title: Preclinical toxicity, toxicokinetics, and antitumoral efficacy studies of DTS-201, a tumor-selective peptidic prodrug of doxorubicin.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 [14C] 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Diatos S.A., Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Ravel
authors.forename: Vincent
authors.initials: V
authors.lastname: Dubois
authors.forename: Jérôme
authors.initials: J
authors.lastname: Quinonero
authors.forename: Florence
authors.initials: F
authors.lastname: Meyer-Losic
authors.forename: Jeanpierre
authors.initials: J
authors.lastname: Delord
authors.forename: Philippe
authors.initials: P
authors.lastname: Rochaix
authors.forename: Céline
authors.initials: C
authors.lastname: Nicolazzi
authors.forename: Fabien
authors.initials: F
authors.lastname: Ribes
authors.forename: Catherine
authors.initials: C
authors.lastname: Mazerolles
authors.forename: Elise
authors.initials: E
authors.lastname: Assouly
authors.forename: Karine
authors.initials: K
authors.lastname: Vialatte
authors.forename: Inès
authors.initials: I
authors.lastname: Hor
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kearsey
authors.forename: André
authors.initials: A
authors.lastname: Trouet
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology; D045744:Cell Line, Tumor; D004285:Dogs; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000096:biosynthesis; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D015260:Neprilysin / Q000096:biosynthesis; D009842:Oligopeptides / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000201:enzymology; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: C438951:N-(succinyl-beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin; D009842:Oligopeptides; D011355:Prodrugs; D004317:Doxorubicin; D008666:Metalloendopeptidases; D015260:Neprilysin; C022510:thimet oligopeptidase