Quantification of Acylfulvene–
and Illudin
S–DNA Adducts in Cells with Variable Bioactivation Capacities
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Abstract
Illudin S and its semisynthetic analogue acylfulvene
(AF) are structurally
similar but elicit different biological responses. AF is a bioreductive
alkylating anticancer agent with a favorable therapeutic index, while
illudin S is in general highly toxic. AF toxicity is dependent on
the reductase enzyme prostaglandin reductase 1 (PTGR1) for activation
to a cytotoxic reactive intermediate. While illudin S can be metabolized
by PTGR1, available data suggest that its toxicity does not correspond
with PTGR1 function. The goal of this study was to understand how
drug cytotoxicity relates to cellular bioactivation capacity and the
identity and quantity of AF– or illudin S–DNA adducts.
The strategy involved identification of novel illudin S–DNA
adducts and their quantitation in a newly engineered SW-480 colon
cancer cell line that stably overexpresses PTGR1 (PTGR1-480). These
data were compared with cytotoxicity data for both compounds in PTGR1-480
versus normal SW-480 cells, demonstrating that AF forms more DNA adducts
and is more cytotoxic in cells with higher levels of PTGR1, whereas
illudin S cytotoxicity and adduct formation are not influenced by
PTGR1 levels. Results are discussed in the context of an overall model
for how changes in relative propensities of these compounds to undergo
cellular processes, such as bioactivation, contributes to DNA damage,
and cytotoxicity