|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.02.2194 on November 28 2005 © 2006 American Society of Clinical Oncology. Safety, Pharmacokinetic, and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients With CancerFrom the Department of Medicine, Gustave-Roussy Institute, Villejuif, France; and SU11248 Working Group, Pfizer Co, Rome, Italy and New York, NY Address reprint requests to Eric Raymond, MD, PhD, Head of the Department of Medical Oncology, Beaujon University Hospital, 100 Boulevard du Général Leclerc, Clichy, France; e-mail: eric.raymond{at}bjn.aphp.fr
PURPOSE: To establish the safety, pharmacokinetics, and recommended dose of sunitinib, a novel oral multitargeting tyrosine kinase inhibitor with antiangiogenic and antitumor properties, in patients with advanced malignancies. PATIENTS AND METHODS: Sunitinib was given orally for 4 weeks every 6 weeks.
RESULTS: Twenty-eight patients received doses ranging from 15 to 59 mg/m2 (ranging from 50 mg every other day to 150 mg/d). Dose-limiting toxicities reported at the maximum-tolerated doses CONCLUSION: At the dose of 50 mg/d (4 weeks on, 2 weeks off), sunitinib displays manageable toxicity. Antitumor activity supports further studies in patients with renal cell carcinoma, gastrointestinal, neuroendocrine, and stromal tumors. Future studies may consider including prospective imaging techniques such as high frequency ultrasound to monitor tumor density.
Tyrosine kinase receptors, including platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptors, and vascular endothelial growth factor receptors (VEGFRs) and their ligands, have been shown to play important roles in tumor growth and angiogenesis.1 Inhibition of VEGF signaling through the use of antibodies2-4 or VEGFR antagonists has demonstrated potent antitumor effects that might be used to circumvent resistance to classical anticancer agents.5-7 Recently, the humanized anti-VEGF monoclonal bevacizumab antibody in combination with chemotherapy was associated with an increased survival in patients with advanced colon cancer.8
Sunitinib (sunitinib malate; SU11248; SUTENT; Pfizer Inc, New York, NY; Fig 1) is a novel oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Sunitinib has been identified as a potent inhibitor of VEGFR-1, VEGFR-2, fetal liver tyrosine kinase receptor 3 (FLT3), KIT (stem-cell factor [SCF] receptor), PDGFR
In vitro metabolism studies demonstrated that sunitinib was primarily metabolized by cytochrome CYP3A4, resulting in formation of a major, pharmacologically active N-desethyl metabolite, SU012662. This metabolite was shown to be equipotent to the parent compound in biochemical tyrosine kinase and cellular proliferation assays, acting toward VEGFR, PDGFR, and KIT.15 SU012662 was the major plasma metabolite in mice, rats, and monkeys in vivo. SU012487 (an N-oxide metabolite) was the major metabolite in dog but was infrequently observed in human. Radiolabeled orally administrated sunitinib in preclinical species was primarily excreted in the feces (rat, > 71%; monkey, > 84%; investigator brochure). Pharmacokinetic/pharmacodynamic data from animal studies showed that target plasma concentrations of sunitinib plus SU012662 capable of inhibiting PDGFR-ß and VEGFR-2 phosphorylation were established in the range of 50 to 100 ng/mL.9-12 Interestingly, those data were consistent with those observed in patients with acute myeloid leukemia in whom exposure to sunitinib led to a sustained inhibition of FLT3 phosphorylation in blast cells.16 Although initial studies were planned to provide continuous administration, the 4-week-on, 2-week-off schedule was selected at the request of the health authorities to allow patients to recover from potential bone marrow and adrenal toxicity observed in animal models. On the basis of the promising preclinical antitumor activity, safety data in animals, and early results in phase I clinical trial in patients with acute myeloid leukemia,17 this phase I dose-escalation study was undertaken to determine the recommended dose, tolerability, basic pharmacokinetics, and antitumor effects of sunitinib given orally daily for 4-week-on, 2-week-off schedule in patients with advanced solid malignancies.
Eligibility Criteria Patients with histologically proven advanced solid malignancy for which no other therapy was possible, with an Eastern Cooperative Oncology Group performance status  2, were included in the study. Eligible patients were women (postmenopausal, surgically sterile, or using effective contraception) or men  18 years of age with adequate bone marrow, liver, and renal function (hemoglobin level 10 g/dL, absolute neutrophil count 1.5 x 109/L, platelet count 75 x 109/L, serum transaminases < 2.5 times the upper limit of normal [ULN], bilirubin < 1.5 x ULN, serum creatinine < 1.5 x ULN, or creatinine clearance > 40 mL/min). Patients were not eligible if they had failed to recover from toxicity of previous chemotherapy, radiotherapy, or immunotherapy or had received any anticancer agent within 4 weeks, including investigational agents, chemotherapy (within 6 weeks for nitrosoureas or mitomycin), immunotherapy, biologic or hormonal therapy, or surgery. Other exclusion criteria included a history of any malignancy other than in situ carcinoma of the cervix or basal-cell carcinoma of the skin, known CNS metastases, or prior cardiovascular disease or diabetes mellitus. Written informed consent was obtained from all patients, and approval from our institutional review boards was obtained.
Pretreatment and Follow-Up Examinations
Drug Administration
Dose Escalation Procedure
Doses were escalated based on occurrence of DLT at cycle 1. If no DLT was seen in three patients during the first cycle, the dose was increased to the next level. If DLT was observed during the first cycle in one patient at any dose level, three additional patients were recruited to that dose level for a total of six patients, with dose escalation proceeding if Treatment could not be delayed for more than 2 weeks for the patient to recover from toxicities. Dose reduction to the next lower dose level was allowed in response to unacceptable toxicity if the patient exhibited evidence of clinical benefit. If unacceptable toxicity occurred after this dose reduction, treatment was stopped.
Bioanalytical Method Blood samples for determination of plasma levels of VEGF and soluble VEGFR were collected predose and 6 hours postdose on day 1 and 28. Samples were centrifuged (3,500 rpm for 5 minutes) and plasma was isolated and frozen at –20°C until analysis. VEGF/soluble VEGFR concentrations were determined by enzyme-linked immunosorbent assay according to the manufacturer's instructions (R&D Systems, Minneapolis, MN). Analysis was performed using two ways of analysis of variance (SAS, SAS Institute, Cary, NC).
Pharmacokinetic Analyses
General Twenty-eight patients were enrolled between June 2001 and September 2003 (Table 1). Twenty-seven patients received at least 4 weeks of sunitinib treatment and were assessable for toxicity (one patient was included but was not considered assessable because of an early tumor progression).
No DLT was observed at starting doses of 30 mg/m2 every other day, which corresponded to 50 or 100 mg every other day (three patients; Table 2). Among the first three patients treated at the second dose-level of 50 mg/d, one patient developed grade 3 edema of the limbs and face. Because the three additional patients who were therefore enrolled did not develop DLT, dose escalation proceeded to 75 to 100 mg/d. None of those three patients receiving 75 mg/d experienced DLTs during cycle 1, and dose escalation proceeded to 100 to 150 mg/d. At this later dose, reversible grade 3 hypertension was observed in one patient and grade 3 asthenia was reported in the other two patients (one patient receiving 100 mg/d and another 150 mg/d). Therefore, the MTD had been exceeded, and nine additional patients were enrolled at the dose of 75 mg/d. Five of 12 patients treated at 75 to 100 mg/d (11 patients receiving a total of 75 mg/d and one patient receiving 100 mg/d) developed DLT at cycle 1 (grade 3 asthenia in three patients, grade 3 hypertension in one patient, and tumor necrosis in one patient [described herein]). Four of the patients receiving a total dose of 75 mg/d at cycle 1 were dose-reduced and treated at 50 mg/d without DLT. Because more than 33% of patients receiving 75 mg/d experienced DLTs at cycle 1, the next lower dose of 50 mg/d was further evaluated by entering three additional patients. Among a total of nine patients who received 50 mg/d, two patients developed DLT: grade 3 edema and grade 4 peripheral thrombocytopenia. Thrombocytopenia was associated with the presence of normal well-differentiated megacaryocytes in bone marrow aspiration, no activation of coagulation, and grade 2 hemolytic anemia with schizocytes, beta 2-microglobulin, and lactate dehydrogenase elevation, suggesting a microangiopathy.
Overall Safety After Repeated Cycles Grade 3 to 4 adverse events per patient and per cycle are summarized in Table 3. Asthenia was the most frequent grade 3 to 4 toxicity at doses 50 mg/d. Asthenia appeared progressively from grade 1 during the first 2 weeks and worsened slightly to grade 3 to 4 during weeks 3 and 4 of each cycle. It was associated with an increased length of rest period during daytime and sleepiness at night. Asthenia was fully reversible during the 2-week-off period of each cycle. Grade 3 to 4 asthenia occurred in six of 12 patients at 75 to 100 mg/d but was restricted to two of nine patients at the recommended dose of 50 mg/d. Age and performance status at study entry did not predict asthenia, and this event was not associated with neurologic symptoms or tumor progression. Grade 3 to 4 nausea and vomiting were infrequently reported.
Hypertension was observed in a total of five patients and required antihypertensive treatment (grade 3 to 4) in two patients treated at doses 75 mg/d. Hypertension usually occurred after 3 to 4 weeks of treatment. After normalization of blood pressure, antihypertensive therapy was maintained during the 2 weeks-off period with twice weekly monitoring. At the recommended dose of 50 mg/d, only one patient presented grade 1 to 2 elevated blood pressure. Careful cardiac monitoring occurred and no cardiac adverse event was reported. Hematologic toxicity, consisting mostly of thrombocytopenia and neutropenia, resolved during the 2 weeks off in most cases and recurred in subsequent cycles with the same dose.
Skin toxicity typically occurred after 3 to 4 weeks of treatment. Grade
Minor Skin Effects Yellow skin coloration appeared after 1 week of treatment in patients receiving 50 mg/d of sunitinib and increased in intensity at the highest doses. Transient skin coloration was associated with a yellow coloration of urine due to the excretion of the drug and metabolites.
Various degrees of hair depigmentation (gray coloration) occurred in 18 of 28 patients who received doses
Asymptomatic subungual splinter hemorrhages (consisting of a mass of blood in a layer of squamous cells adherent to the undersurface of the nail; Fig 4) were found in seven patients, associated with acral erythema in six patients.
Pharmacokinetic and Pharmacodynamic Analysis Pharmacokinetic parameters of sunitinib and its major metabolite SU012662 are summarized in Tables 4 and 5. Overall, sunitinib displayed a long half-life and a large volume of distribution with moderate interpatient variability. Trough plasma concentrations of sunitinib and SU012662 increased with increasing dose (Fig 5A). However, AUC values increased less than proportionally with doses. Accumulation ratios of sunitinib were greater than one with detectable trough drug levels, suggesting drug accumulation over time. At the recommended dose, the maximum plasma concentration occurred approximately 5 hours after administration and half-life ranged from 41 to 86 hours. Doses of 50 mg/d led to plasma concentration ranging from 50 to 100 ng/mL. Most patients with DLT had combined (sunitinib plus SU012662) trough plasma concentrations 100 ng/mL (Fig 5B).
To assess the need for dosing based on BSA, a simulation was performed in which observed values for AUC sum based on the 30, 42, and 59 mg/m2/d doses were adjusted to reflect fixed doses of sunitinib of 50, 75 to 100, and 100 to 150 mg, respectively. Simulated AUC sum values were approximated based on the actual AUC sum and the actual dose (in milligrams) each patient received during cycle 1. The degrees of variability between BSA-normalized and fixed dosing were comparable at days 1 and 28 for both sunitinib (R2 range, 0.002 to 0.12) and SU012662 (R2 range, 0.0004 to 0.085), and no or minimal improvement in variability would be expected from normalizing the dose based on BSA. VEGF concentrations increased slightly during the first month of treatment with sunitinib (Fig 6A). This was associated with a decrease in the mean sVEGFR-2 level in plasma in our trial (Fig 6B).
Antitumor Effects Among 22 assessable patients, sunitinib induced tumor shrinkage and tumor necrosis. As shown in Table 6, six patients had objective responses: four prolonged partial responses and two cases of more than 90% central tumor necrosis with viable cells in peripheral areas on postoperative pathologic specimens. Responses were observed in three patients with local and/or lung metastasis of renal cell carcinomas (lasting 28, 36, and 54 weeks), in one patient with bulky peritoneal recurrences of a neuroendocrine tumor (lasting 21 weeks) and in one patient with lung metastases of an adenocarcinoma of unknown primary, and one patient with a peritoneal recurrence of an imatinib mesylate resistant gastrointestinal stromal tumor (GIST; Fig 7). In addition, five patients (with renal cell carcinoma, cervical carcinoma, and a neuroendocrine tumor) developed long-lasting minor responses and tumor stabilization.
Six patients developed evidence of tumor necrosis that led to tumor cavitations in four patients with further development of fistula in two patients (local recurrences of a cervical and neuroendocrine tumor in irradiated areas), lethal peritoneal hemorrhage in one patient (peritoneal recurrence of GIST), and infection of necrotic area in the lung in another patient (lung metastasis of undifferentiated carcinoma of nasopharyngeal type). High-frequency ultrasound Doppler echography18 performed in these six patients revealed that intratumoral vessels progressively disappeared after 1 week of treatment, with an increase of necrosis in the central areas of tumors (Fig 8). Consistent with evidence of antitumor activity and necrosis, lactate dehydrogenase levels increased during cycle 1 in several patients.
Multitarget signaling inhibitors have recently been proposed as a new paradigm to enlarge the spectrum of activity of targeting agents. In this study, asthenia and hypertension were found to be the main DLTs of sunitinib at doses 75 mg/d. The occurrence of DLTs was associated with combined trough sunitinib/SU012662 plasma levels more than 100 ng/mL. Based on safety data from patients entered at the 50 mg/d dose level and those nine patients treated at higher doses and subsequently dose-reduced to 50 mg/d, this dose of 50 mg/d for 4 weeks every 6 weeks was recommended for further phase II trials. AUC sum values obtained using BSA-normalized and fixed dosing were found to be comparable, suggesting that normalizing the dose based on BSA would not improve variability. Fixed dosing on a milligram basis was therefore considered appropriate for phase II studies.
The adverse-event profile of sunitinib in our study was consistent with observations in other phase I trials in patients with acute myeloid leukemia and solid tumors exploring alternative schedules.16,17 Hypertension and asthenia have been observed with several other inhibitors of VEGF and VEGFRs.3,4,7 Other adverse events were skin toxicity, including dry skin, edema, and hand-foot syndromes with/without bullous lesions, observed only at doses
Reversible hair depigmentation was observed with sunitinib at
Although tumor evaluation was not the primary objective of this study, objective responses (four partial responses and two stable diseases with intratumoral necrosis) were observed at doses of sunitinib In this study, tumor necrosis could result in fistula formation, infection, eventually associated with lactate dehydrogenase elevation and rapid disappearance of intratumoral blood flow using ultrasound. Necrosis was also reported with bevacizumab treatment in patients with lung cancer.33 The necrosis induced by bevacizumab and sunitinib underlines the important role of VEGF/VEGFR signaling in the maintenance of tumor vasculature. Future studies may consider including prospective imaging techniques, such as high frequency ultrasound, to monitor tumor density. In conclusion, based on evidence of antitumor activity, phase II trials have been initiated in patients with renal cell carcinoma, neuroendocrine tumors, and GIST resistant to imatinib mesylate.34 Considering the good safety profile at the recommended dose, other schedules are currently being investigated using 2-week-on, 2-week-off, and continuous sunitinib administration.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank the nurses of the GARD unit for their contribution to the pharmacokinetic sampling of this study; and Siham Djelloul-Ceballos, William Sargent, and Marie-Pierre Chevalier from Pfizer Inc, for their critical reading of the manuscript.
S.F. and C.D. contributed equally to this work. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Kerbel R, Folkman J: Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727-739, 2002[CrossRef][Medline] 2. Ferrara N, Hillan KJ, Gerber HP, et al: Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391-400, 2004[CrossRef][Medline] 3. Willett CG, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145-147, 2004[CrossRef][Medline] 4. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003 5. Bergers G, Song S, Meyer-Morse N, et al: Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287-1295, 2003[CrossRef][Medline] 6. Shaheen RM, Tseng WW, Davis DW, et al: Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. Cancer Res 61:1464-1468, 2001 7. Ahmad T, Eisen T: Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin Cancer Res 10:6388S-6392S, 2004 8. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 9. Abrams TJ, Lee LB, Murray LJ, et al: SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2:471-478, 2003 10. Mendel DB, Laird AD, Xin X, et al: In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327-337, 2003 11. Murray LJ, Abrams TJ, Long KR, et al: SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 20:757-766, 2003[CrossRef][Medline] 12. Abrams TJ, Murray LJ, Pesenti E, et al: Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer. Mol Cancer Ther 2:1011-1021, 2003 13. Morimoto AM, Tan N, West K, et al: Gene expression profiling of human colon xenograft tumors following treatment with SU11248, a multitargeted tyrosine kinase inhibitor. Oncogene 23:1618-1626, 2004[CrossRef][Medline] 14. Yee KW, Schittenhelm M, O'Farrell AM, et al: Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3-ITD positive leukemic cells. Blood 104:4202-4209, 2004 15. Baratte S, Sarati S, Frigerio E, et al: Quantitation of SU11248, an oral multi-target tyrosine kinase inhibitor, and its metabolite in monkey tissues by liquid chromatograph with tandem mass spectrometry following semi-automated liquid-liquid extraction. J Chromatogr A 1024:87-94, 2004[Medline] 16. O'Farrell AM, Foran JM, Fiedler W, et al: An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res 9:5465-5476, 2003 17. Fiedler W, Serve H, Dohner H, et al: A phase I study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 105:986-993, 2004[Medline] 18. Rouffiac V, Bouquet C, Lassau N, et al: Validation of a new method for quantifying in vivo murine tumor necrosis by sonography. Invest Radiol 39:350-356, 2004[CrossRef][Medline] 19. Robert C, Faivre S, Raymond E, et al: Subungual splinter hemorrhages: A clinical window to inhibition of vascular endothelial growth factor receptors? Ann Intern Med 143:313-314, 2005 20. Osusky KL, Hallahan DE, Fu A, et al: The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effects on existing tumor vessels. Angiogenesis 7:225-233, 2004[CrossRef][Medline] 21. Marx GM, Steer CB, Harper P, et al: Unexpected serious toxicity with chemotherapy and antiangiogenic combinations: Time to take stock! J Clin Oncol 20:1446-1448, 2002 22. Kuenen BC, Levi M, Meijers JC, et al: Potential role of platelets in endothelial damage observed during treatment with cisplatin, gemcitabine, and the angiogenesis inhibitor SU5416. J Clin Oncol 21:2192-2198, 2003 23. Kitamura R, Tsukamoto K, Harada K, et al: Mechanisms underlying the dysfunction of melanocytes in vitiligo epidermis: Role of SCF/KIT protein interactions and the downstream effector, MITF-M. J Pathol 202:463-475, 2004[CrossRef][Medline] 24. Hemesath TJ, Price ER, Takemoto C, et al: MAP kinase links the transcription factor Microphthalmia to c-Kit signaling in melanocytes. Nature 391:298-301, 1998[CrossRef][Medline] 25. Botchkareva NV, Khlgatian M, Longley BJ, et al: SCF/c-kit signaling is required for cyclic regeneration of the hair pigmentation unit. FASEB J 15:645-658, 2001 26. Tsao AS, Kantarjian H, Cortes J, et al: Imatinib mesylate causes hypopigmentation in the skin. Cancer 98:2483-2487, 2003[CrossRef][Medline] 27. Etienne G, Cony-Makhoul P, Mahon FX: Imatinib mesylate and gray hair. N Engl J Med 347:446, 2002[Medline] 28. Schueneman AJ, Himmelfarb E, Geng L, et al: Hair depigmentation is a biological readout for pharmacological inhibition of KIT in mice and humans. J Pharmacol Exp Ther 307:476-480, 2003 29. Robert C, Spatz A, Faivre S, et al: Tyrosine kinase inhibition and grey hair. Lancet 361:1056, 2003[Medline] 30. Stroobants S, Goeminne J, Seegers M, et al: 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer 39:2012-2020, 2003[CrossRef][Medline] 31. Demetri GD, George S, Heinrich MC, et al: Clinical activity and tolerability of the multi-targeted tyrosine kinase inhibitor SU11248 in patients (pts) with metastatic gastrointestinal stromal tumor (GIST) refractory to imatinib mesylate. Proc Am Soc Clin Oncol 22:814, 2003 (abstr 3273) 32. Toner GC, Mitchell PL, De Boer R, et al: PET imaging study of SU11248 in patients with advanced malignancies. Proc Am Soc Clin Oncol 22:191, 2003 (abstr 767) 33. Johnson DH, Fehrenbacher L, Novotny WF, et al: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:2184-2191, 2004 34. Demetri GD, Desai J, Fletcher JA, et al: SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST). J Clin Oncol 22:3001, 2004 (July 15 suppl) Submitted April 4, 2005; accepted September 22, 2005. Related Editorial
This article has been cited by other articles:
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
, and PDGFRß in both biochemical and cellular assays.
