Tosedostat: Inhibiting Aminopeptidases In Cancers
AMINOPEPTIDASES AND THEIR INHIBITION:
Aminopeptidases are zinc dependent enzymes that are made and released by the glands of the small intestine. These proteins catalyze the hydrolysis of various amino acids from the -NH2 terminal of proteins and hence the use of inhibitors which would block their functions to target protein handling becomes an attractive approach in various diseases and especially in cancers. One example of the above statement is the therapeutic use and success of aminopeptidase inhibitors in the treatment of myeloma cancer cells where these molecules disrupt the immunoglobulins folding [1]. Tosedostat is one such aminopeptidase inhibitor that was seen to have anti-proliferative effect. Both Tosedostat (CHR-2797) and its active metabolite CHR-79888 exert their anti-proliferative effects by disrupting cell cycle proteins and their turn-over and most importantly, Tosedostat aminopeptidase inhibitor shows selective anti-proliferative action against transformed or malignant cancer cells over normal cells thus affirming its candidature as a potent anti-cancer compound.
PHARMACOLOGICAL PROPERTIES OF TOSEDOSTAT:
Tosedostat suppliers provide it under the trade name of CHR2797 as well. Tosedostat IC50 for an effective aminopeptidase inhibition is 100 nM, 150 nM, 220 nM, >1000 nM, >5000 nM, >10000 nM and >30000 nM for Leucyl aminopeptidases, puromycin-sensitive aminopeptidase, aminopeptidase N and aminopeptidase B, puromycin-insensitive leucine aminopeptidase, leukotriene A4 hydrolase and methionine aminopeptidase-2, respectively. Tosedostat prices are moderate and one can buy Tosedostat 5 mg vial for around $80. Tosedostat stability at temperatures lower than -20oC is more than 2 years. Tosedostat solubility is unknown. This orally administered aminopeptidase inhibitor has shown good synergistic anti-tumor effects with Paclitaxel and Carboplatin [2].
PRECLINICAL AND CLINICAL ASSESSMENT OF TOSEDOSTAT:
Tosedostat clinical trials were warranted after it was seen to strongly inhibits lung tumor growth and metastatic potential of mammary tumors in murine xenograft models [3]. In mammary carcinoma cell lines also, Tosedostat decreased tumor progression, volume and cell number in rat HOSP1 P models when administered orally [4]. The antiproliferative effects of Tosedostat are mediated by its blocking of protein recycling by depleting amino acids [5]. In the in vitro models of Acute myeloid lymphoma (AML), Tosedostats co-administration with Cytarabine (Ara-C) resulted in potent cytotoxicity in a dose-dependent manner sparing normal marrow progenitor cells simultaneously [6].
These preclinical successes led to its use in clinical studies and a phase II trial successfully evaluated the efficacy, safety profile and tolerability of Tosedostat in elderly patients suffering with refractory or relapsed form of AML [7]. Its combination with Paclitaxel was seen to be well tolerated in advanced solid tumors patients in a phase Ib dose-escalation study [8]. Another phase I/II study demonstrated the oral daily dosage of Tosedostat to be well tolerated at 130 mg daily to result in considerable antileukemic action in relapsing and/or elderly patients suffering from AML or myelodysplastic syndrome [9]. In advanced solid tumors patients also, the maximum tolerated dose (MTD), pharmacokinetics, toxicity and therapeutic potential of Tosedostat was determined [2]. In a clinical study by Chroma Therapeutics, the same parameters were assessed in elderly patients suffering from AML who enrolled in a phase II clinical trial (NCT00780598).
REFERENCES:
1. Moore HE, e.a., Aminopeptidase inhibition as a targeted treatment strategy in myeloma. Mol Cancer Therap, 2009.
2. Reid AHM, e.a., A First-in-Man Phase I and Pharmacokinetic Study on CHR-2797 (Tosedostat), an Inhibitor of M1 Aminopeptidases, in Patients with Advanced Solid Tumors. Clinical Cancer Res, 2009.
3. Hooftman LW, e.a., Antiproliferative effect of CHR-2797, a novel aminopeptidase inhibitor, in the human breast cancer xenograft, MDA-MB 435 Proc Amer Assoc Cancer Res, 2005.
4. Drummond AH, e.a., In vivo efficacy of CHR-2797, a novel aminopeptidase inhibitor, in a syngeneic rat HOSP.1 mammary carcinoma model Proc Amer Assoc Cancer Res, 1995.
5. Krige D, e.a., CHR-2797: An Antiproliferative Aminopeptidase Inhibitor that Leads to Amino Acid Deprivation in Human Leukemic Cells. Cancer Res, 2008.
6. Jenkins C, e.a., Aminopeptidase inhibition by the novel agent CHR-2797 (tosedostat) for the therapy of acute myeloid leukemia. Leukemia Research, 2011.
7. Cortes J, e.a., A Phase II Study to Evaluate the Efficacy, Safety and Tolerability of Tosedostat (CHR-2797) in Elderly Subjects with Treatment Refractory or Relapsed Acute Myeloid Leukemia. Clinical Lymphoma Myeloma and Leukemia, 2011.
8. Herpen CML, e.a., A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours. British Journal of Cancer, 2010.
9. Lwenberg B, e.a., Phase I/II Clinical Study of Tosedostat, an Inhibitor of Aminopeptidases, in Patients With Acute Myeloid Leukemia and Myelodysplasia. Journal of Clinical Oncology, 2010.
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