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

Abstract

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-201in 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-201toxicity 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-201compared 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.

Tumoral CD10 Expression Correlates with Aggressive Histology and Prognosis in Patients with Malignant Pleural Mesothelioma

“…29,30 Recently, CD10 was demonstrated to be a novel marker of cisplatin resistance and cancer stem cells using cell lines from other solid malignancies. 31 In addition, CD10 has been reported to cleave and activate a peptidic prodrug of doxorubicin, 32,33 and recent clinical trials suggest that chemotherapy with doxorubicin could be effective in patients with malignant pleural mesothelioma, with improvements in quality of life and an acceptable level of toxicity. 34,35 Therefore, CD10 is a potential marker for investigating chemotherapy sensitivity or resistance in patients with malignant pleural mesothelioma.…”

Repeated-dose toxicity of HSP27-binding heptapeptide in mice

“…Only a few articles that showed the toxicity data of peptide drug are available (Ravel et al, 2008;Sileno et al, 2006;Woodburn et al, 2008). Hematide, a synthetic peptidic erythropoiesis stimulating agent at a dose of 50 mg/kg (smaller dosage than that of heptapeptide) weekly for 5 weeks for rats and 12 weeks for monkeys induced polycythemia, which was considered the cause of deaths (Woodburn et al, 2008).…”

“…DTS-201, at doses of 100 or 150 mg/ kg, decreased the WBC counts and reduced body-weight gain or loss. Laboratory investigations and the full histopathologic examination identified lymphoid depeletion, degeneration of the testes and atrophied endometrial cells, and myelin degeneration and/ or inflammation of the sciatic nerve and roots of the spinal nerves in rats (Ravel et al, 2008). Therefore, heptapeptide may be a safe drug, when compared to other peptide drugs, even though larger scale experiments, using several species, are needed for evaluating the safety of heptapeptide.…”

Protein– and Peptide–Drug Conjugates

“…There may also happen complete change in therapeutic outcome of drugs (i.e., release of drugs with linked amino acid residues may show different activity than free drug) or the conjugate itself may become highly active (Yang et al, 2014). Peptide-drug conjugates, with PEG chains as a linker have flexibility to allow interaction of targeting peptide with its receptors and also improve the hydrophilicity and provide longer circulation time to conjugates (Ravel et al, 2008;Tai, Shukla, Qin, Li, & Cheng, 2011). Few thoroughly researched peptide-drug conjugates are discussed below and physicochemical properties and pharmacological outcomes of some are depicted in Table 4.…”