DE-310, a macromolecular prodrug of the topoisomerase-I-inhibitor exatecan (DX-8951), in patients with operable solid tumors

Wente, Moritz N.; Kleeff, Jörg; Büchler, Markus W.; Wanders, J.; Cheverton, Peter; Langman, Stephen; Friess, Helmut

doi:10.1007/s10637-005-1442-2

Cited by 16 publications

(12 citation statements)

References 31 publications

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“…Similar results were achieved with DE-310 (see Figure 22), a 340-kDa carboxymethyldextran conjugate of the camptothecin analogue DX-8951, in six patients with different tumors. [128] Although these results are in marked contrast to previous biodistribution studies in tumorbearing animals, [129,130] they should not be overestimated.…”

Section: Passive Targetingmentioning

confidence: 66%

Prodrug Strategies in Anticancer Chemotherapy

Kratz¹,

Müller²,

Ryppa³

et al. 2008

ChemMedChem

438

425

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The majority of clinically approved anticancer drugs are characterized by a narrow therapeutic window that results mainly from a high systemic toxicity of the drugs in combination with an evident lack of tumor selectivity. Besides the development of suitable galenic formulations such as liposomes or micelles, several promising prodrug approaches have been followed in the last decades with the aim of improving chemotherapy. In this review we elucidate the two main concepts that underlie the design of most anticancer prodrugs: drug targeting and controlled release of the drug at the tumor site. Consequently, active and passive targeting using tumor-specific ligands or macromolecular carriers are discussed as well as release strategies that are based on tumor-specific characteristics such as low pH or the expression of tumor-associated enzymes. Furthermore, other strategies such as ADEPT (antibody-directed enzyme prodrug therapy) and the design of self-eliminating structures are introduced. Chemical realization of prodrug approaches is illustrated by drug candidates that have or may have clinical importance.

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Section: Passive Targetingmentioning

confidence: 66%

Prodrug Strategies in Anticancer Chemotherapy

Kratz¹,

Müller²,

Ryppa³

et al. 2008

ChemMedChem

438

425

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“…A clinical study demonstrated that G-DX-8951 concentration in tumor tissues are approximately ten fold greater than DX-8951, suggesting that G-DX-8951 might partially contribute to the cytotoxic activity of DE-310. 27) Structural requirements for drug release from macromolecular prodrugs have been discussed by Soyez et al 28) who concluded that, whereas general trends could be found, the type of carrier and drug used greatly influences the degradation rate and pattern due to specificities of substrate-enzyme reactions. Taking into account the difference in cytotoxic effects between DX-8951 and G-DX-8951, the present study was initiated to investigate how these two forms appear from DE-310 hydrolysis.…”

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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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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“…This heterogeneity gives rise to considerable variation in the EPR effect of a tumor at different regions and during different stages. Second, because of the vast difference in the progression rates between frequently studied animal models (usually mouse models) and most human solid tumors, the vasculature in the latter is much more mature and less disorganized, bringing into question the existence of the EPR effect in human patients . Thus, it is still unclear whether the results of EPR‐based nanomedicines tested in animals can be clinically translated.…”

Section: Challenges In the Epr‐based Tumor‐targeted Drug Deliverymentioning

confidence: 99%

Macrophages as Active Nanocarriers for Targeted Early and Adjuvant Cancer Chemotherapy

Shao

Shen

et al. 2016

Small

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Taking advantage of the highly permeable vasculature and lack of lymphatic drainage in solid tumors (EPR effect), nanosized drug delivery systems or nanomedicines have been extensively explored for tumor-targeted drug delivery. However, in most clinical cases tumors such as the early stage tumors and post-surgery microscopic residual tumors have not yet developed such pathological EPR features, i.e., EPR-deficient. Therefore, nanomedicines may not be applicable for such these tumors. Macrophages by nature can actively home and extravasate through the tight vascular wall into tumors and migrate to their hypoxic regions, and possess perfect stealth ability for long blood circulation and impressive phagocytosis for drug loadings. Thus, nanomedicines loaded in macrophages would harness both merits and gain the active tumor homing capability independent of the EPR effect for treatments of the EPR-deficient tumors. Herein, the critical considerations, current progress, challenges and future prospects of macrophages as carriers for nanomedicines are summarized, aiming at rational design of EPR-independent tumor-targeting active nanomedicines for targeted early and adjuvant cancer chemotherapy.

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DE-310, a macromolecular prodrug of the topoisomerase-I-inhibitor exatecan (DX-8951), in patients with operable solid tumors

Cited by 16 publications

References 31 publications

Prodrug Strategies in Anticancer Chemotherapy

Prodrug Strategies in Anticancer Chemotherapy

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

Macrophages as Active Nanocarriers for Targeted Early and Adjuvant Cancer Chemotherapy

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