Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance.
OBJECTIVE
17-DMAG is a hydrophilic derivative of the molecular chaperone inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG; NSC-330507), which is currently being evaluated for the treatment of cancer in clinical trials. 17-DMAG offers a potential advantage over 17-AAG because its aqueous solubility eliminates the need for complicated formulations that are currently used for administration of 17-AAG. In addition, 17-DMAG undergoes only limited metabolism compared to 17-AAG. The present results are from preclinical toxicity studies evaluating 17-DMAG in rats and dogs.


METHODS
Doses of 0, 2.4, 12 and 24 mg/m2 per day were administered to rats, while dogs received doses of 0, 8 or 16 mg/m2 per day. In both species, 17-DMAG was administered i.v. (slow bolus for rats; 1-h infusion for dogs) daily for 5 days. An additional cohort of dogs received 16 mg/m2 per day orally for 5 days. Clinical observations were noted, and standard hematology and clinical chemistry parameters were monitored. Selected tissues were evaluated microscopically for drug-related lesions. Tissue and plasma 17-DMAG concentrations were measured by HPLC/MS at selected time-points on days 1 and 5.


RESULTS
Daily i.v. administration of 17-DMAG at doses of 24 mg/m2 per day in rats or 16 mg/m2 per day in dogs produced lethality on day 6, approximately 24 h following the last dose. Body weight loss was common in rats and dogs. Drug-related gastrointestinal, bone marrow and hepatic toxicities were also common in rats and dogs. Dogs also exhibited signs of renal and gallbladder toxicity. Plasma concentrations of 17-DMAG increased proportionately with dose in rats and disproportionately with dose in dogs. In rat tissues, however, only fourfold to sixfold increases in 17-DMAG concentrations were observed with a tenfold increase in dose. The highest concentrations of 17-DMAG were found in the liver of rats, with progressively lower concentrations in the spleen, lung, kidney and plasma. Regardless of the route of administration, higher drug concentrations were present in plasma (rat and dog) and tissue (rat) samples obtained on day 5 compared to those obtained on day 1. Although plasma concentrations decreased with time, 17-DMAG was still detected in dog plasma for at least 24 h after drug administration.


CONCLUSIONS
With the recent approval of 17-DMAG for clinical use, the data generated from these preclinical studies will provide guidance to clinicians as they administer this drug to their patients. The MTD of 17-DMAG was 12 mg/m2 per day in rats and 8 mg/m2 per day in dogs; therefore, the recommended starting dose for phase I trial is 1.3 mg/m2 per day for 5 days. Gastrointestinal and bone marrow toxicity were dose-limiting in rats, and gastrointestinal, renal, gallbladder and bone marrow toxicity were dose-limiting in dogs. All adverse effects were fully reversible in surviving animals after treatment was complete.
Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Executive Plaza North, Room 8040, Rockville, MD 20852, USA. glazee@mail.nih.gov
Elizabeth R
ER
Glaze
Amy L
AL
Lambert
Adaline C
AC
Smith
John G
JG
Page
William D
WD
Johnson
David L
DL
McCormick
Alan P
AP
Brown
Barry S
BS
Levine
Joseph M
JM
Covey
Merrill J
MJ
Egorin
Julie L
JL
Eiseman
Julianne L
JL
Holleran
Edward A
EA
Sausville
Joseph E
JE
Tomaszewski
D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000633:toxicity*; D016227:Benzoquinones; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D019963:Clinical Chemistry Tests; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005704:Gallbladder / Q000187:drug effects / Q000473:pathology; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D006403:Hematologic Tests; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D047029:Lactams, Macrocyclic; D008136:Longevity / Q000187:drug effects; D008297:Male; D011809:Quinones / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D020127:Recovery of Function; D013045:Species Specificity; D018675:Toxicity Tests
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D011809:Quinones; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C001277:geldanamycin