Doxorubicin (DOX) is an anticancer agent with a wide spectrum of activity. Cumulative dose-related cardiotoxicity, however, is a major side-effect of DOX, in addition to the acute toxicities, such as myelosuppression, nausea and vomiting. The success of DOX, and its limitations in clinical use, have directed research endeavours for the development of analogues of DOX with an improved therapeutic index. Among these are iododoxorubicin, AD-32 and epidoxorubicin (Weiss, 1992). Iododoxorubicin was noted to be promising in phase I trials, but in phase II trials the response rate was too low to warrant further development. AD-32 has greater anti-tumour activity, and less cardiotoxicity, than DOX, but drug formulation and solubility problems prevented its further clinical development. Of the available analogues, only epidoxorubicin appears to have a reduced cardiotoxicity with retention of antitumour activity and is in use in current cancer chemotherapy.Another way to improve the selectivity and efficacy of chemotherapy is the use of non-toxic prodrugs that are preferentially converted into active anticancer agents at the tumour site (Sinhababu and Thakker, 1996). N-L-leucyl-DOX is a prodrug of DOX, to be activated by tumour peptidases (Deprez-de Campeneere et al, 1982). In human ovarian cancer xenografts, N-L-leucyl-DOX was more effective than DOX . Clinical studies on N-L-leucyl-DOX, however, have indicated premature activation of the prodrug in the circulation, because of which the selectivity of the prodrug would be reduced . Elevated enzyme levels in tumour tissue have been reported for β-glucuronidase (Connors and Whisson, 1966). Bosslet et al (1995) and Schumacher et al (1996) have shown that this enzyme is released in the extracellular space as a result of necrosis in tumours. The enzyme can only be detected in very low concentrations in the circulation (Fishman, 1970). Therefore, β-glucuronidase may be exploited for the specific activation of glucuronide prodrugs in tumour tissue.We have developed glucuronide derivatives of anthracyclines and showed that these prodrugs, such as epirubicin-glucuronide (Haisma et al, 1992) and daunorubicin-glucuronides (Leenders et al, 1995;Houba et al, 1996), are relatively non-toxic in vitro and can be activated by β-glucuronidase to yield the active anthracycline. Treatment with the glucuronide prodrug daunorubicin-GA3 (DNR-GA3) induced a better tumour growth delay than daunorubicin (DNR) when studied at equitoxic doses in 3 human ovarian cancer xenografts which were sensitive to DNR (Houba et al, 1998). Comparison of the distribution and pharmacokinetics of DNR and DNR-GA3 demonstrated that the prodrug DNR-GA3 was selectively activated by human β-glucuronidase present in the tumours and resulted in a higher DNR AUC in tumours and lower A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer Summary The doxorubicin (DOX) prodrug N-[4-doxorubicin-N-carbonyl (oxymethyl) phenyl] O-β-glucuro...
Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans- cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC 50 inhibition in WNT/β - catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.
A glucuronide doxorubicin prodrug N‐[4‐doxorubicin‐N‐carbonyl (oxymethyl) phenyl] O‐β‐glucuronyl carbamate (DOX‐GA3) has been developed to improve the antitumor effects of doxorubicin (DOX). The prodrug was originally designed to be activated into drug by human β‐glucuronidase (GUS) released from tumor cells in necrotic areas of tumor lesions. The aim of this study was to further improve the antitumor effects of DOX‐GA3 by means of antibody‐directed enzyme prodrug therapy (ADEPT). We thus investigated if the administration of an enzyme‐immunoconjugate prepared from the pancarcinoma Ep‐CAM specific monoclonal antibody (MAb) 323/A3 and β‐glucuronidase would result in improved antitumor effects because of additional enzyme localization in tumor tissue. In vitro, the prodrug DOX‐GA3 was found to be 12‐times less toxic than the parent drug DOX in a human ovarian cancer cell line. Immunospecific and complete activation of the prodrug took place when the cells were pretreated with 323/A3‐β‐glucuronidase conjugate. In nude mice bearing s.c. human ovarian cancer xenografts (FMa) the maximum tolerated dose (MTD) of DOX‐GA3 (500 mg/kg weekly × 2) was much higher when compared with that of DOX (8 mg/kg weekly × 2). In mice bearing well‐established FMa xenografts, the standard treatment of DOX at the MTD (8 mg/kg weekly × 2) resulted in a tumor growth inhibition of 67%. Treatment with DOX‐GA3 at a single dose of 500 mg/kg resulted in a better tumor growth inhibition of 87%. The combination of DOX‐GA3 (500 mg/kg) with 323/A3‐mGUS conjugate and anti‐GUS MAb 105, to clear circulating conjugate, improved the antitumor effect even further to 98%. At the lower dose of 250 mg/kg DOX‐GA3 tumor growth inhibition (34%) was not better than that of DOX. The combination, however, of DOX‐GA3 at 250 mg/kg and 323/A3‐mGUS conjugate plus MAb 105 again greatly improved the antitumor effect (growth inhibition of 93%). DOX given at 8 mg/kg weekly x 2 did not result in tumor regressions. As a result of ADEPT, the number of regressions of tumors improved from 0 out of 12 to 9 out of 11 at a dose of 250 mg/kg DOX‐GA3. At the higher prodrug dose (500 mg/kg) the number of regressions improved from 2 out of 12 to 9 out of 10 as a result from the addition of enzyme‐immunoconjugate. Our studies show that the efficacy of the widely used anti‐cancer agent DOX may be improved by using the prodrug DOX‐GA3, in combination with the tumor‐specific enzyme‐immunoconjugate 323/A3‐mGUS and a conjugate clearing antibody. © 2001 Wiley‐Liss, Inc.
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