Preclinical Murine Models for Lung Cancer: Clinical Trial Applications

Table 3

Preclinical and clinical trial summaries for lung cancer therapies (CCSP: clara cell secretory protein; rtTA: reverse tetracycline transactivator protein; EGFR: epidermal growth factor receptor; RR: response rate; PFS: progression free survival).

Drug name	Route	Mechanism	Preclinical dosage	Preclinical frequency	FDA approval	Preclinical model	Preclinical results	Clinical Dosage	Clinical Frequency	Results of Clinical Trials	References
Gefitinib	Oral	HER1/EGFR inhibitor	0.01 μM; 50–200 mg/kg	qd × 5 days × 2 weeks	2009	Xenograft-A549 cells in athymic nude	Tumor regression and increase in median survival	250 mg	qd	Positive	[66, 67]
Erlotinib	Oral	HER1/EGFR inhibition	0.5% (w/v) I.P. or; 25 mg/kg/day	qd × 5 days × q4 weeks	2005	Xenograft-HCC827, A549, NCI358 cells in female BALB/cA nude mice; Transgenic-CCSP-rtTA; Tet-07-EGFR^L858R	Tumor regression observed in HCC827 xenografts	150 mg	qd	Positive	[26, 49, 68]
Vandetanib	Oral	VEGF/EGFR inhibitor	25 mg/kg	qd	Not approved	Xenograft-H1975 cells in female athymic nude mice	Inhibition of tumor growth (not dramatic)	50–145 mg/m^2	qd	Negative	[69]
BIBW2992	Oral	HER2/EGFR inhibitor	20 mg/kg	qd	October 2010 Phase III clinical trial	Xenograft-H1975 cells in female athmyic NMRI-nu/nu mice; Transgenic-CCSP-rtTA; Tet-07-EGFR^L858R	Dramatic tumor regression T/C ratio 2%	20–70 mg	D1, 8, 15 q4 weeks	Positive	[37, 70]
Crizotinib	Oral	ALK inhibitor	10 mg/kg	qd	Phase III clinical trials	Transgenic-SP-C-EML4-ALK in C57BL/6J mice	Tumor regression and increase in median survival	250 mg	2 d × 6 months	Positive	[57, 71, 72]
Navelbine (Vinorelbine)	Oral,; IV	Antimicrotubule; chemotherapy	1.25–5 mg/kg	qd × 9 days	1994	Immune-C57B1 mice used for transplantation of LLC	72.7% inhibition of tumor growth	25–30 mg/m^2	q weekly	Positive	[73, 74]
Paclitaxel	IV	Antimicrotubule; chemotherapy	12–24 mg/kg	qd × 5 days	1992	Xenograft-A549, NCI-H23, NCI-H460, DMS-273, NCI-H226, and DMS-114 cells in nude mice	Significant tumor regression, more effective than cisplatin	135 mg/m^2	q3 weeks	Positive	[36, 75]
Abraxane	IV	Antimicrotubule; chemotherapy	250 mg/kg IP	qd × 3 weeks	Phase III clinical trials for lung cancer	Xenograft-H460 cells in female athymic nu/nu mice	Significant tumor regression	260 mg/m^2	q3 weeks	Positive	[23, 34]
Gemcitabine	IV	Nucleoside analog chemotherapy	50–160 mg/kg	q3-4 days	2006	Xenograft-A549 and H1299 cells in female nude mice	Reduced mean tumor double time by 50% in 13 days	1000 mg/m^2	D1, 8, 15 q28 days	Positive	[32, 76]
Pemetrexed	IV	Folate antimetabolite chemotherapy	30 mg/kg	q3-4 days	2004	Xenograft-H460 cells in female athymic nude	Tumor regression duration and dose dependent	500 mg/m^2	q21 days	Positive	[35, 77]
Doxorubicin	IV	Anthracycline antibiotic chemotherapy	3.0–12 mg/kg	qd	1950’s	Xenograft-Nu/nu-Balb/c/ABom, normal Balb/c (13); CB-17 scid/scid with TL-1 s.c. 2 × 10(6) cells in 0.2mL saline (14)	Effective in arresting tumor growth	40–75 g/m^2	q21–28 days	Positive	[41, 78]
Cisplatin	IV	Platinum-based chemotherapy	7 mg/kg I.P	qd × 2 weeks q4 weeks	1969	Xenograft-A549, H1299 nude mice; Transgenic-LSLK-RasG12D on 129svJae background	Significantly reduced tumor burden, but left long-term resistance	60 to 100 mg/m^2	q21 days	Positive	[32, 79, 80]
Carboplatin	IV	Platinum-based chemotherapy	50 mg/kg I.P.	qd	1989	Xenograft-A549 and H1299 cells in athmyic nude mice; Immune-C57B1 mice used for transplantation of LLC	Two-drug regimen response rates 30–50% prolonged median survival of >1 year	200–360 mg/m^2	q4 weeks	Positive	[32, 40, 81]
Etoposide	IV,; oral	DNA topoisomerase II inhibitor	1–32 mg/kg	qd × 5 days	1960’s	Xenograft-H460 cells in female athmyic nude mice	Tumor growth regression	100 mg/m^2 IV; 200 mg/m^2 PO	q3 weeks	Positive	[82, 83]
Bevacizumab	IV	Monoclonal antibody VEGF-A inhibitor	5 mg/kg	qd × 4 weeks	2004	Xenograft-H1299 cells in athymic BALB/c female nude mice	Reduced vascularity, reduced interstitial pressure and tumor growth	15 mg/kg	q3 weeks	Positive	[84, 85]
Sunitinib	oral	Multitargeted RTK inhibitor (VEGF, CKit, PDGFα, cRET)	40 mg/kg	qd × 6 weeks	Phase II clinical trials for lung cancer	Xenograft-NCI-H226, NCI-H526 or NCI-H82 in athmyic female nu/nu mice	Significant tumor growth regression	37.5–50 mg	continuous qd or qd × 4 weeks q6 weeks	Negative	[42, 86]
Sorafinib	oral	Multi-targeted RTK inhibitor (VEGF, CKit, PDGFα, cRET)	40–80 mg/kg	qd × 9 days	Phase III clinical trials for lung cancer	Xenograft-H460, A549, NCI-H23 cells in female NCr-nu/nu mice	Significant tumor growth regression	400 mg	bid	Negative	[33, 87]
Cetuximab	IV	Monoclonal antibody EGFR inhibitor	20 μL/g	q3 weeks	2008	Xenograft-A549, NCI-H358, HCC-827, H1975, H460 cells in female athmyic nu/nu mice	Significant tumor growth inhibition	250–400 mg/m^2	400 mg/m^2—; 250 mg/m^2 q weekly	Negative	[28, 88]