DE‐310, a novel macromolecular carrier system for the camptothecin analog DX‐8951f: Potent antitumor activities in various murine tumor models

Abstract

he effect of current therapeutic agents appears when the agent acts on the target organ in the body. Since drug molecules that are distributed to organs that are not targeted may cause side effects, treatment is generally performed using a dose at which efficacy is obtained without unacceptable side effects. However, most antitumor chemotherapeutic agents show clinical effects only at doses that cause side effects such as digestive toxicity and myelosuppression. Therefore, in the development of new antitumor chemotherapeutic agents, it is important to discover compounds having a stronger antitumor effect and weaker toxicity compared with current antitumor chemotherapeutic agents. For example, CPT-11 was found to exhibit higher antitumor activity with less toxicity than camptothecin (CPT) and showed promising activity in clinical evaluation.1-8) However, it causes side effects such as severe watery diarrhea and there are marked inter-patient variations in both its effects and toxicity. 7, 9, 10) To obtain a more effective analogue with a lower toxicity, DX-8951f was designed.11) DX8951f is the most active inhibitor of topo I and tumor growth both in vitro and in vivo among the currently available CPT derivatives. [12][13][14] However, even with DX-8951f, there is no apparent increase in the selectivity to tumor tissue versus normal tissue and the half-life of the compound is relatively short (t 1/2 of 0.3 h mice). 15)The ideal antitumor drug would have high antitumor activity but no toxicity, i.e., it would be a compound for which efficacy and side effects are completely separate, but it is difficult to achieve this with low-molecular compounds, as the history of antitumor chemotherapeutics shows. Various approaches for superior targeting of antitumor compounds have been investigated by many researchers, and there have been trials of macromolecular pro-drugs. 16,17) Based on the results obtained from examinations of macromolecular conjugates using doxorubicin in DDS Institute, Ltd., we started to study drug delivery using a macromolecular carrier based on a DX-8951-conjugate, in order to enhance the antitumor effect and to reduce the hematological toxicity of DX-8951f.A novel macromolecular carrier system, based on the wellknown enhanced permeability and retention (EPR) effect, 18) was designed to target DX-8951 to tumors and to provide sustained release of DX-8951 in tumors. We conducted extensive optimization studies of the peptidyl spacer, molecular weight of the carrier, DX-8951 content and degree of carboxymenthylation.19) DE-310 is composed of DX-8951 and a biodegradable carrier, carboxymethyldextran polyalcohol (CM-Dex-PA), which are covalently linked by a peptidyl spacer (Gly-Gly-PheGly, GGFG).19) It has an average molecular weight of 340,000 (DX-8951 content: less than 8%, degree of carboxymethylation: ca. 0.3-0.4 per sugar residue). 19) In the present study, we examined the therapeutic efficacy of DE-310 against a variety of human and murine tumors in mice. Materials and MethodsCompounds. Fig. 1A), ...

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

“…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. 8) High levels and prolonged retention of conjugated DX-8951, DX-8951, and G-DX-8951 have been observed in tumor tissues after intravenous injection of DE-310 in Meth A tumor-bearing mice. 26) Thus, liberated DX-8951s are believed to exhibit a cytotoxic effect in tumor tissues.…”

“…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.…”

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

“…The degree of tissue perfusion may also have some bearing on the relatively high concentrations of all three drug components observed in the spleen and peritoneum of patient 3. The high levels of drug determined in bile and to a lesser degree the gall bladder is supportive of the preclinical pharmacokinetic data that determined that the primary route of excretion of DX-8951 and its metabolites was the feces [44].…”

“…Pre-clinical studies have shown that DE-310 elicits anti-tumor activity in various tumor models, whereas the activity occurred at lower doses and with a more profound effect than with DX-8951 alone [40]. Furthermore, high levels and prolonged retention of conjugated DX-8951 and free DX-8951 have been observed in tumor tissues after the dose of DE-310 in Meth A (fibrosarcoma) mice [41].…”

“…Furthermore, high levels and prolonged retention of conjugated DX-8951 and free DX-8951 have been observed in tumor tissues after the dose of DE-310 in Meth A (fibrosarcoma) mice [41]. Two phase I dose-escalating studies have recently been completed, assessing different dosing schedules with administration of DE-310 in patients with advanced solid malignancies or lymphomas [42,43].…”