Proliferative bone lesions in rats given anticancer compounds.
Proliferative endosteal lesions were observed in metaphysis and diaphysis of femur and sternebra of Wistar (CRL:[WI]BR) rats administered 3 chemically-distinct anticancer compounds with dissimilar mechanisms of action: trimetrexate glucuronate, an antifolate; pentostatin, an adenosine deaminase inhibitor; and CI-980, a mitotic inhibitor. Islands of woven bone, often circumscribed by conspicuous myelostromal proliferation, were seen on Days 8-28 in rats given trimetrexate glucuronate daily by gavage, and on Day 4 but not Day 29 in rats given a single intravenous dose of pentostatin. Intravenous administration of CI-980 for 1 or 5 days resulted in marrow necrosis, marked centripetal new bone formation, and myelostromal proliferation on Days 4 and 8, respectively. These lesions were not present at the termination of these latter studies (Days 29 and 35, respectively). In conclusion, anticancer compounds induced local bone marrow injury and the release of local inflammatory mediators which may have provided the stimulus for bone formation and myelostromal proliferation.
Courtney
C L
CL
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Kim
S N
SN
Walsh
K M
KM
Watkins
J R
JR
Dominick
M A
MA
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001846:Bone Development / Q000187:drug effects; D001847:Bone Diseases / Q000139:chemically induced* / Q000473:pathology; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology*; D002219:Carbamates / Q000008:administration & dosage / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D004338:Drug Combinations; D005260:Female; D005965:Glucuronates / Q000008:administration & dosage / Q000633:toxicity; D007275:Injections, Intravenous; D008297:Male; D015649:Pentostatin / Q000008:administration & dosage / Q000633:toxicity; D011719:Pyrazines / Q000008:administration & dosage / Q000633:toxicity; D011725:Pyridines / Q000008:administration & dosage / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D016597:Trimetrexate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity
D000970:Antineoplastic Agents; D002219:Carbamates; D004338:Drug Combinations; D005965:Glucuronates; D011719:Pyrazines; D011725:Pyridines; D015649:Pentostatin; C072383:canertinib dihydrochloride; C056321:trimetrexate glucuronate; D016597:Trimetrexate