Table 3.

Literature classifications.

Study type	Effect studied	Experimental model	Result
Biology
In vitro/in vivo	Development of a strategy to combat ophthalmic diseases with angiogenesis	Retinal cultures, explants and in vivo eye model	Analysis of angiogenesis inhibitors for the treatment of ophthalmic neo-vascular diseases, such as age-related macular degeneration and diabetic retinopathy
Computational chemistry	Screening for a novel class of broadly applicable drug candidates for the inhibition of RTKs	Computational chemistry	The solution of the three-dimensional co-crystal structure of FGF RTK with two of Sugen’s TK inhibitors
In vitro/in vivo	Tyrosine kinase inhibition, proliferation indexes endothelium tumor growth	Receptor phosphorylation in3T3 cells 3H-thymidine uptake by EC, tumor growth of A375, A431, Calu-6 C6, LNCAP, PH4-VEGF, 3T3HER2, 488G2m2, SF763T, and SF67T	IC50 = 1.04 μM, 100-fold less than other TRKs. Reduced 3H uptake. Reduced growth of tumors except for SF763T and SF67T
Synthesis chemistry	Synthesis and biological evaluation of RTK inhibitors	Synthesis chemistry	3-Subsituted indolin-2-ones exhibited selectivity toward particular RTKs
In vitro	Assessment of SU-5416 selectivity against Flk-1/KDR kinase	Human endothelial cells	SU-5416 was reported as a potent and selective Flk-1/KDR kinase inhibitor, which blockaded receptor auto-phosphorylation, endothelial cell mitogenesis, tumor growth, angiogenesis and micro-hemodynamics
In vitro/in vivo	Assessment of SU-5416 potency against a broader range of RTK kinases	HUVECs and mice transplant	The derivative 3,5-dimethyl pyrrole-analog was found to be the superior compound, with an IC50 = 40 nM. SU-5416 was also highly selective for Flk-1/KDR, being essentially inactive at other RTKs. This compound dramatically inhibited tumor size and neo-vascularization with a broader anti-tumor spectrum: i.p. administration blockaded eight out of ten different cell lines grown subcutaneously. Although the plasma half-life was short (30 min), the half-life for activity against Flk-1 was about 20 h, ostensibly due to the lipophilicity of the compound
In vivo	Assessment of subcutaneous tumor growth of cells derived from various tissues	Mice	Systemic administration of SU-5416 at non-toxic doses (25 mg/kg/day) resulted in the inhibition of subcutaneous tumor growth of cells derived from various tissue origins. The anti-tumor effect of SU-5416 was accompanied by the appearance of pale white tumors that were resected from drug-treated animals
In vitro/in vivo	Evaluation of the biochemical and biological functions of SU-5416 and other RTK inhibitors	C-KIT	SU-5416 and SU-6668 inhibited the biochemical and biological functions of C-KIT (IC50 = 0.1–1 μM)
In vivo	Evaluation of SU-5416 possible inhibition of Flt-1 receptor	Mice and rats	SU-5416 inhibited the TK VEGF receptor, Flt-1. SU-5416 and SU-6668 exhibited comparative differences in toxicity profile following intravenous administration
Metabolism
In vitro	Analysis of VEGF-stimulated thymidine uptake	Cultured human endothelial cells (HUVECs)	SU-5416 inhibited VEGF-stimulated thymidine uptake at 0.1 μM, whereas FGF-1-mediated thymidine uptake was inhibited only at a concentration of 10 μM
In vivo	Determination of toxicity metabolism and elimination	Patients with advanced malignances	SU-5416 in a dose-escalating trial exhibited mild toxicity, and the elimination t½ was approximately 50 min
In vivo	Assessment of SU-5416 half-life and prolonged effects	Mice and human tumor xenograft models	SU-5416 exhibited a short plasma half-life, but prolonged in vivo effects. This compound inhibited VEGF-dependent KDR phosphorylation by blockading subcellular localization
In vitro/in vivo	To investigate the metabolism of SU-5416 and its major metabolites by HPLC	Mouse, rat, dog, monkey and human liver microsomes	Microsomes, incubated with SU-5416 (25 μM) in the presence of NADPH-generating system, showed the compound’s conversion to at least 6 polar metabolites, where the overall rate of metabolism followed the rank monkey ⩾ mouse≈ rat > dog > human
In vivo	The effect of a combination of SU-5416 and fluorouracil/leucovorin on the progression of colon cancer	Patients with untreated metastatic colon cancer	SU-5416 (85 or 145 mg/m2) exhibited as response rate of 36% with as time to progression of 9 months, a time to failure of 8.5 months and a median survival time of 22.5 months

Clinical
Initiation of clinical trials with Flk-1 TK angiogenesis inhibitors	Patients with solid tumor cancers	The safety and efficacy of the company’s lead compound, SU-5416, were established
Initiation of phase I angiogenesis inhibitor study	Patients with solid tumors and tumor metastasis	The initiation of this study represented the first time a small-molecule inhibitor targeting the angiogenic mechanism has been administered in humans. This was carried out to assess the safety and dosage range of SU-5416, which was administered intravenously on a twice-weekly schedule. SU-5416 has been well tolerated at a dose of 4.4 to 65 mg/m2. The drug exhibited only mild toxicity, and the elimination t½ was approximately 50 min. In four out of five patients experiencing tumor stabilization, a decrease in tumor permeability and leakiness was demonstrated
Initiation of phase I/II clinical trial in Kaposi’s sarcoma	Patients (n = 30) with AIDS-related Kaposi’s sarcoma	The study endpoints, carried out at five US medical centers specializing in AIDS-related malignancies, included measurement of objective response and time-to-disease progression in addition to safety and pharmacokinetic parameters
Initiation of registrational studies with SU-5416	Patients with Kaposi’s sarcoma, colorectal and basal cell cancer	Of the patients who remained in the study evaluating various doses, the majority exhibited well tolerance with mild negative repercussion. Expected side effects included nausea, vomiting, headache and transient increase in liver transaminases. Most patients showed stable disease for a prolonged period of time
Initiation of multiple phase II and I/II studies	Patients with solid tumors (including renal, head and neck, sarcoma, and prostate cancers) (n = 500–700) in approximately 20 leading cancer centers in the USA	The trials planned to test SU-5416 as either a single agent or in combination with other drugs in a variety of cancer indications
Entrance of SU-5416 into phase II/III trials	Patients with AIDS-related Kaposi’s sarcoma, colorectal and non-small cell lung cancer	The study offered multiple information of the drug’s potency, safety and efficacy
Phase II trial in combination with paclitaxel	Patients with angiosarcoma and cervical cancer	SU-5416 in combination with standard-dose paclitaxel (175 mg/m2, q3w) showed the regimen is tolerated, with no effect on paclitaxel pharmacokinetics
Phase I/II study in combination with 5-fluorouracil and leucovorin	Patients with metastatic colorectal cancer	Patients were found to be free of tumor growth and spread for a median time of 9.2 months