Enhancement of hypoxia-activated prodrug TH-302 anti-tumor activity by Chk1 inhibition

BMC Cancer

Table 3 Enhanced TH-302 cytotoxicity by Chk1 inhibitors is only observed in p53-deficient but not p53-proficient cells

Cell line	Cell type	p53 status	AZD 7762 (μM)	LY 2603618 (μM)	PF 477736 (μM)	TH-302 (Normoxia; 21% O₂)				TH-302 (Hypoxia; N₂)
Cell line	Cell type	p53 status	AZD 7762 (μM)	LY 2603618 (μM)	PF 477736 (μM)	-	+AZD 7762 (μM)	+LY 2603618 (μM)	+PF 477736 (μM)	-	+AZD 7762 (μM)	+LY 2603618 (μM)	+PF 477736 (μM)
HeLa	Cervical	p53 ^-/-	0.7	3.2	0.3	>1000	95	90	200	100	0.5	0.4	2.1
H460	NSCLC	p53 ^+/+	0.2	1.2	4.3	25	25	22	19	0.4	0.2	0.2	0.2
DU145	Prostate	p53 ^+/-	0.4	2.3	0.7	210	80	110	340	2.7	1.1	0.9	1.9
MCF10A p53^+/+	Breast	p53 ^+/+	0.9	5.7	1	110	44	61	75	0.6	0.4	0.5	0.6
MCF10A p53^-/-	Breast	p53 ^-/-	0.5	4.1	0.7	88	24	22	34	0.7	0.1	0.2	0.2
SW48 p53^+/+	Colon	p53 ^+/+	0.1	4.1	0.4	39	16	35	39	0.09	0.04	0.07	0.2
SW48 p53^-/-	Colon	p53 ^-/-	0.1	0.6	0.1	110	19	22	27	1.5	0.2	0.2	0.2

IC₅₀ values in μM. Inhibitor concentrations used for combination studies (all in μM): AZD7762: HeLa (0.2); H460 (0.05); DU145 (0.1); MCF10A p53^+/+ and MCF10Ap53^-/-(0.1); SW48 p53^+/+ and SW48 p53^-/-(0.03). LY2603618: HeLa (0.7); H460 (0.2); DU145 (0.4); MCF10A p53^+/+ and MCF10Ap53^-/-(1); SW48 p53^+/+(0.5); SW48 p53^-/- (0.2). PF47736: HeLa (0.1); H460 (2); DU145 (0.1); 0.1 MCF10A p53^+/+ and MCF10Ap53^-/-(0.1); SW48 p53^+/+ (0.2); SW48 p53^-/-(0.05).

ISSN: 1471-2407