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

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 mug/ ml. The area under the plasma 17DMAG concentration versus time curve was 1072 mug/ml min, corresponding to a total body clearance of 70 ml/kg/min. Peak 17DMAG concentrations in liver (118.8 +/- 5.7 mug/g), kidney (122.9 +/- 10.6 mug/g), heart (81.3 +/- 8.1 mug/g), and lung (110.6 +/- 25.4 mug/g) occurred at 5 - 10 min, while peak concentrations in spleen (70.6 +/- 9.6 mug/g) and tumor (9.0 +/- 1.0 mug/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.