ANG1005

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ANG1005
Clinical data
Legal status Investigational
Identifiers
ATC code ?
Chemical data
Formula ?
Mol. mass 5109 Daltons

ANG1005 is a promising chemotherapy drug that was developed by a biotechnology company located in Montreal, Canada known as Angiochem Inc. This drug is inserted intravenously and is currently in early clinical stages of development and dose escalation.[1] However, ANG1005 consists of a 19 amino acid long peptide vector known as Angiopep that is conjugated to a taxane derivative involved in mitotic inhibition known as paclitaxel. Various Angiopep vectors have been composed but solely differ by their anti-cancer moieties. This has then been shown to be a prospective cancer therapy drug that can not only be conjugated to paclitaxel but also peptides, monoclonal antibodies, siRNA and many other biological aspects. ANG1005 will then possess the potential to treat a variety of CNS diseases including glioma.[2] Research has shown reduction in tumour growth in mice and rats with glioblastoma tumors.[3][4][5]

Use[edit]

This drug was specifically designed to treat brain tumors that consist of a unique feature known as the blood brain barrier (BBB) that prevents many developed cancer therapy drugs to pass through the brain capillaries and into the parenchyma.[6] Paclitaxel is generally prevented from reaching its target in the cell due to the presence of the efflux pump P-glycoprotein (P-gp) at the blood barrier. This is known as a multidrug resistant-associated protein (MRP1) that causes resistance amongst many organic drugs that are not conjugated to acidic ligands.[7] This receptor is an ATP - driven transporter that will pump drugs, drug metabolites, and endogenous metabolites out of the cell.

Mechanism of action[edit]

ANG1005 contains paclitaxel which stabilizes microtubule polymer formation. Microtubules are composed of polymers consisting of the protein tubulin. Therefore, paclitaxel will bind at the site of β-tubulin and induce polymerization thus protecting the microtubule from disassembling in mitosis. This will block the progression of mitosis due to a prolonged activation of the microtubule in the mitotic checkpoint, resulting in cell apoptosis or reversion to the G0 phase. However, ANG1005 will effectively transport across the BBB with approximately a 100 fold higher transport rate compared to a free paclitaxel.[8] ANG1005 will cross the capillary medium via receptor mediated transcytosis of the low-density lipoprotein receptor-related protein 1 (LRP1) which is upregulated in some cancers.[9] Ester hydrolyzing enzymes (esterases) will then catalyze a highly stereospecific reaction, resulting in hydrolysis of the ANG1005 ester to carboxylic acids. This will result in the intracellular release of paclitaxel and subsequent action on tubulin.

Concentration has been found to play a key role ANG1005’s administration. Studies show that a high concentration will suppress microtubule detachment which is necessary for mitosis to occur.[10] The microenvironment of cells may also differ from that of rapidly proliferating cancer cells. This is generally more oxygen deficient and acidic. These conditions will then result in a selective pressure towards cancer cell proliferation. It has been shown that cancer cell lines exposed to this hypoxic or serum-deprived condition will upregulate LPR1 expression, thus leading to an increased uptake of ANG1005.[11] However, these receptors are also present in non-cancerous cells, thus presenting a challenge due to non-specific targeting. It is then believed that because these receptors are overexposed in tumors, that receptor binding may be in favor of the cancer cells.

ANG1005mechanism

Clinical trials[edit]

In 2008, two Phase-I clinical trials of ANG1005 were started ; one in patients with advanced cancer and brain metastases,[12] and another in patients with recurrent malignant glioma.[13] Favourable initial tolerability results in brain cancer were reported in March 2009.[14] and more in October 2009 and updated in June 2010.[9]

References[edit]

  1. ^ "Angiochems ANG1005 Demonstrates Preliminary Clinical Safety and Tolerability in Brain Cancers". [dead link]
  2. ^ "ANG1005 - A Promising New Targeted Taxane Derivative". Retrieved 5 June 2013. 
  3. ^ Régina A, Demeule M, Ché C, Lavallée I, Poirier J, Gabathuler R, Béliveau R, Castaigne JP (2008). "Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2". Br J Pharmacol 155 (2): 185–197. doi:10.1038/bjp.2008.260. PMC 2538693. PMID 18574456. 
  4. ^ Thomas FC, Taskar K, Rudraraju V, Goda S, Thorsheim HR, Gaasch JA, Mittapalli RK, Palmieri D, Steeg PS, Lockman PR, Smith QR (November 2009). "Uptake of ANG1005, a Novel Paclitaxel Derivative, Through the Blood-Brain Barrier into Brain and Experimental Brain Metastases of Breast Cancer". Pharm Res 26 (11): 2486–94. doi:10.1007/s11095-009-9964-5. PMC 2896053. PMID 19774344. 
  5. ^ Patel MM, Goyal BR, Bhadada SV, Bhatt JS, Amin AF (2009). "Getting into the brain: approaches to enhance brain drug delivery". CNS Drugs 23 (1): 35–58. doi:10.2165/0023210-200923010-00003. PMID 19062774. 
  6. ^ "Uptake of ANG1005, a Novel Paclitaxel Derivative, Through the Blood-Brain Barrier into Brain and Experimental Brain Metastases of Breast Cancer". Retrieved 5 June 2013. 
  7. ^ "Angiopep-2 modified PE-PEG based polymeric micelles for amphotericin B delivery targeted to the brain". Retrieved 5 June 2013. 
  8. ^ "Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1". 
  9. ^ a b "Angiochem Presents Complete Phase 1 /2 Clinical Data for ANG1005: Further Demonstrating Benefits of Targeting LRP-1 Pathway in Cancer". Pharmalive.com.  (paid subscription required)[unreliable medical source?][verification needed]
  10. ^ "Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2". British Journal of Pharmacology. 
  11. ^ "nfluence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein". British Journal of Cancer. 
  12. ^ "A Phase 1, Open-Label, Dose Escalation Study of ANG1005 in Patients With Advanced Solid Tumors and Metastatic Brain Cancer". 3 June 2010. Retrieved 16 August 2010. 
  13. ^ "angiochems-ang1005-demonstrates-preliminary-clinical-safety-and-tolerability-in-brain-cancers" (Press release). CheckOrphan.com. Halsin Partners. Retrieved 16 August 2010. [unreliable medical source?]
  14. ^ "AngioChem's ANG1005 Shows Promise In The Treatment Of Brain Cancers". 23 October 2008. 

External links[edit]