Table 6.

Associated toxicities of NOTCH-based therapies used preclinically for non-small cell lung cancer.

Treatment		Dose	Toxicity	Reference
Type	Name
GSI	MRK-003	100 mg/kg po 3 days	✓Diarrhea, dehydration, severe weight loss	(193)
	PF-3084014	150 mg/kg po 7 days	✓Goblet cell hyperplasia ✓↓ Total whole blood count, lymphocytes, basophils, eosinophils, leukocytes ✓Mild jejunal eosinophilic inflammation	(194)
		100 mg/kg GSI, 3 weeks * 2 cycles; 1.0 mg/kg dexamethasone on weeks 1 and 3	✓Dexamethasone ameliorates gastrointestinal effects (DLT)
	LY-411575	1–10 mg/kg po 5 or 15 days	✓Altered lymphocyte development, thymus atrophy, ↓ body weight ✓↑ Goblet cell number, secretion of mucin into the intestinal lumen, epithelial erosion, infiltration of inflammatory cells in the lamina propria and necrosis ✓Skin: epidermal/epithelial hyperplasia, follicular/epidermal inclusion cysts	(192, 195)
	GSI	10 µmol/kg 1 day	✓Gastrointestinal mucous metaplasia, conversion of cryptal cells into goblet cells (goblet cell hyperplasia)	(197)
	DBZ	✓2.5 mL/kg ip 5 days ✓3–30 µmol/kg ip 5 days ✓10 µmol/kg daily 4 weeks	✓Distension of the stomach and intestine ✓↑ Mucous, goblet cell metaplasia (duodenum, jejunum) and hyperplasia, apoptosis (small intestinal crypt epithelial cells, large intestinal glands), villus atrophy, and severe diarrhea ✓Splenic marginal zone lymphoid tissue atrophy	(188, 190, 196)
		DBZ 10 µmol/kg ip Dexamethasone 15 mg/kg ip Daily 5 or 10 days	✓DBZ: ↑ intestinal secretory metaplasia, goblet cell hyperplasia and ↓ proliferation small intestine crypt cells ✓Combination: normal goblet cell numbers and tissue architecture of intestinal epithelium	(198)
mAb	OMP59R5 (anti-NOTCH2/3)	40 mg/kg every other day	✓Minimal intestinal toxicity ✓Rodent teeth affectance (long-term repeated high doses)	(124)
	HD105 (anti-DLL4 and anti-VEGF)	1–3 mg/kg QW for 8 weeks 10 mg every 3 days (5 doses, 30 mg/kg)	✓↑ Activation of endothelial cells ✓Sinusoidal dilation ✓Centrilobular hepatocyte atrophy	(202)
	Anti-DLL4	10 mg/kg 2 weeks	✓No impact on intestinal goblet cell differentiation	(199)
Natural agents	Delta-tocotrienol (blueberries)	200–800 mg/kg sc 14–30 days	✓Dose-dependent severity (up to moderately severe) of dermatitis and inflammation ✓No adverse effects were observed in any tissues or organs	(203)
	Curcumin (ginger and other plants)	iv 14 days: ✓250 mg/kg ✓500–1,000 mg/kg	✓250 mg/kg: piloerection and minor weight loss ✓500 mg/kg: ↓ spontaneous motility and bowel movements, piloerection and ↓ weight (in 3 mice) ✓1,000 mg/kg: lethal within 1 h of administration, respiratory distress, bradypnea, and paralytic gait	(201)

GSI, gamma-secretase inhibitor; mAb, monoclonal antibody; ip, intraperitoneal; po, per os (oral administration); sc, subcutaneous; iv, intravenous; QW, once every week; ↑, increase/upregulated; ↓, decrease/downregulated; DLT, dose-limiting toxicity.