Semester

Summer

Date of Graduation

1999

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Michael R. Miller.

Abstract

Acetaminophen is a common analgesic/antipyretic. This research projected investigated the interaction of acetaminophen with breast cancer cells. The first goal was to determine if acetaminophen induces proliferation in cancerous and normal, human breast cells. Pharmacological concentrations of acetaminophen stimulated proliferation (3H-thymidine incorporation into DNA, % S phase cells, cell numbers) of estrogen and progesterone receptor positive (ER+/PR+) but not of ER-/PR+ or of ER-/PR- cancer or normal breast cells. The second goal was to determine if estrogen receptors play a role in acetaminophen-induced proliferation of ER+ breast cancer cells. Antiestrogens inhibited acetaminophen-induced proliferation, suggesting that ERs are involved in proliferation. However, acetaminophen did not bind to ERs in ER+ breast cancer cells, indicating that while acetaminophen mimics some of estradiol effects, it does so by a different mechanism. The third goal was to determine if the p-phenol moiety in acetaminophen plays a role in the proliferation of ER+ breast cancer cells. The effects of the positional isomers of acetaminophen on proliferation followed the order: p- > m- > o-acetamidophenol. These findings indicate that the p-phenol is important for proliferation of ER+ breast cancer cells. The fourth goal was to determine if metabolism of acetaminophen occurs in breast cancer cells. Microsomes from ER+ breast cancer cells that undergo proliferation in response to acetaminophen did not metabolize acetaminophen to detectable levels except when cells were pretreated with inducers of cytochrome P450. By contrast, ER- breast cancer cells metabolized acetaminophen to detectable levels in both, cells non-induced and induced with cytochrome P450 inducers. The fifth goal was to determine if acetaminophen affects tumor growth in nude mice inoculated with ER+ human breast cancer cells. Acetaminophen (150 mg/kg/day), like estradiol, stimulated tumor growth relative to negative controls up to day 36 following inoculation with ER+ cells. However, after day 36, all tumors regressed. Taken together, the data in this project is novel and helps to understand the interaction of acetaminophen with breast cancer cells, an area largely understudied.

Download

Share

COinS