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Cancer-Chemother-Pharmacol-2005 Jan;55(1):21-32. Epub 2004 Aug 27. Related
Articles, Links
Pharmacokinetics and pharmacodynamics of 17-demethoxy
17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17
SCID mice bearing MDA-MB-231 human breast cancer xenografts.
Eiseman JL, Lan J, Lagattuta TF, Hamburger DR, Joseph E, Covey JM, Egorin MJ.
PURPOSE: 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG,
NSC 707545) is a water-soluble analogue of
17-(allylamino)-17-demethoxygeldanamycin (17AAG), a compound currently in
clinical trials. These preclinical studies: (1) characterized 17DMAG
concentrations in plasma, normal tissues, and tumor after i.v. delivery to mice;
and (2) correlated tumor and normal tissue 17DMAG concentrations with
alterations in heat shock protein 90 (HSP90) and selected HSP90-chaperoned
proteins. METHODS: At specified times after i.v. administration of 75 mg/kg
17DMAG, SCID mice bearing s.c. MDA-MB-231 human breast xenografts were killed
and plasma and tissues were retained. 17DMAG concentrations were determined by
HPLC. Raf-1, heat shock protein 70 (HSP70), and HSP90 in tissues were determined
by Western blotting. RESULTS: Peak plasma 17DMAG concentration was 15.4+/-1.4
microg/ml. The area under the plasma 17DMAG concentration versus time curve was
1072 microg/ml min, corresponding to a total body clearance of 70 ml/kg/min.
Peak 17DMAG concentrations in liver (118.8+/-5.7 microg/g), kidney (122.9+/-10.6
microg/g), heart (81.3+/-8.1 microg/g), and lung (110.6+/-25.4 microg/g)
occurred at 5-10 min, while peak concentrations in spleen (70.6+/-9.6 microg/g)
and tumor (9.0+/-1.0 microg/g) occurred at 30-45 min. At 48 h, 17DMAG was
detectable in tumor but not in any normal tissue. Raf-1 in tumors of
17DMAG-treated mice killed at 4, 7, 24 and 48 h was about 20% lower than in
tumors from vehicle-treated mice. HSP90 and HSP70 in tumors of 17DMAG-treated
animals were significantly lower than in tumors of control animals at 4, 7, and
24 h. Hepatic Raf-1 was decreased by more than 60% at all times after 17DMAG
treatment; however, hepatic HSP90 was not affected. HSP70 was undetectable in
livers of vehicle-treated mice or mice killed at 2 or 4 h after 17DMAG
treatment, but was detected in livers at 7, 24 and 48 h. 17DMAG did not affect
renal Raf-1. In contrast, renal HSP70 and HSP90 were decreased by more than 50%
at 2 and 4 h after 17DMAG treatment. Renal HSP70 increased approximately twofold
above that in kidneys from vehicle-treated control mice at 7 and 24 h, while
HSP90 relative protein concentration was no different from that in controls.
CONCLUSIONS: Plasma pharmacokinetics of 17DMAG in tumor-bearing mice were
similar to those previously reported in nontumor-bearing mice. 17DMAG was
distributed widely to tissues but was retained for longer in tumors than normal
tissues. Raf-1, HSP90, and HSP70 were altered to different degrees in tumors,
livers, and kidneys of 17DMAG-treated animals. These data illustrate the complex
nature of the biological responses to 17DMAG.
PMID: 15338192
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