Thimet oligopeptidase (EC 3.4.24.15) activates CPI-0004Na, an extracellularly tumour-activated prodrug of doxorubicin

Dubois, Vincent; Nieder, Matthew; Collot, Françoise; Negrouk, A; Nguyễn, Thị Thu Hà; Gangwar, Sanjeev; Reitz, Beverly A.; Wattiez, Ruddy; Dasnois, L; Trouet, André

doi:10.1016/j.ejca.2005.10.030

Cited by 12 publications

(10 citation statements)

References 24 publications

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“…In addition, nearly half of STS are found to be CD10 positive, with high-grade sarcomas exhibiting stronger expression (19). TOP is an endopeptidase that is particularly well suited for the in vivo activation of ALGP-doxo, because its activity is inhibited in oxygenated environments such as blood, but enhanced in reduced and anoxic environments that are characteristic for tumoral processes, including sarcomas (20)(21)(22)(23). CD26 and FAP are exopeptidases that are both members of the dipeptidyl aminopeptidase family of serine proteases and possess the same enzymatic activity.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Antitumoral Efficacy of PhAc-ALGP-Doxorubicin, an Enzyme-Activated Doxorubicin Prodrug, in Patient-Derived Soft Tissue Sarcoma Xenograft Models

Cornillie

Woźniak

Pokreisz

et al. 2017

Molecular Cancer Therapeutics

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Given the very limited efficacy of doxorubicin (doxo) in soft tissue sarcoma, there is a clear need for more active and less toxic treatments for this family of diseases. However, due to the rarity of these malignancies and lack of reliable preclinical models, development of new therapies has lagged behind. We evaluated the efficacy of PhAc-ALGP-doxorubicin (ALGP-doxo), a prodrug metabolized to doxo by peptidases present in tumor cells and/or tumor microenvironment, in a synovial sarcoma (SynSa) and two dedifferentiated liposarcoma (DDLPS) patient-derived xenograft models. Sixty-eight mice were engrafted bilaterally with human DDLPS or SynSa and randomized to control, doxo, or ALGP-doxo treatment, which were administered using an intraperitoneal minipump. Tumor volume measurement, histopathology, and Western blotting were used to assess treatment efficacy. Tumor regrowth was evaluated in a subset of mice over a period of 2 weeks after treatment cessation. Although tumor volume in the control and doxo groups increased steadily, ALGP-doxo caused tumor volume stabilization in the DDLPS xenografts and significant tumor shrinkage in the SynSa model, continuing after treatment cessation. A significant decrease in proliferation and increase in apoptosis compared with control and doxo was observed during and after treatment with ALGP-doxo in all models. In conclusion, ALGP-doxo shows considerably higher antitumoral efficacy compared with doxo in all patient-derived xenograft models tested. Administration of a 30- to 40-fold higher dose of ALGP-doxo than doxo is tolerated without significant adverse events. These results warrant further testing of this prodrug in anthracycline-sensitive and -resistant models of soft tissue sarcoma. .

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Section: Introductionmentioning

confidence: 99%

In Vivo Antitumoral Efficacy of PhAc-ALGP-Doxorubicin, an Enzyme-Activated Doxorubicin Prodrug, in Patient-Derived Soft Tissue Sarcoma Xenograft Models

Cornillie

Woźniak

Pokreisz

et al. 2017

Molecular Cancer Therapeutics

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“…It was reported that THOP1 secreted by tumor cells was a very likely candidate for the extracellular activation of CPI-0004Na which was a prodrug of doxorubicin, and the improved therapeutic index of CPI-0004Na compared with free doxorubicin was confirmed in three tumor xenograft models of prostate, breast, and lung cancer [10], [25]. Another study about cytotoxic T lymphocytes (CTLs) suggested THOP1 could strengthen the immune defense against intracellular pathogens and cancer by contributing to the C-terminal trimming of CTL epitopes [26].…”

Section: Discussionmentioning

confidence: 97%

Expression of THOP1 and Its Relationship to Prognosis in Non-Small Cell Lung Cancer

et al. 2014

PLoS ONE

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BackgroundThe study was designed to detect the expression level of thimet oligopeptidase (THOP1) protein in non-small cell lung cancer (NSCLC) and investigate its correlation with clinicopathologic features and prognosis.MethodsImmunohistochemical staining was used to determine the expression of THOP1 protein in 120 NSCLC specimens and 53 distant normal lung tissues. Quantitative real-time PCR and western blotting were employed to measure the expression of THOP1 in 16 pairs of primary NSCLC and corresponding normal tissues.ResultsAnalysis of immunohistochemical staining suggested low THOP1 expression was found in 71 (59.2%) of the 120 NSCLC specimens and significantly correlated with positive lymph node metastasis (P = 0.048). However, low THOP1 expression was found in 22 (41.5%) of the 53 normal lung tissues. Chi-square test suggested that the expression of THOP1 was significantly higher in the normal lung tissues than that in the NSCLC specimens (P = 0.032). Real-Time PCR and western blotting showed that NSCLC specimens had decreased THOP1 mRNA and protein expression compared to corresponding normal tissues. Univariate analysis demonstrated that low THOP1 expression significantly predicted decreased 5-year disease-free survival (P = 0.038) and overall survival (P = 0.017). In addition, positive lymph node metastasis (P = 0.025) and advanced TNM stage (P = 0.009) significantly predicted decreased 5-year overall survival. However, multivariate Cox regression analysis showed that only low THOP1 expression retained its significance as an independent prognostic factor for unfavorable 5-year disease-free survival (P = 0.046) and overall survival (P = 0.021).ConclusionsTHOP1 may have clinical potentials to be employed as a promising biomarker to identify individuals with better prognosis and a novel antitumor agent for therapy of patients with NSCLC.

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“…These results were strongly supported by pharmacokinetic and tissue distribution studies that showed that normal tissues were much less exposed to doxorubicin after equimolar administration of DTS-201 compared with free doxorubicin, whereas the exposure of the xenografted tumors was almost doubled (6). Two peptidases, neprilysin (CD10) and TOP, had also been identified as candidates for the selective cleavage of DTS-201 into N-L-leucyldoxorubicin or N-L-alanyl-L-leucyl-doxorubicin, respectively, in the vicinity of tumor cells (8,9). However, other as yet unidentified enzymes may also result in tumor-specific DTS-201 activation.…”

Section: Resultsmentioning

confidence: 99%

“…These endopeptidases are released in the extracellular space of solid tumors by stromal, tumor, and neoangiogenic endothelial cells or expressed at their cell surface (10,11). The extracellular localization of these enzymes allows them to cleave and activate 9). With the exception of some classes of lymphocytes and the brush borders of some epithelia, CD10 expression in normal tissues is limited, whereas it is overexpressed in a wide range of tumor types (12).…”

mentioning

confidence: 99%

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

Ravel¹,

Dubois²,

Quinonero³

et al. 2008

Clinical Cancer Research

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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.

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Thimet oligopeptidase (EC 3.4.24.15) activates CPI-0004Na, an extracellularly tumour-activated prodrug of doxorubicin

Cited by 12 publications

References 24 publications

In Vivo Antitumoral Efficacy of PhAc-ALGP-Doxorubicin, an Enzyme-Activated Doxorubicin Prodrug, in Patient-Derived Soft Tissue Sarcoma Xenograft Models

In Vivo Antitumoral Efficacy of PhAc-ALGP-Doxorubicin, an Enzyme-Activated Doxorubicin Prodrug, in Patient-Derived Soft Tissue Sarcoma Xenograft Models

Expression of THOP1 and Its Relationship to Prognosis in Non-Small Cell Lung Cancer

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

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