Ravel Denis, Dubois Vincent, Quinonero Jérôme, Meyer-Losic Florence, Delord Jeanpierre, Rochaix Philippe, Nicolazzi Céline, Ribes Fabien, Mazerolles Catherine, Assouly Elise, Vialatte Karine, Hor Inès, Kearsey Jonathan, Trouet André
Diatos S.A., Paris, France.
Clin Cancer Res. 2008 Feb 15;14(4):1258-65. doi: 10.1158/1078-0432.CCR-07-1165.
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.
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.
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.
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.
临床上显然需要具有较低全身毒性的细胞毒性药物。DTS - 201（CPI - 0004Na）是阿霉素的肽类前药，在实验模型中显示出改善的治疗指数。本研究的目的是在启动I期临床试验之前完成其临床前特征分析。
临床前开发计划包括对DTS - 201在小鼠、大鼠和犬中的一般毒性和心脏毒性特征进行详细评估，以及在啮齿动物中进行质量平衡和抗肿瘤疗效研究。还对人乳腺和前列腺肿瘤活检组织中的中性内肽酶和硫醇寡肽酶表达（DTS - 201的两种酶激活剂）进行了特征分析。
DTS - 201在啮齿动物和犬中的毒性靶器官通常与阿霉素相同，尽管剂量要高得多。重要的是，在大鼠中，高达8倍剂量的DTS - 201长期治疗的心脏毒性明显低于阿霉素。质量平衡研究表明，静脉注射[14C]DTS - 201后不会在体内蓄积。在前列腺癌、乳腺癌和肺癌的三种肿瘤异种移植模型中证实了DTS - 201与游离阿霉素相比具有改善的治疗指数。到目前为止，在所有测试的实验性人类肿瘤类型以及大多数人乳腺和前列腺肿瘤活检组织中均表达中性内肽酶和/或硫醇寡肽酶。
与游离阿霉素相比，DTS - 201在一般毒性、心血管耐受性和异种移植小鼠模型的体内疗效方面给出了有前景的结果。综上所述，这些结果以及在人类肿瘤活检组织中存在激活酶的证实为在癌症患者中进行I期临床研究提供了有力的理论依据。
