TY - JOUR
T1 - Potentiation of a topoisomerase i inhibitor, karenitecin, by the histone deacetylase inhibitor valproic acid in melanoma
T2 - translational and phase l/ll clinical trial
AU - Daud, Adil I.
AU - Dawson, Jana
AU - Deconti, Ronald C.
AU - Bicaku, Elona
AU - Marchion, Douglas
AU - Bastien, Sem
AU - Hausheer, Frederick A.
AU - Lush, Richard
AU - Neuger, Anthony
AU - Sullivan, Daniel M.
AU - Munster, Pamela N.
PY - 2009/4/1
Y1 - 2009/4/1
N2 - Purpose: The novel topoisomerase I inhibitor karenitecin (KTN) shows activity against melanoma. We examined whether histone deacetylase inhibition could potentiate the DNA strand cleavage, cytotoxicity as well as the clinical toxicity, and efficacy of KTN in melanoma. Experimental Design: Apoptosis, COMET, and xenograft experiments were carried out as described previously. A phase I/II trial of valproic acid (VPA) and KTN was conducted in patients with stage IV melanoma, with any number of prior therapies, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Results: VPA pretreatment potentiated KTN-induced apoptosis in multiple melanoma cell lines and in mouse A375 xenografts. VPA increased KTN-induced DNA strand breaks. In the phase I/II trial, 39 patients were entered, with 37 evaluable for toxicity and 33 evaluable for response. Somnolence was the dose-limiting toxicity. The maximum tolerated dose for VP Awas 75 mg/kg/d; at maximum tolerated dose, serum VPA was ∼ 200 Ag/mL (1.28 mmol/L). At the dose expansion cohort, 47% (7 of 15) of patients had stable disease; median overall survival and time to progression were 32.8 and 10.2 weeks, respectively. Histone hyperacetylation was observed in peripheral blood mononuclear cells at maximum tolerated dose. Conclusion: VPA potentiates KTN-induced DNA strand breaks and cytotoxicity. VPA can be combined at 75 mg/kg/d for 5 days with full-dose KTN without overlapping toxicities. In metastatic poor prognosis melanoma, this combination is associated with disease stabilization in 47% of patients. Further testing of this combination appears warranted.
AB - Purpose: The novel topoisomerase I inhibitor karenitecin (KTN) shows activity against melanoma. We examined whether histone deacetylase inhibition could potentiate the DNA strand cleavage, cytotoxicity as well as the clinical toxicity, and efficacy of KTN in melanoma. Experimental Design: Apoptosis, COMET, and xenograft experiments were carried out as described previously. A phase I/II trial of valproic acid (VPA) and KTN was conducted in patients with stage IV melanoma, with any number of prior therapies, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Results: VPA pretreatment potentiated KTN-induced apoptosis in multiple melanoma cell lines and in mouse A375 xenografts. VPA increased KTN-induced DNA strand breaks. In the phase I/II trial, 39 patients were entered, with 37 evaluable for toxicity and 33 evaluable for response. Somnolence was the dose-limiting toxicity. The maximum tolerated dose for VP Awas 75 mg/kg/d; at maximum tolerated dose, serum VPA was ∼ 200 Ag/mL (1.28 mmol/L). At the dose expansion cohort, 47% (7 of 15) of patients had stable disease; median overall survival and time to progression were 32.8 and 10.2 weeks, respectively. Histone hyperacetylation was observed in peripheral blood mononuclear cells at maximum tolerated dose. Conclusion: VPA potentiates KTN-induced DNA strand breaks and cytotoxicity. VPA can be combined at 75 mg/kg/d for 5 days with full-dose KTN without overlapping toxicities. In metastatic poor prognosis melanoma, this combination is associated with disease stabilization in 47% of patients. Further testing of this combination appears warranted.
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U2 - 10.1158/1078-0432.CCR-08-1931
DO - 10.1158/1078-0432.CCR-08-1931
M3 - Article
C2 - 19318485
AN - SCOPUS:65249131145
SN - 1078-0432
VL - 15
SP - 2479
EP - 2487
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -