Preclinical antitumor and antiangiogenic activity of a metronomic schedule of cisplatin against human transitional cell carcinom

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Sub-category: Bladder Cancer
Category: Genitourinary Cancer
Meeting: 2009 ASCO Annual Meeting
Citation: J Clin Oncol 27, 2009 (suppl; abstr e16018)
Abstract No: e16018
Author(s): W. Jian,
J. M. Levitt, S. P. Lerner, G. Sonpavde; Baylor College of Medicine,
Houston, TX; Baylor College of Medicine, Texas Oncology, Houston, TX
Background: Conventional
cisplatin every 3 weeks is frequently precluded in patients with TCC
due to renal dysfunction. A metronomic schedule of other
chemotherapeutic agents demonstrates anti-angiogenic and anti-tumor
activity coupled with better tolerability. A rationale can be made to
preclinically evaluate the activity of a metronomic (weekly or 3 days a
week) schedule of cisplatin in a preclinical system of TCC.
The activity of cisplatin was assessed in vitro against HUVECs (human
umbilical vein endothelial cells). MTT, flow cytometry with
Annexin-FITC and scratch assays were employed to assess proliferation,
apoptosis and migration, respectively. The activity of cisplatin was
evaluated in vivo in murine xenograft models of TCC. The subcutaneous
xenografts included 5 x 106 RT4 or 5637 human TCC cells
injected into 6- to 8-week-old female athymic BALB/c nu/nu mice.
Cisplatin was administered 4 mg/kg IP (intraperitoneal) weekly for up
to 6 weeks and compared with untreated mice. Then, 3 groups of
tumor-bearing mice received either no therapy, cisplatin 6 mg/kg weekly
or cisplatin 2 mg/kg for 3 days a week for up to 6 weeks. Tumor size is
measured twice a week. Nephrotoxicity is assessed by serum creatinine
and kidney histopathological examination. IHC (immunohistochemistry) of
xenografts is performed to measure proliferation (ki-67), apoptosis
(cleaved caspase-3) and angiogenesis (CD31).
Results: Cisplatin
demonstrated significant anti-proliferative, anti-migration and
pro-apoptotic activity against HUVECs in vitro. Cisplatin 4 mg/kg
weekly inhibited tumor growth, induced higher apoptosis and
down-regulated angiogenesis and proliferation in vivo compared to
controls. Results from the experiment comparing cisplatin 6 mg/kg
weekly with 2 mg/kg 3 days a week (i.e. more metronomic, with
potentially more anti-angiogenic and anti-tumor activity and less
nephrotoxic) will be presented.
Conclusions: A metronomic
schedule of cisplatin inhibits tumor growth and demonstrates
anti-angiogenic activity in a preclinical model of human TCC. The
clinical evaluation of a metronomic schedule of cisplatin may be