Structure–activity relationships of carboxymethylpullulan-peptide-doxorubicin conjugates—systematic modification of peptide spacers

Nogusa, Hideo; Yano, Toshiro; Kashima, Nobukazu; Yamamoto, Keiji; Okuno, Satoshi; Hamana, Hiroshi

doi:10.1016/s0960-894x(99)00678-2

Cited by 18 publications

(14 citation statements)

References 12 publications

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“…It was believed that the GGFG sequence was a substrate of lysosomal enzymes, [17][18][19] as well as GFLG 20,21) or some others. [22][23][24][25] Nogusa et al [17][18][19] examined effect of peptide spacers on the release and antitumor activity of the drug, doxorubicin (DXR), conjugated with carboxymethyl-pullulan (CMPul). CMPul-GGFG-DXR showed the highest release of the drug, followed by CMPul-GFGG-DXR and CMPul-GGGG-DXR, when the conjugates were incubated with lysosomes for 24 h. 17) Among the three conjugates, CMPul-GGFG-DXR indicated the strongest antitumor effect against rat bearing Walker-256, and Yoshida sarcoma.…”

Section: Discussionmentioning

confidence: 99%

“…CMPul-GGFG-DXR showed the highest release of the drug, followed by CMPul-GFGG-DXR and CMPul-GGGG-DXR, when the conjugates were incubated with lysosomes for 24 h. 17) Among the three conjugates, CMPul-GGFG-DXR indicated the strongest antitumor effect against rat bearing Walker-256, and Yoshida sarcoma. 18) Their research group subsequently reported that anti-tumor activity of CMPul-GGFG-DXR was equivalent to that of CMPul-GFLG-DXR, 19) which has a well-known GFLG spacer. 20,21) Our previous studies have shown that DE-310 elicits significant anti-tumor activity in various tumor models, whereas the activity occurred at lower doses and with a more profound effect than DX-8951 alone.…”

Section: Discussionmentioning

confidence: 99%

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Relationship between Drug Release of DE-310, Macromolecular Prodrug of DX-8951f, and Cathepsins Activity in Several Tumors

Shiose

Ochi

Kuga

et al. 2007

Biological & Pharmaceutical Bulletin

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Utilization of drug delivery systems is an attractive approach to improving efficacy and safety of anticancer drugs. Long-circulating macromolecular or particulate carriers are known to preferentially accumulate in solid tumors, due to the "enhanced permeability and retention (EPR)" effect, 1) i.e., leakiness of tumor angiogenic blood vessels and lack of effective lymphatic drainage. SMANCS (neocartinostatin polymer conjugate), Doxil (doxorubicin liposome), and Daunozome (daunorubicin liposome) 2,3) that exploit the EPR effect have already been launched in the market. Besides, PK1 (doxorubicin-HPMA polymer), 4) XYOTAX (paclitaxelpolyglutamate), 5) and NK911 (doxorubicin micelle) 6) are under clinical investigation.DE-310 is a novel macromolecular prodrug of the topoisomerase-I inhibitor (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]-pyrano) [3Ј,4Ј:6,7]indolizino[1,2-b]quinoline-10,13-dione (DX-8951).7) DX-8951 is covalently linked with carboxymethyl dextran polyalcohol (CM-Dex-PA) via the Gly-Leu-Phe-Gly (GGFG) tetrapeptide spacer (Fig. 1). 7) It has been demonstrated that a single dose of 11.4 mg/kg DE-310 exhibited stronger anti-tumor activity in mice than repeated doses (10 mg/kg daily for 5 d) of DX-8951f (exatecan; DX-8951 monomethansulfonate salt).8) Taking into account that DX-8951f belongs to time-dependent anti-cancer drugs, 9) slow release of DX-8951 from DE-310 in addition to long-term retention in tumor tissues would have been beneficial in exhibiting such an effective anti-tumor activity.The peptide spacer of DE-310 was designed to be cleaved by cysteine protease, cathepsins. Expression of cathepsins B, H, and L in tumor tissues and their involvement in tumor progression have been indicated. 10) Cathepsin B is expressed more highly in malignant tumors 11) and is responsible for destruction of basal membranes, processing of matrix proteases, and inactivation of protein inhibitors.12) On the other hand, cathepsin H is highly expressed in colon cancer cells, 13) and cathepsin L is secreted in metastatic bone marrow tumor.14) It is likely that the level of cathepsin species in tumor tissues would be one of the factors determining antitumor activity of DE-310.In this study, we examined the drug release from DE-310 by cathepsins B, H, and L obtained from human liver to identify the products of hydrolysis and determine the rate of hydrolysis for each cathepsin species. Then, we examined in vitro drug release from DE-310 in different murine or human tumor cell types, in addition to the activity or expression of cathepsins B, H and L in the cells. Correlation between the drug release and cathepsin levels was analyzed to quantitatively delineate the mechanism of drug release from DE-310. In addition, tumor tissue distribution of DE-310 was investi-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Relationship between Drug Release of DE-310, Macromolecular Prodrug of DX-8951f, and Cathepsins Activity in Several Tumors

Shiose

Ochi

Kuga

et al. 2007

Biological & Pharmaceutical Bulletin

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“…Chemicals CMPul-FG-DXR was synthesized at the Drug Delivery System Institute, Ltd. (Noda, Chiba) using pullulan with a molecular weight of 65 000 (M w /M n =1.2) according to a procedure described elsewhere. 6,8) DXR was obtained from Kyowa Hakko Kogyo (Tokyo). The conjugate had a degree of substitution of carboxymethyl groups of 0.6 per glucose unit and a DXR content of 6.0%.…”

Section: Methodsmentioning

confidence: 99%

“…A tumor fragment (8 mm 3 ) of Lewis murine lung carcinoma was implanted s.c. into the back of BDF 1 mice. M5076 reticulosarcoma (1×10 6 ) was injected i.v. to BDF 1 mice.…”

Section: Methodsmentioning

confidence: 99%

“…4) Our previous report described carboxymethylpullulan (CMPul)-DXR conjugate via Gly-Gly-Phe-Gly as being more effective than DXR in rats bearing Walker 256 carcinosarcoma and Yoshida sarcoma. 5,6) We have further developed CMPul-DXR conjugates with a short spacer and have found that the conjugate via Phe-Gly showed good distribution in tumor tissue with a high content of free DXR. 7) The objectives of the present study were to evaluate the in vivo antitumor activity of CMPul-Phe-Gly-DXR conjugates (CMPul-FG-DXR) in the murine tumor model in comparison with that of DXR.…”

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confidence: 99%

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Improved in vivo Antitumor Efficacy and Reduced Systemic Toxicity of Carboxymethylpullulan‐peptide‐doxorubicin Conjugates

Nogusa¹,

Hamana²,

Uchida³

et al. 2000

Japanese Journal of Cancer Research

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Synthesis, characterization, and in vitro and in vivo evaluation of a novel pectin–adriamycin conjugate

Tang

Xie

Ding

et al. 2010

Bioorganic & Medicinal Chemistry

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Structure–activity relationships of carboxymethylpullulan-peptide-doxorubicin conjugates—systematic modification of peptide spacers

Cited by 18 publications

References 12 publications

Relationship between Drug Release of DE-310, Macromolecular Prodrug of DX-8951f, and Cathepsins Activity in Several Tumors

Relationship between Drug Release of DE-310, Macromolecular Prodrug of DX-8951f, and Cathepsins Activity in Several Tumors

Improved in vivo Antitumor Efficacy and Reduced Systemic Toxicity of Carboxymethylpullulan‐peptide‐doxorubicin Conjugates

Synthesis, characterization, and in vitro and in vivo evaluation of a novel pectin–adriamycin conjugate

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