Dataset Information

Gold(III)-dithiocarbamato peptidomimetics in the forefront of the targeted anticancer therapy: preclinical studies against human breast neoplasia.

ABSTRACT: Since the serendipitous discovery of cisplatin, platinum-based drugs have become well-established antitumor agents, despite the fact that their clinical use is limited by many severe side-effects. In order to both improve the chemotherapeutic index and broaden the therapeutic spectrum of current drugs, our most recent anti-neoplastic agents, Au(III) complexes, were designed as carrier-mediated delivery systems exploiting peptide transporters, which are up-regulated in some cancers. Among all, we focused on two compounds and tested them on human MDA-MB-231 (resistant to cisplatin) breast cancer cell cultures and xenografts, discovering the proteasome as a major target both in vitro and in vivo. 53% inhibition of breast tumor growth in mice was observed after 27 days of treatment at 1.0 mg kg(-1) d(-1), compared to control. Remarkably, if only the most responsive mice are taken into account, 85% growth inhibition, with some animals showing tumor shrinkage, was observed after 13 days. These results led us to file an international patent, recognizing this class of gold(III) peptidomimetics as suitable candidates for entering phase I clinical trials.

SUBMITTER: Nardon C

PROVIDER: S-EPMC3879379 | biostudies-other | 2014

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Gold(III)-dithiocarbamato peptidomimetics in the forefront of the targeted anticancer therapy: preclinical studies against human breast neoplasia.

Nardon Chiara C Schmitt Sara M SM Yang Huanjie H Zuo Jian J Fregona Dolores D Dou Q Ping QP

PloS one 20140102 1

Since the serendipitous discovery of cisplatin, platinum-based drugs have become well-established antitumor agents, despite the fact that their clinical use is limited by many severe side-effects. In order to both improve the chemotherapeutic index and broaden the therapeutic spectrum of current drugs, our most recent anti-neoplastic agents, Au(III) complexes, were designed as carrier-mediated delivery systems exploiting peptide transporters, which are up-regulated in some cancers. Among all, we ...[more]

PMID: 24392119

Similar Datasets

Project description:The validity of preclinical studies of candidate therapeutic agents has been questioned given their limited ability to predict their fate in clinical development, including due to design flaws and reporting bias. In this study, we examined this issue in depth by conducting a meta-analysis of animal studies investigating the efficacy of the clinically approved kinase inhibitor, sorafenib. MEDLINE, Embase, and BIOSIS databases were searched for all animal experiments testing tumor volume response to sorafenib monotherapy in any cancer published until April 20, 2012. We estimated effect sizes from experiments assessing changes in tumor volume and conducted subgroup analyses based on prespecified experimental design elements associated with internal, construct, and external validity. The meta-analysis included 97 experiments involving 1,761 animals. We excluded 94 experiments due to inadequate reporting of data. Design elements aimed at reducing internal validity threats were implemented only sporadically, with 66% reporting animal attrition and none reporting blinded outcome assessment or concealed allocation. Anticancer activity against various malignancies was typically tested in only a small number of model systems. Effect sizes were significantly smaller when sorafenib was tested against either a different active agent or combination arm. Trim and fill suggested a 37% overestimation of effect sizes across all malignancies due to publication bias. We detected a moderate dose-response in one clinically approved indication, hepatocellular carcinoma, but not in another approved malignancy, renal cell carcinoma, or when data were pooled across all malignancies tested. In support of other reports, we found that few preclinical cancer studies addressed important internal, construct, and external validity threats, limiting their clinical generalizability. Our findings reinforce the need to improve guidelines for the design and reporting of preclinical cancer studies. Cancer Res; 76(16); 4627-36. ©2016 AACR.

Project description:PurposeProstate-specific membrane antigen (PSMA) continues to be the hallmark biomarker for prostate cancer as it is expressed on nearly all prostatic tumors. In addition, increased PSMA expression correlates with castration resistance and progression to the metastatic stage of the disease. Recently, we combined both an albumin-binding motif and an irreversible PSMA inhibitor to develop the novel PSMA-targeted radiotherapeutic agent, CTT1403. This molecule was novel in the field of PSMA-targeted agents as its key motifs resulted in extended blood circulation time and tumor uptake, rapid and extensive internalization into PSMA+ cells, and promising therapeutic efficacy. The objective of this study was to perform IND-enabling translational studies on CTT1403 in rodent models.ProceduresA dose optimization study was performed in PC3-PIP (PSMA+) tumor-bearing mice. Treatment groups were randomly selected to receive one to three 14-MBq injections of CTT1403. Control groups included (1) saline, (2) non-radioactive [175Lu]CTT1403, or (3) two injections of 14 MBq CTT1751, a Lu-177-labeled non-targeted albumin-binding moiety. Tumor growth was monitored up to 120 days. Small-animal single photon emission tomography/X-ray computed tomography imaging was performed with CTT1403 and CTT1751 in PC3-PIP tumor-bearing mice to visualize infiltration of the Lu-177-labeled agent into the tumor. In preparation for a first-in-human study, human absorbed doses were estimated based on rat biodistribution out to 5 weeks to determine a safe CTT1403 therapy dose in humans.ResultsTwo to 3 injections of 14 MBq CTT1403 yielded significant tumor growth inhibition and increased survival compared with all control groups and mice receiving 1 injection of 14 MBq CTT1403. Five of 12 mice receiving 2 or 3 injections of CTT1403 survived to the 120-day post-treatment study endpoint. Dosimetry identified the kidneys as the dose-limiting organ, with an equivalent dose of 5.18 mSv/MBq, resulting in a planned maximum dose of 4.4 GBq for phase 1 clinical trials.ConclusionsThe preclinical efficacy and dosimetry of CTT1403 suggest that this agent has significant potential to be safe and effective in humans.

Dataset Information

Gold(III)-dithiocarbamato peptidomimetics in the forefront of the targeted anticancer therapy: preclinical studies against human breast neoplasia.

Publications

Gold(III)-dithiocarbamato peptidomimetics in the forefront of the targeted anticancer therapy: preclinical studies against human breast neoplasia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure