SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R C E L L B I O L O G Y P R O G R A M
THEODORE J. LAMPIDIS, PH.D.
Professor of Cell Biology and Anatomy
DESCRIPTION OF RESEARCH
Dr. Lampidis’ research has evolved from his
preliminary work on the physiology and
pharmacology of cultured cardiac cells. A video/
electronic-computerized system was developed to
monitor cardiac cell function in vitro. Using pulsating
myocardial cells as a model, he focused on
why the widely used anti-tumor agent, Adriamycin,
affected the hearts of patients treated with
this drug. This initial idea led Dr. Lampidis to
study drug selectivity between certain types of
tumor and normal cells and the chemical requirements
of anti-cancer drugs for reduced cardiotoxicity
and increased tumoricidal potency.
Dr. Lampidis’ efforts then turned toward
understanding the mechanisms of drug resistance
to mitochondrial agents such as rhodamine 123
and the structure/function requirements of various
chemotherapeutic agents for recognition by
p-glycoprotein-mediated multiple drug resistance
(MDR). Molecular and immunochemical probes
of MDR and other cellular resistance mechanisms
(i.e., multi-drug resistance-related protein
(MRP)), were developed in his laboratory to
detect and study these phenomena. He and his
colleagues found that chemical charge and
lipophilicity play critical roles in determining
whether anti-cancer drugs are recognized by tumor
cells expressing these MDR mechanisms.
As an outcome of their studies on mitochondrial
agents, the researchers realized that tumor
cells treated with the uncoupling agent, rhodamine
123, were strikingly similar to the poorly oxygenated
cancer cells located at the inner core of solid
tumors. In both conditions, the cells rely exclusively
on anaerobic metabolism for survival.
Moreover, cells in the center of a tumor divide
more slowly than outer-growing aerobic cells and
consequently are more resistant to standard chemotherapeutic
agents, which target the more rapidly
dividing cells. Thus, by the nature of their
slow growth, these tumor cells exhibit a form of
MDR, which contributes significantly to chemotherapy
failures in the treatment of solid tumors.
Anaerobiosis, however, also provides a natural
window of selectivity for agents that interfere
with glycolysis. This concept forms the basis for
Dr. Lampidis’ current initiative to exploit the
natural selectivity that inhibitors of glycolysis
should have for hypoxic cells that are slowly
growing at the inner core of solid tumors. His
background and work on mitochondrial localizing
drugs and MDR uniquely position him to
stimulate new initiatives in his laboratory in this
promising area of research.
A long-term goal for Dr. Lampidis is the addition
of the appropriate glycolytic inhibitors
(which are presently being designed and synthesized)
to current clinical protocols, which may
significantly improve the success rate of cancer
chemotherapy. Moreover, studying how tumor
cells react to combinations of oxidative phosphorylation
and glycolytic inhibitors could lead to
the design of future novel approaches to more
successfully treat cancer.
SELECTED PUBLICATIONS
2002
Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ .
Hypoxia increases tumor cell sensitivity to glycolytic
inhibitors: a strategy for solid tumor therapy
(Model C). Biochemical Pharmacology 64:1745-
51, 2002.
2003
Savaraj, N, Wu, C, Wangpaichitr, M, Kuo, MT,
Lampidis, TJ , Robles, C, Furst, AJ, and Feun, L.
Overexpression of mutated MRP4 in cisplatin
resistant small cell lung cancer cell line: collateral
sensitivity to azidothymidine. International Journal
of Oncology 23:173-9, 2003.
Hu, YP, Haq, B, Carraway, KL, Savaraj, N, and
Lampidis, TJ . Multidrug resistance correlates
with overexpression of Muc4 but inversely with
P-glycoprotein and multidrug resistance related
protein in transfected human melanoma cells.
Biochemical Pharmacology 65:1419-25, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 79