Trastuzumab
From Wikipedia, the free encyclopedia
| Image:Trastuzumab.gif | |
| Trastuzumab
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| Systematic (IUPAC) name | |
| Humanized anti-HER2 antibody | |
| Identifiers | |
| CAS number | 180288-69-1 |
| ATC code | ? |
| PubChem | ? |
| DrugBank | BTD00098 |
| Chemical data | |
| Formula | C6470H10012N1726O2013S42 |
| Mol. weight | 145531.5 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | 2-12 days |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
? |
| Legal status | |
| Routes | ? |
Trastuzumab (Herceptin®) is a monoclonal antibody that acts on the HER2/neu (erbB2) receptor. Herceptin's principal use is as an anti-cancer therapy in breast cancer in patients whose tumors overexpress (produce more than the usual amount of) this receptor. Trastuzumab is administered either once a week or once every three weeks intravenously for 30 to 90 minutes.
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[edit] Mechanism of action
Amplification of ErbB2 occurs in 30% of early-stage breast cancers.<ref name="Bange">Bange, J, Zwick E, Ullrich A. (2001). "Molecular targets for breast cancer therapy and prevention". Nature Medicine 7: 548 – 552. PMID 11329054.</ref> It encodes the transmembrane tyrosine kinase p185-erbB2 glycoprotein. Although the signaling pathways induced by the erbB2 receptor are incompletely characterized, it is thought that activation of the PI3K/Akt pathway is important. This pathway is normally associated with mitogenic signaling involving the MAPK pathway. However in cancer the growth promoting signals from erbB2 are constitutively transmitted — promoting invasion, survival and angiogenesis of cells.<ref name="Menard">Ménard, S, Pupa SM, Campiglio M, Tagliabue E (2003). "Biologic and therapeutic role of HER2 in cancer". Oncogene 22: 6570 – 6578. PMID 14528282.</ref> Furthermore overexpression can also confer therapeutic resistance to cancer therapies. The prime mechanism that causes increase in proliferation speed is due to induction of p27Kip1, an inhibitor of cdk2 and of cell proliferation, to remain in the cytoplasm instead of translocation in to the nucleus.<ref name="Kute">Kute, T, Lack CM, Willingham M, Bishwokama B, Williams H, Barrett K, Mitchell T, Vaughn JP (2004). "Development of Herceptin resistance in breast cancer cells". Cytometry 57A: 86 – 93. PMID 14750129.</ref> This is caused by phosphorylation by Akt.
Herceptin is a monoclonal antibody which binds to the extracellular segment of the erbB2 receptor. Cells treated with Herceptin undergo arrest during the G1 phase of the cell cycle so there is reducted proliferation. It has been suggested that Herceptin induces some of its effect by downregulation of erbB2 leading to disruption of receptor dimerization and signaling through the downstream PI3K cascade. P27Kip1 is then not phosphorylated and is able to enter the nucleus and inhibit cdk2 activity, causing cell cycle arrest.<ref name="Kute"/> Also, Herceptin suppresses angiogenesis by both induction of antiangiogenic factors and repression of proangiogenic factors. It is thought that a contribution to the unregulated growth observed in cancer could be due to proteolytic cleavage of erbB2 that results in the release of the extracellular domain. Herceptin has been shown to inhibit erbB2 ectodomain cleavage in breast cancer cells.<ref name="Albenall">Albanell, J, Codony J, Rovira A, Mellado B, Gascon P. (2003). "Mechanism of action of anti-HER2 monoclonal antibodies: scientific update on trastuzumab and 2C4". Advances in Experimental Medicine and Biology 532: 253 – 268. PMID 12908564.</ref> There may be other undiscovered mechanisms by which Herceptin induces regression in cancer.
[edit] Impact
Herceptin has had a "major impact in the treatment of HER2-positive metastatic breast cancer".<ref name="TanSwain">Tan, AR, Swain SM (2002). "Ongoing adjuvant trials with trastuzumab in breast cancer". Seminars in Oncology 30 (5 Suppl 16): 54 – 64. PMID 14613027.</ref> The combination of Herceptin with chemotherapy has been shown to increase both survival and response rate, in comparison to Herceptin alone.<ref name="NahtaEsteva">Nahta, R, Esteva1 FJ (2003). "HER-2-Targeted Therapy – Lessons Learned and Future Directions". Clinical Cancer Research 9: 5078 – 5048. PMID 14613984.</ref> It is possible to determine the "erbB2 status" of a tumour, which can be used to predict efficacy of treatment with Herceptin. If it is determined that a tumour is overexpressing the erbB2 oncogene then a patient is eligible for treatment with Herceptin.<ref name="YuHung">Yu, D, Hung M (2000). "Overexpression of ErbB2 in cancer and ErbB2-targeting strategies". Oncogene 19: 6115 – 6121. PMID 11156524.</ref> It is surprising that although erbB2 has great affinity for the receptor and the fact that such a high dose can be administered (due to its low toxicity) 70% of patients do not respond to treatment. In fact resistance is developed rapidly by treatment, in virtually all patients. It is suggested that a mechanism of resistance is the lack of p27Kip1 translocation to the nucleus in some strains, enabling cdk2 to induce cell proliferation.<ref name="Kute"/>
Some recent clinical trials have found trastuzumab reduces the risk of relapse in breast cancer patients by 50% when given in the adjuvant setting (i.e. after breast cancer surgery, before the cancer has spread any further) for one year.<ref name="Romond">Romond, EH, Perez EA, Bryant J, et al. (2005). "Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer". New England Journal of Medicine 353: 1673 – 1684. PMID 16236738.</ref><ref name="Piccart">Piccart-Gebhart MJ, MJ (2005). "Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer". New England Journal of Medicine 353: 1659 – 1672. PMID 16236737.</ref> In one British trial this translated as follows: 9.4% of those on the drug relapsed as opposed to the 17.2% of those not on Herceptin.
There has been some recent debate as to whether these benefits may have been over-stated.<ref name="Littlejohns">Littlejohns, P (2006). "Trastuzumab for early breast cancer: evolution or revolution?". Lancet Oncology 7 (1): 22 – 3. PMID 16408378.</ref>
[edit] Side effects
One of the significant complications of trastuzumab is its effect on the heart. Trastuzumab is associated with cardiac dysfunction in 2-7% of cases. The risk of cardiomyopathy is increased when trastuzumab is combined with anthracycline chemotherapy (which itself is associated with cardiac toxicity).
[edit] History
The biotech company Genentech gained FDA approval for trastuzumab in September 1998. The drug was jointly developed by that company, where the antibody was first discovered by scientists that included Dr. Axel Ullrich, and the Jonsson Cancer Center at UCLA, where Dr. Dennis Slamon subsequently worked further on trastuzumab's development.
In the clinical trials leading up to trastuzumab's approval, 42% of patients taking trastuzumab in combination with the chemotherapy drug paclitaxel had significant responses. The comparable rate for the taxane alone was only 16%.
[edit] Costs
Trastuzumab costs about seventy thousand dollars for a full course of treatment.<ref>Fleck L. "The costs of caring: Who pays? Who profits? Who panders?". Hastings Cent Rep 36 (3): 13-7. PMID 16776017.</ref> Recently there has been controversy in New Zealand and the UK about public health funding of this drug due to its high cost and perceived limited benefit based on the complexity of screening requirements. The debate has largely centred around whether the drug should be provided to all patients with HER2 positive metastatic cancer or only some.<ref>Breast cancer drug to remain unfunded. New Zealand Herald (2006-10-16). Retrieved on 2006-12-01.</ref> The campaign waged by cancer victims to get the governments to pay for their treatment has gone to the highest levels in the courts and the cabinet to get it licensed against the judgement of the regulator.<ref>The Herceptin judgement. BBC News (2006-04-12). Retrieved on 2006-12-01.</ref><ref>Update on Herceptin appraisal. National Institute for Health and Clinical Excellence. Retrieved on 2006-12-01.</ref> After a sustained campaign from cancer sufferers, the Ontario Ministry of Health in July 2005 that it would pay for treatments with Herceptin and two other new and controversial anti-cancer drugs.<ref>Ontario to pay for cancer drugs. Canadian Broadcasting Corporation (2005-07-22). Retrieved on 2006-12-01.</ref>
Few reporters have questioned the pricing of this drug, but when asked Genetech refuses to give details to explain the high costs.<ref>Will Herceptin Media Blitz Help Or Harm Patients?. Scoop (2006-02-14). Retrieved on 2006-12-01.</ref>
[edit] See also
[edit] Footnotes
[edit] Further reading
- Bazell, Robert. Her-2: the making of Herceptin, a revolutionary treatment for breast cancer. Random House, 1998. 214 pages. ISBN 0-679-45702-X.
- The Guardian. The selling of a wonder drug. 29th March 2006
[edit] External links
- Herceptin (manufacturer's website)
