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12-06-2008, 05:08 PM
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#1
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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understanding what limits/allows the brain penetration of lapatinib(tykerb)
Drug Metab Dispos. 2008 Dec 4. [Epub ahead of print]
An Unexpected Synergist Role of P-glycoprotein and Breast Cancer Resistance Protein on the CNS Penetration of the Tyrosine Kinase Inhibitor Lapatinib (GW572016).
Polli JW, Olson KL, Chism JP, St John-Williams LA, Yeager RL, Woodard SM, Otto VR, Castellino S, Demby VE.
GlaxoSmithKline.
Lapatinib is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers overexpressing human epidermal receptor 2 (HER2, ErbB2). This work investigated the role of P-glycoprotein (Pgp, the protein from the Mdr1a/b gene) and Breast cancer resistance protein (Bcrp, the protein from the Bcrp1 gene) in modulating the CNS penetration of lapatinib at steady state conditions in FVBn mice (wild-type), Mdr1a/b(-/-), Bcrp1(-/-) and Mdr1a/b(-/-)/Bcrp1(-/-) knockout mice. Following an intravenous infusion of lapatinib for 24 hours to a targeted steady state plasma concentration of 700 ng/mL (0.3 mg/kg/h) or 7000 ng/mL (3 mg/kg/h), lapatinib brain-to-plasma ratios were approximately 3- to 4-fold higher in Mdr1a/b(-/-) knockout mice (ratio range 0.09 to 0.16) compared to wild-type mice (ratio range 0.03 to 0.04). There was no difference in the brain-to-plasma ratio in the Bcrp1(-/-) knockout mice (ratio range 0.03 to 0.04) compared to wild-type mice. In contrast, Mdr1a/b(-/-)/Bcrp1(-/-) triple knockout mice had a 40-fold higher brain-to-plasma ratio (ratio range 1.2 to 1.7), suggesting that Pgp and Bcrp work in concert to limit the brain-to-plasma ratio of lapatinib in mice. This finding has important potential consequences for the treatment of brain tumors in breast cancer patients treated with tyrosine kinase inhibitors as well as the basic understanding of ABC transporters expressed in the blood-brain barrier on the central nervous system disposition of drugs.
PMID: 19056914
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12-06-2008, 05:40 PM
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#2
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Senior Member
Join Date: Nov 2004
Location: Misty woods of WA State
Posts: 4,128
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Hope this means that someone is getting to the bottom of WHY Tykerb showed more promise than actually occurred in human patients.
At the American Society of Cancer Researchers meetin in April we (Christine, Maryann, Joe and me) met several people who said they were working on this topic.
We need drugs to work for MORE of us.
__________________
"When I hear music, I fear no danger. I am invulnerable. I see no foe. I am related to the earliest times, and to the latest." H.D. Thoreau
Live in the moment.
MY STORY SO FAR ~~~~
Found suspicious lump 9/2000
Lumpectomy, then node dissection and port placement
Stage IIB, 8 pos nodes of 18, Grade 3, ER & PR -
Adriamycin 12 weekly, taxotere 4 rounds
36 rads - very little burning
3 mos after rads liver full of tumors, Stage IV Jan 2002, one spot on sternum
Weekly Taxol, Navelbine, Herceptin for 27 rounds to NED!
2003 & 2004 no active disease - 3 weekly Herceptin + Zometa
Jan 2005 two mets to brain - Gamma Knife on Jan 18
All clear until treated cerebellum spot showing activity on Jan 2006 brain MRI & brain PET
Brain surgery on Feb 9, 2006 - no cancer, 100% radiation necrosis - tumor was still dying
Continue as NED while on Herceptin & quarterly Zometa
Fall-2006 - off Zometa - watching one small brain spot (scar?)
2007 - spot/scar in brain stable - finished anticoagulation therapy for clot along my port-a-catheter - 3 angioplasties to unblock vena cava
2008 - Brain and body still NED! Port removed and scans in Dec.
Dec 2008 - stop Herceptin - Vaccine Trial at U of W begun in Oct. of 2011
STILL NED everywhere in Feb 2014 - on wing & prayer
7/14 - Started twice yearly Zometa for my bones
Jan. 2015 checkup still shows NED
2015 Neuropathy in feet - otherwise all OK - still NED.
Same news for 2016 and all of 2017.
Nov of 2017 - had small skin cancer removed from my face. Will have Zometa end of Jan. 2018.
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12-07-2008, 10:17 AM
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#3
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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this article also raises hope that they might be able to test
for pGP and BCRP SNPs/genotype prior to deciding what drug to give--in order to skip the ineffective drug and give the drug/drugs most likely to work in THAT PARTICULAR PATIENT as it is uncertain that there is one best drug that will work in ALL patients with brain mets.
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12-07-2008, 12:13 PM
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#4
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Senior Member
Join Date: Nov 2004
Location: Misty woods of WA State
Posts: 4,128
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HALLELIUJA!!!
Testing like that WOULD be a giant step forward and save many of our beautiful friends here.
__________________
"When I hear music, I fear no danger. I am invulnerable. I see no foe. I am related to the earliest times, and to the latest." H.D. Thoreau
Live in the moment.
MY STORY SO FAR ~~~~
Found suspicious lump 9/2000
Lumpectomy, then node dissection and port placement
Stage IIB, 8 pos nodes of 18, Grade 3, ER & PR -
Adriamycin 12 weekly, taxotere 4 rounds
36 rads - very little burning
3 mos after rads liver full of tumors, Stage IV Jan 2002, one spot on sternum
Weekly Taxol, Navelbine, Herceptin for 27 rounds to NED!
2003 & 2004 no active disease - 3 weekly Herceptin + Zometa
Jan 2005 two mets to brain - Gamma Knife on Jan 18
All clear until treated cerebellum spot showing activity on Jan 2006 brain MRI & brain PET
Brain surgery on Feb 9, 2006 - no cancer, 100% radiation necrosis - tumor was still dying
Continue as NED while on Herceptin & quarterly Zometa
Fall-2006 - off Zometa - watching one small brain spot (scar?)
2007 - spot/scar in brain stable - finished anticoagulation therapy for clot along my port-a-catheter - 3 angioplasties to unblock vena cava
2008 - Brain and body still NED! Port removed and scans in Dec.
Dec 2008 - stop Herceptin - Vaccine Trial at U of W begun in Oct. of 2011
STILL NED everywhere in Feb 2014 - on wing & prayer
7/14 - Started twice yearly Zometa for my bones
Jan. 2015 checkup still shows NED
2015 Neuropathy in feet - otherwise all OK - still NED.
Same news for 2016 and all of 2017.
Nov of 2017 - had small skin cancer removed from my face. Will have Zometa end of Jan. 2018.
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12-08-2008, 08:25 AM
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#5
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Senior Member
Join Date: Jul 2006
Posts: 869
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Could someone clarify this for me as well as Steph's comment in simpler language. thanks Ceesun
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12-08-2008, 08:52 AM
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#6
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Senior Member
Join Date: Jul 2008
Location: Durham NC
Posts: 73
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yes, please clarify! I'm glad I'm not the only one re-reading that stuff just to end up scratching my head.
Beth
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12-08-2008, 01:18 PM
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#7
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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pGP and BCRP work like pumps at interfaces allowing in some compounds and rejecting and pumping back out others
various parts of the body where what is let in makes a life and death difference have specialized cells which contain them eg, cells in the absorbing parts of the gastrointestinal system, cells lining the airways (often NKT cells in those two loations) as well as the blood-brain barrier.
This study bred mice to lack either one or the other or both and found that when both were not available one had the most penetration of lapatinib, with more of it being pumped out and unavailable to the brain if only one or the other were lacking in the mice and the least penetration if both pGp and BRCP were present ie, not genetically bred out.
Hope this helps!
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