Ecteinascidin 743 and Nuclear Excision Repair
Ecteinascidin 743 (Et 743), a complex natural product produced by a marine tunicate
(Rinehart et al., 1990), also seems to work by trapping DNA-binding proteins at sites
where structural distortion of the DNA is recognized (Garcia-Nieto et al., 2000; Zewail-
Foote et al., 2001). It is therefore similar to cisplatin as it seems to hijack proteins such
as Sp1 and those involved in NER on DNA; however, it is different from cisplatin
because it occupies the minor groove and bends DNA into the major groove (Zewail-
Foote & Hurley, 1999), so the target proteins are different. Et 743 might also be
analogous to topoisomerase poisons such as SN-38 because it has been reported to result
in protein-associated strand breaks, probably involving NER (Takebayashi et al., 2001)
(Figure 2e), although these strand breaks were not been observed in a subsequent study
(Erba et al., 2001). In any event, the unique features of the drug–DNA complex (major
groove bend associated with minor groove occupancy, extrahelical protrusion, and
hydrogen-bonded stabilization of the helix) (Zewail-Foote et al., 2001) provide Et 743
with structural and biological consequences that set it apart from other known agents.
Analogous to the effects of topoisomerase I and II poisons, for which depletion of
proteins leads to drug resistance, deficiencies in NER proteins also lead to resistance to
the effects of Et 743 (Zewail-Foote et al., 2001), and cells selected to be resistant to Et
743 have a defective XPG gene (Takebayashi et al., 2001). There could be an additional
advantage to sequestering repair proteins involved in NER as it is predicted to result in
the persistence of DNA lesions, such as the cisplatin–DNA adduct, if Et 743 and cisplatin
are given in combination. This, in turn, would result in synergy if the persistence of
cisplatin–DNA adducts is related to efficacy (Reed, 1998). Et 743 has a second
mechanism of action that involves multidrug resistance (MDR1) reversal (Jin et al.,
2000). MDR1 is a p-glycoprotein-mediated pump of broad specificity that effluxes drugs
from cancer cells, and Et 743 prevents this efflux. It is not as yet clear what the
underlying mechanism is for this reversal (Synold et al., 2001). While Et 743 competes
for binding of the transcriptional factor NF-Y to its cognate sequence in the
transcriptional region of the MDR1 gene (Minuzzo et al., 2000), the concentrations
required to do this are 103-fold higher than required to suppress MDR1 in cells. Erba, E., Bergamaschi, D., Bassano, L., Damia, G., Ronzoni, S., Faircloth, G. T. &
D'Incalci, M. D. Ecteinascidin-743 (ET-743), a natural marine compound, with a
unique mechanism of action. Eur. J. Cancer 37, 97–105 (2001). Garcia-Nieto, R., Manzanares, I., Cuevas, C. & Gago, F. Increased DNA binding
specificity for antitumor ecteinascidin 743 through protein-DNA interactions? J.
Med. Chem. 43, 4367–4369 (2000). Jin, S. Gorfajn, B., Faircloth, G. & Scotto, K. W. Ecteinascidin 743, a transcription-
targeted chemotherapeutic that inhibits MDR1 activation. Proc. Natl. Acad. Sci.
U.S.A. 97, 6775–6779 (2000). Minuzzo, M., Marchini, S., Broggini, M., Faircloth, G., D'Incalci, M. & Mantovani, R..
Interference of transcriptional activation by the antineoplastic drug Ecteinascidin-
743. Proc. Natl. Acad. Sci. U.S.A. 97, 6780–6784 (2000). Reed, E. Platinum–DNA adduct, nucleotide excision repair, and platinum-based anti-
cancer chemotherapy. Cancer Treatment Reviews 24, 331–344 (1998). Rinehart., K. L. et al. Ecteinascidins 729, 743, 745, 759A, 759B, and 770: potent
antitumor agents from the Caribbean tunicate Ecteinascidia turbinate. J. Org.
Chem. 55, 4512–4515 (1990). Synold, T. W., Dussault, I. & Forman, B. M. The orphan nuclear receptor SXR
coordinately regulates drug metabolism and efflux. Nature Med. 7, 584–590 (2001). Zewail-Foote, M. & Hurley, L. H. Ecteinascidin 743: a minor groove alkylator that
bends DNA toward the major groove. J. Med. Chem. 42, 2943–2497 (1999). Zewail-Foote, M. et al. The inefficiency of incisions of Ecteinascidin 743–DNA adducts
by the UvrABC nuclease and the unique structural feature of the DNA adducts can
be used to explain the repair-dependent toxicities of this antitumor agent. Chem.
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