Preclinical Toxicity, Toxicokinetics, and Antitumoral Efficacy Studies of DTS-201, a Tumor-Selective Peptidic Prodrug of Doxorubicin

• Published in: Clinical cancer research 2008-02, Vol.14 (4), p.1258-1265
• Main Authors: RAVEL, Denis, DUBOIS, Vincent, VIALATTE, Karine, HOR, Inès, KEARSEY, Jonathan, TROUET, André, QUINONERO, Jerome, MEYER-LOSIC, Florence, DELORD, Jean Pierre, ROCHAIX, Philippe, NICOLAZZI, Céline, RIBES, Fabien, MAZEROLLES, Catherine, ASSOULY, Elise
• Format: Article
• Language: English
• Subjects: activating enzymes; Animals; anthracycline; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - enzymology; cardiotoxicity; Cell Line, Tumor; CPI-0004Na; Dogs; doxorubicin; Doxorubicin - analogs & derivatives; Doxorubicin - metabolism; Doxorubicin - pharmacology; Female; Humans; Male; Medical sciences; Metalloendopeptidases - biosynthesis; Mice; Neoplasms, Experimental - drug therapy; Neprilysin - biosynthesis; Oligopeptides - pharmacology; Pharmacology. Drug treatments; prodrug; Prodrugs - pharmacology; Prostatic Neoplasms - enzymology; Rats; tumor-selective prodrug; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-1165

Purpose: There is a clear clinical need for cytotoxic drugs with a lower systemic toxicity. DTS-201 (CPI-0004Na) is a peptidic prodrug of doxorubicin that shows an improved therapeutic index in experimental models. The purpose of the current study was to complete its preclinical characterization before initiation of phase I clinical trials. Experimental Design: The preclinical development program consisted of a detailed assessment of the general and cardiac toxicity profiles of DTS-201 in mice, rats, and dogs, together with mass balance and antitumoral efficacy studies in rodents. Neprilysin and thimet oligopeptidase expression, two enzymatic activators of DTS-201, was also characterized in human breast and prostate tumor biopsies. Results: The target organs of DTS-201 toxicity in rodents and dogs are typically those of doxorubicin, albeit at much higher doses. Importantly, chronic treatment with DTS-201 proved to be significantly less cardiotoxic than with doxorubicin at doses up to 8-fold higher in rats. The mass balance study showed that [ 14 C] DTS-201 does not accumulate in the body after intravenous administration. The improved therapeutic index of DTS-201 compared with free doxorubicin was confirmed in three tumor xenograft models of prostate, breast, and lung cancer. Neprilysin and/or thimet oligopeptidase are expressed in all experimental human tumor types thus far tested as well as in a large majority of human breast and prostate tumor biopsies. Conclusion: DTS-201 gave promising results in terms of general toxicity, cardiovascular tolerance, and in vivo efficacy in xenograft mouse models compared with free doxorubicin. Taken together, these results and the confirmation of the presence of activating enzymes in human tumor biopsies provide a strong rationale for a phase I clinical study in cancer patients.