The cyclopropylpyrroloindole analogues are
DNA minor-groove binders containing a cyclopropyl group, which mediates N3-adenine covalent adduct formation in a sequence-selective fashion.
Carzelesin (U-80244) is a cyclopropylpyrroloindole
prodrug containing a relatively nonreactive chloromethyl precursor to the cyclopropyl function. Activation of
carzelesin requires two steps, (a) hydrolysis of a
phenylurethane substituent to form
U-76073, followed by (b) ring closure to form the cyclopropyl-containing
DNA-reactive
U-76074. The formation of the
DNA-reactive
U-76074, via
U-76073, from
carzelesin was shown to proceed very slowly in
phosphate-buffered saline (t1/2 greater than 24 h) but to occur rapidly in plasma from mouse, rat, dog, and human (initial t1/2 values ranging from 18 min for mouse to 52 min for rat) and in cell culture medium (t1/2 approximately 40 min). Although
carzelesin was less potent in terms of in vitro cytotoxicity and in vivo optimal dosage and showed low affinity for binding to
DNA, it was therapeutically more efficacious against mouse
L1210 leukemia than was
U-76074 or
adozelesin (U-73975), another cyclopropylpyrroloindole analogue which is currently in phase I clinical trials.
Carzelesin also proved to be more efficacious than
U-76074 or
adozelesin against mouse pancreatic ductal 02
adenocarcinoma, a system reported to be resistant to every agent tested.
Carzelesin was highly effective against this
tumor and produced 97%
tumor growth inhibition. In addition, i.v. administered
carzelesin showed significant activity (National Cancer Institute criteria) against i.v. or s.c. implanted
Lewis lung carcinoma, i.p. or s.c. implanted
B16 melanoma, s.c. implanted colon 38
carcinoma, and five s.c. implanted human
tumor xenografts, including clear cell Caki-1
carcinoma, colon CX-1
adenocarcinoma, lung LX-1
tumor, ovarian 2780
carcinoma, and prostatic DU-145
carcinoma.
Carzelesin treatment produced 100% complete remissions (no palpable
tumor mass at the termination of the experiment) in mice bearing early-stage human ovarian 2780. Pharmacologically,
carzelesin proved to be relatively schedule and route independent and was highly active against i.p. implanted
L1210 leukemia, regardless of whether the analogue was given i.v., i.p., s.c., or p.o. These results, collectively, suggest that
carzelesin is absorbed and distributed well. Both
carzelesin and
adozelesin caused marked
tumor shrinkage in mice bearing human lung LX-1 or advanced-stage human ovarian 2780
carcinoma; however,
tumor regrowth occurred shortly after the treatment with
adozelesin was stopped. Little or no apparent
tumor regrowth occurred
after treatment with
carzelesin.(ABSTRACT TRUNCATED AT 400 WORDS)