site of TF-MMC and TF in the HepG2 cell were from 40-times to 50-times greater than those in the hepatocyte. Furthermore, TF-MMC was internalized into the HepG2 cell and the hepatocyte as well as TF. The rates of internalization of TF-MMC and TF into the HepG2 cell were nearly identical to those into the hepatocyte. However, the levels of the internalization into the HepG2 cell were remarkably higher than those into the hepatocyte because the number of receptors in the HepG2 cell was larger than that in the hepatocyte, and the rate of release from the HepG2 cell was slower than that from the hepatocyte. TF-MMC inhibited the growth of the HepG2 cells. The 50% growth inhibition (GI 50 ) of TF-MMC against the HepG2 cell was 0.9 m mg MMC/ml, which was a little higher than that of MMC (GI 50 ‫5.0؍‬ m mg/ml). These results indicated that the TF-MMC might be useful for delivery of MMC to the HepG2 cell.

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“…4) We demonstrated that TF-MMC internalized into the HL60 cell, and a part of the internalized TF-MMC degraded and exposed cytotoxicity against the HL60 cell.…”

mentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 80%

“…4) A curve fitting was done using a nonlinear least-squares program, MULTI. 125 I]TF reached the maximum value at 10 min and 20 min, respectively.…”

Section: )mentioning

confidence: 99%

mentioning

confidence: 97%

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Receptor Mediated Endocytosis and Cytotoxicity of Transferrin-Mitomycin C Conjugate in the HepG2 Cell and Primary Cultured Rat Hepatocyte.

Tanaka

Fujishima

Kaneo

2001

Biological & Pharmaceutical Bulletin

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Transferrin/transferrin receptor‐mediated drug delivery

Qian

2002

Medicinal Research Reviews

406

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Since transferrin was discovered more than half a century ago, a considerable effort has been made towards understanding tranferrin-mediated iron uptake. However, it was not until recently with the identification and characterization of several new genes related to iron homeostasis, such as the hemochromatosis protein HFE and the iron transporter DMT1, that our knowledge has been advanced dramatically. A major pathway for cellular iron uptake is through internalization of the complex of iron-bound transferrin and the transferrin receptor, which is negatively modulated by HFE, a protein related to hereditary hemochromatosis. Iron is released from transferrin as the result of the acidic pH in endosome and then is transported to the cytosol by DMT1. The iron is then utilized as a cofactor by heme and ribonucleotide reductase or stored in ferritin. Apart from iron, many other metal ions of therapeutic and diagnostic interests can also bind to transferrin at the iron sites and their transferrin complexes can be recognized by many cells. Therefore, transferrin has been thought as a "delivery system" for many beneficial and harmful metal ions into the cells. Transferrin has also be widely applied as a targeting ligand in the active targeting of anticancer agents, proteins, and genes to primary proliferating malignant cells that overexpress transferrin receptors. This is achieved by conjugation of transferrin with drugs, proteins, hybride systems with marcomolecules and as liposomal-coated systems. Conjugates of anticancer drugs with transferrin can significantly improve the selectivity and toxicity and overcome drug resistance, thereby leading to a better treatment. The coupling of DNA to transferrin via a polycation such as polylysine or via cationic liposomes can target and transfer of the extrogenous DNA particularly into proliferating cells through receptor-mediated endocytosis. These kinds of non-viral vectors are potential alternatives to viral vectors for gene therapy, if the transfection efficiency can be improved. Moreover, transferrin receptors have shown potentials in delivery of therapeutic drugs or genes into the brain across blood-brain barrier.

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