| Reference | 1. Pediatr Blood Cancer. 2012 Feb;58(2):200-9. doi: 10.1002/pbc.23016. Epub 2011 May
5. <br />
Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical
testing program. <br />
Houghton PJ(1), Lock R, Carol H, Morton CL, Gorlick R, Anders Kolb E, Keir ST,
Reynolds CP, Kang MH, Maris JM, Billups CA, Zhang MX, Madden SL, Teicher BA,
Smith MA. <br />
Author information: <br />
(1)Nationwide Children/’s Hospital, Columbus, OH, USA.
[email protected] <br />
BACKGROUND: Genz-644282 is a novel non-camptothecin topoisomerase I poison that
is in clinical development.
PROCEDURES: Genz-644282 was tested against the PPTP in vitro panel (0.1 nM to
1 μM), and in vivo using three times per week × 2 schedule repeated at day 21 at
its maximum tolerated dose (MTD) of 4 mg/kg. Subsequently Genz-644282 was tested
at 4, 3, 2, and 1 mg/kg in 3 models to assess the dose-response relationship.
mRNA gene signatures predictive for Genz-644282 response in vitro were applied to
select 15 tumor models that were evaluated prospectively.
RESULTS: In vitro, Genz-644282 demonstrated potent cytotoxic activity with a
median IC(50) of 1.2 nM (range 0.2-21.9 nM). In vivo, Genz-644282 at its MTD
(4 mg/kg) induced maintained complete responses (MCR) in 6/6 evaluable solid
tumor models. At 2 mg/kg Genz-644282 induced CR or MCR in 3/3 tumor models
relatively insensitive to topotecan, but there were no objective responses at
1 mg/kg. Further testing at 2 mg/kg showed that Genz-644282 induced objective
regressions in 7 of 17 (41%) models. There was a significant correlation between
predictive response scores based on Affymetrix U133Plus2 baseline tumor
expression profiles and the observed in vivo responses to Genz-644282.
CONCLUSIONS: Genz-644282 was highly active within a narrow dose range
(2-4 mg/kg), typical of other topoisomerase I poisons. As with other
topoisomerase I poisons, how accurately these data will translate to clinical
activity will depend upon the drug exposures that can be achieved in children
treated with this agent. <br />
2. Mol Cancer Ther. 2011 Aug;10(8):1490-9. doi: 10.1158/1535-7163.MCT-10-1043. Epub
2011 Jun 2. <br />
Molecular and cellular pharmacology of the novel noncamptothecin topoisomerase I
inhibitor Genz-644282. <br />
Sooryakumar D(1), Dexheimer TS, Teicher BA, Pommier Y. <br />
Author information: <br />
(1)Laboratory of Molecular Pharmacology, Center for Cancer Research, National
Cancer Institute, NIH, Bethesda, MD 20892, USA. <br />
Camptothecin derivatives are powerful anticancer drugs because of their ability
to trap topoisomerase I (Top1)-DNA cleavage complexes. However, they exhibit
clinical limitations due to the instability of their α-hydroxylactone
six-membered E-ring structure. In addition, they exhibit bone marrow and
intestinal toxicity, especially in adults, and are drug efflux substrates. Here,
we report a novel Top1 inhibitor, Genz-644282. We show that Genz-644282 and its
metabolites induce Top1 cleavage at similar, as well as unique genomic positions,
compared with camptothecin. The compound also induces protein-linked DNA breaks
and Top1-DNA cleavage complexes that persist longer after compound removal than
camptothecin. Concentration-dependent and persistent γH2AX formation was readily
observed in cells treated with Genz-644282, and was present in greater than 50%
of the cell population following 24 hours compound exposure. The compound shows
partial cross-resistance in cell lines resistant to camptothecin. These cell
lines include the human prostate DU145RC0.1 and the leukemic CEM/C2 cells.
Limited cross-resistance to Genz-644282 was also found in the Top1 knockdown
colon cancer (HCT116) and breast cancer (MCF7) cell lines and in human
adenocarcinoma cells (KB31/KBV1) that overexpress (P-glycoprotein, ABCB1), a
member of the ATP-binding cassette family of cell surface transport proteins
known to confer MDR. Together, our results provide the first molecular and
cellular characterization of Genz-644282 and its clinically relevant metabolites. <br />
3. Clin Cancer Res. 2011 May 1;17(9):2777-87. doi: 10.1158/1078-0432.CCR-10-0542.
Epub 2011 Mar 17. <br />
Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer
treatment. <br />
Kurtzberg LS(1), Roth S, Krumbholz R, Crawford J, Bormann C, Dunham S, Yao M,
Rouleau C, Bagley RG, Yu XJ, Wang F, Schmid SM, Lavoie EJ, Teicher BA. <br />
Author information: <br />
(1)Genzyme Corporation, Framingham, Massachussetts 01701, USA.
[email protected] <br />
PURPOSE: Genz-644282
[8,9-dimethoxy-5-(2-N-methylaminoethyl)-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]na
phthyridin-6-one] has emerged as a promising candidate for antitumor agents. This
report describes the bone marrow colony-forming unit, granulocyte macrophage
(CFU-GM) and tumor cell CFU activity of topoisomerase I (Top1) inhibitors, such
as Genz-644282, topotecan, irinotecan/SN-38, and ARC-111, and examines their
activity in several human tumor xenograft models.<br />
EXPERIMENTAL DESIGN: Colony-forming assays were conducted with mouse and human
bone marrow and eight human tumor cell lines. In addition, 29 human tumor cell
lines representing a range of histology and potential resistance mechanisms were
assayed for sensitivity to Genz-644282 in a 72-hour exposure assay. The efficacy
of Genz-644282 was compared with standard anticancer drugs (i.e., irinotecan,
docetaxel, and dacarbazine) in human tumor xenografts of colon cancer, renal cell
carcinoma, non-small cell lung cancer, and melanoma.<br />
RESULTS: Human bone marrow CFU-GM was more sensitive to the Top1 inhibitors than
was mouse bone marrow CFU-GM. The ratio of mouse to human IC(90) values was more
than 10 for the camptothecins and less than 10 for Genz-644282, which had more
potency as a cytotoxic agent toward human tumor cells in culture than the
camptothecins in the colony-forming and 72-hour proliferation assays. Genz-644282
has superior or equal antitumor activity in the human tumor xenografts than the
standard drug comparators.<br />
CONCLUSIONS: On the basis of preclinical activity and safety, Genz-644282 was
selected for development and is currently undergoing phase 1 clinical trial. <br />
|
