Induction of spermidine/spermine N1-acetyltransferase in breast cancer tissues treated with the polyamine analogue N1, N11-diethylnorspermine.
OBJECTIVE
The polyamine analogue, N1, N11-diethylnorspermine (DENSpm), is currently being evaluated in clinical trials for the treatment of solid tumors. The response of solid tumors to this drug has been associated with superinduction of the polyamine catabolic enzyme, spermine/spermidine N1-acetyltransferase (SSAT). Therefore, to estimate the response of breast cancers to DENSpm, we measured induction of SSAT in breast cancer explants treated in vitro with this polyamine analogue.


METHODS
Expression of SSAT protein was evaluated by immunohistochemistry in tissue explants from 38 invasive breast cancer tumors incubated in vitro in the presence (or absence) of DENSpm. In addition, SSAT enzymatic activity was measured in tissue explants from four tumors with high cellularity.


RESULTS
SSAT expression was significantly increased in 30 of 38 tumor samples treated with DENSpm compared to untreated controls. This induction of SSAT protein expression was found specifically in neoplastic cells of the treated samples, and was seen in all histologic patterns (ductal, lobular, and mucinous) of breast cancer examined. In tumor samples evaluated for changes in SSAT enzymatic activity, these changes correlated closely with changes in protein expression.


CONCLUSIONS
Immunohistochemical staining for induction of SSAT correlates with measures of enzymatic activity in a small sample where measurements were possible and suggests that immunohistochemistry may be used for predicting response of breast cancers to DENSpm. A high proportion of breast cancers induced SSAT in response to DENSpm, supporting the continued consideration of this class of agents for treatment of breast cancer.
Gabrielson
Edward
E
Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231-1000, USA.
Tully
Ellen
E
Hacker
Amy
A
Pegg
Anthony E
AE
Davidson
Nancy E
NE
Casero
Robert A
RA
D000123:Acetyltransferases / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology*; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000970:Antineoplastic Agents; D013096:Spermine; D000099228:Diamine N-Acetyltransferase; C059685:N(1),N(11)-diethylnorspermine