Purpose
We reported that nontoxic suramin treatments enhance the activity of chemotherapy in preclinical models, a finding supported by the results of subsequent phase I/II trials in chemotherapy-naive non-small cell lung cancer (NSCLC) patients who received/carboplatin (P/C) combination therapy. The present study evaluated whether suramin enhances the activity of docetaxel in human NSCLC xenografts.
Methods
The in vitro effect of suramin on docetaxel activity was evaluated using 3-D histocultures of chemotherapy-naive A549 tumors. For in vivo activity evaluation, we first established the P/C pretreatment schedule that produced tumor growth inhibition, but not tumor eradication, and established the maximally tolerated docetaxel/suramin regimens. In the second study, P/C-treated animals received physiological saline, single-agent suramin (10 mg/kg), docetaxel (10 mg/kg), or the combination twice weekly for 3 weeks.
Results
The in vitro results showed that 20 μM suramin, which had no activity as single agent, enhanced the docetaxel activity (measured as 50% inhibition of DNA synthesis) by more than 10-fold. The in vivo studies showed reduced tumor growth by P/C (30% growth in 14 days vs. 75% in control). In contrast, docetaxel produced tumor regression (15% reduction) in P/C-treated animals, significantly reduced, on a cellular level, the viable cell density and the proliferating fraction (40% reduction for both measurements), and enhanced the apoptotic fraction 4-fold (p < 0.05 for all effects). Suramin had no activity or toxicity (measured as body weight loss) but significantly enhanced the docetaxel activity. Compared to docetaxel alone, the combination showed earlier onset of tumor size reduction, greater extent of tumor regression (31 vs. 15%), greater reduction of viable cell density and proliferating fraction (additional 15–25% reduction), and greater apoptotic fraction (additional 2.5-fold increase) (p < 0.05 for all parameters).
Conclusions
Results of the present study indicate that nontoxic suramin treatments enhanced the activity of docetaxel in P/C-pretreated A549 xenograft tumors in mice without enhancing host toxicity. These encouraging results provided the basis for phase I/II trials of docetaxel plus low-dose suramin in patients with NSCLC in second-/third-line settings.
Similar content being viewed by others
Abbreviations
- aFGF:
-
acidic fibroblast growth factor
- bFGF:
-
basic fibroblast growth factor
- BrdU:
-
bromodeoxyuridine
- IC50:
-
concentration producing 50% inhibition of DNA precursor
- NSCLC:
-
non-small cell lung cancer
- P/C:
-
paclitaxel/carboplatin
References
S. Song M. G. Wientjes Y. Gan J. L. Au (2000) ArticleTitleFibroblast growth factors: an epigenetic mechanism of broad spectrum resistance toanticancer drugs Proc. Natl. Acad. Sci. USA 97 8658–8663
C. Betscholtz A. Johnsson C.-H. Heldin B. Westermark (1986) ArticleTitleEfficient reversion of simian sarcoma virus-transformation and inhibition of growth factor-induced mitogenesis by suramin Proc. Natl. Acad. Sci. USA 83 6440–6444
R. J. Coffey A. S. Goustin A. M. Soderquist G. D. Shipley J. Wolfshohl G. Carpenter H. L. Moses (1987) ArticleTitleTransforming growth factor alpha and beta expression in human colon cancer lines: implications for an autocrine model Cancer Res. 47 4590–4594
J. S. Garrett S. R. Coughlin H. L. Niman P. M. Tremble G. M. Giels L. T. Williams (1984) ArticleTitleBlockade of autocrine stimulation in simian sarcoma virus transformed cells reverses down-regulation of platelet-derived growth factor receptors Proc. Natl. Acad. Sci. USA 81 7466–7470
M. Hosang (1985) ArticleTitleSuramin binds to platelet-derived growth factor and inhibits its biological activity J. Cell. Biochem. 29 265–273
C. E. Myers R. LaRocca C. Stein M. Cooper N. Dawson P. Choyke M. Linehan M. Urich (1990) ArticleTitleTreatment of hormonally refractory prostate cancer with suramin Proc. Am. Soc. Clin. Oncol. 9 113
M. Pollak M. Richard (1990) ArticleTitleSuramin blockade of insulinlike growth factor I-Stimulated proliferation of human osteosarcoma cells J. Natl. Cancer Inst. 82 1349–1352
L. T. Williams P. M. Tremble M. F. Lavin M. E. Sunday (1984) ArticleTitlePlatelet-derived growth factor receptors form a high affinity state in membrane preparations. Kinetics and affinity cross-linking studies J. Biol. Chem. 259 5287–5294
A. Ogden, S.-H. Song, M. G. Wientjes, and J. L. S. Au. Nontoxic doses of suramin enhance the activity of gemcitabine and paclitaxel in human pancreatic tumors. Proc. Am. Assoc. Cancer Res. 45 [Abstract #2148] (2003).
S. Song M. G. Wientjes C. Walsh J. L. Au (2001) ArticleTitleNontoxic doses of suramin enhance activity of paclitaxel against lung metastases Cancer Res. 61 6145–6150
Y. Xin, D. Chen, S. Song, G. Lyness, M. G. Wientjes, and J. L. S. Au. Low-dose suramin enhances antitumor activity of mitomycin C in bladder tumors. Proc. Am. Assoc. Cancer Res. 45: (2003).
B. Yu, S.-H. Song, M. G. Wientjes, and J. L. S. Au. Suramin enhances activity of CPT-11 in human colorectal xenograft tumors. Proc. Am. Assoc. Cancer Res. 44:174 (2003).
Y. Zhang S.-H. Song J. L. S. Au M. G. Wientjes (2001) ArticleTitleNontoxic doses of suramin enhances activity of doxorubicin in prostate tumors J. Pharmacol. Exp. Ther. 299 426–433
G. Lyness, S. Jang, Y. Gan, Y. Zhang, M. G. Wientjes, J. L. S. Au. Fibroblast growth factors and chemoresistance in renal cell carcinomas. Proc. Am. Assoc. Cancer Res. 43:953 (2002).
M. A. Villalona-Calero G. A. Otterson M. G. Wientjes A. Murgo R. Jensen T.-K. Yeh D. Chen S. Song M. Grever J. L. S. Au (2003) ArticleTitlePhase II evaluation of low dose suramin as a modulator of paclitaxel/carboplatin (P/C) in non-small cell lung cancer (NSCLC) patients Lung Cancer 41 IssueIDS2 149
M. A. Villalona-Calero M. G. Wientjes G. A. Otterson S. Kanter D. Young A. Murgo B. Fischer C. DeHoff D. Chen S.-H. Song J. L. S. Au (2003) ArticleTitlePhase I study of low-dose suramin as a chemosensitizer in patients with advanced non-small lung cancer Clin. Cancer Res. 9 3303–3311
D. H. Johnson L. Fehrenbacher W. F. Novotny R. S. Herbst J.J. Nemunaitis D. M. Jablons C. J. Langer R. F. DeVore SuffixIII J. Gaudreault L. A. Damico E. Holmgren F. Kabbinavar (2004) ArticleTitleRandomized 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
J. H. Schiller D. Harrington C. P. Belani C. Langer A. Sandler J. Krook J. Zhu D. H. Johnson (2002) ArticleTitleComparison of four chemotherapy regimens for advanced non-small-cell lung cancer N. Engl. J. Med. 346 92–98
F. V. Fossella J. S. Lee W. K. Hong (1997) ArticleTitleManagement strategies for recurrent non-small cell lung cancer Semin. Oncol. 24 455–462
F. V. Fossella R. DeVore R. N. Kerr J. Crawford R. R. Natale F. Dunphy L. Kalman V. Miller J. S. Lee M. Moore D. Gandara D. Karp E. Vokes M. Kris Y. Kim F. Gamza L. Hammershaimb (2000) ArticleTitleRandomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group J. Clin. Oncol. 18 2354–2362
M. H. Cohen G. A. Williams R. Sridhara G. Chen W. D. McGuinn SuffixJr. D. Morse S. Abraham A. Rahman C. Liang R. Lostritto A. Baird R. Pazdur (2004) ArticleTitleUnited States Food and Drug Administration drug approval summary: gefitinib (ZD1839; Iressa) tablets Clin. Cancer Res. 10 1212–1218
J. G. Paez P. A. Janne J. C. Lee S. Tracy H. Greulich S. Gabriel P. Herman F. J. Kaye N. Lindeman T. J. Boggon K. Naoki H. Sasaki Y. Fujii M. J. Eck W. R. Sellers B. E. Johnson M. Meyerson (2004) ArticleTitleEGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy Science 304 1497–1500
N. Hanna F. A. Shepherd F. V. Fossella J. R. Pereira F. Marinis ParticleDe J. Pawel Particlevon U. Gatzemeier T. C. Tsao M. Pless T. Muller H. L. Lim C. Desch K. Szondy R. Gervais Shaharyar C. Manegold S. Paul P. Paoletti L. Einhorn P. A. Jr. SuffixJr. (2004) ArticleTitleRandomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy J. Clin. Oncol. 22 1589–1597
Y. Gan M. G. Wientjes R. A. Badalament J. L. S. Au (1996) ArticleTitlePharmacodynamics of doxorubicin in human bladder tumors Clin. Cancer Res. 2 1275–1283
Y. Gan M. G. Wientjes D. E. Schuller J. L. S. Au (1996) ArticleTitlePharmacodynamics of taxol in human head and neck tumors Cancer Res. 56 2086–2093
F. Elferink W. J. Vijgh Particlevan der I. Klein W. W. Bokkel Huinink R. Dubbelman J. G. McVie (1988) ArticleTitlePharmacokinetics of carboplatin after intraperitoneal administration Cancer Chemother. Pharmacol. 21 57–60
N. Tinker B. Spiegeleer ParticleDe H. Sharma H. Jackson C. McAuliffe J. P. Reman (1990) ArticleTitleThe tissue distribution in rats of [195mPt]carboplatin following intravenous, intraperitoneal and oral administration Int. J. Radiat. Appl. Instrum., B 17 427–436
R. Gold M. Schmied G. Giegerich H. Breitschopf H. P. Hartung K. V. Toyka H. Lassmann (1994) ArticleTitleDifferentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation techniques Lab. Invest. 71 219–225
B. Gu D. Wu H. Lu M. Li H. Gao Y. Wan (2001) ArticleTitlePotentiation of docetaxel antitumor activity by batimastat against mouse forestomach carcinoma Chin. Med. Sci. J. 16 223–226
U. Vanhoefer S. Cao A. Harstrick S. Seeber Y. M. Rustum (1997) ArticleTitleComparative antitumor efficacy of docetaxel and paclitaxel in nude mice bearing human tumor xenografts that overexpress the multidrug resistance protein (MRP) Ann. Oncol. 8 1221–1228
F. V. Fossella (1999) ArticleTitleDocetaxel in the treatment of non-small cell lung cancer: review of single-agent trials Semin. Oncol. 26 17–23
R. M. Hoffman (1991) ArticleTitleThree-dimensional histoculture: origins and applications in cancer research Cancer Cells 3 86–92
F. Fossella J. R. Pereira J. Pawel Particlevon A. Pluzanska V. Gorbounova E. Kaukel K. V. Mattson R. Ramlau A. Szczesna P. Fidias M. Millward C. P. Belani (2003) ArticleTitleRandomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group J. Clin. Oncol. 21 3016–3024
J. R. Rigas (2004) ArticleTitleTaxane-platinum combinations in advanced non-small cell lung cancer: a review Oncologist 9 IssueIDSuppl. 2 :16–23
V. Roa A. Conner R. B. Mitchell (1998) ArticleTitleCarboplatin and paclitaxel for previously treated patients with non-small-cell lung cancer Cancer Investig. 16 381–384
C. P. Belani (1998) ArticleTitleSingle agents in the second-line treatment of non-small cell lung cancer Semin. Oncol. 25 10–14
S. Sato J. Kigawa Y. Kanamori H. Itamochi T. Oishi M. Shimada T. Iba J. Naniwa K. Uegaki N. Terakawa (2004) ArticleTitleActivity of docetaxel in paclitaxel-resistant ovarian cancer cells Cancer Chemother. Pharmacol. 53 247–252
L. M. Witters S. M. Santala L. Engle V. Chinchilli A. Lipton (2003) ArticleTitleDecreased response to paclitaxel versus docetaxel in HER-2/neu transfected human breast cancer cells Am. J. Clin. Oncol. 26 50–54
C. A. Stein R. V. LaRocca R. Thomas N. McAtee C. E. Myers (1989) ArticleTitleSuramin: an anticancer drug with a unique mechanism of action J. Clin. Oncol. 7 499–508
A. Falcone A. Antonuzzo R. Danesi G. Allegrini L. Monica E. Pfanner G. Masi S. Ricci M. Tacca ParticleDel P. F. Conte (1999) ArticleTitleSuramin in combination with weekly epirubicin for patients with advanced hormone-refractory prostate carcinoma Cancer 86 470–476
P. J. Rosen E. F. Mendoza E. M. Landaw B. Mondino M. D. Graves J. H. McBride P. Turcillo J. deKernion A. Belldegrun (1996) ArticleTitleSuramin in hormone-refractory metastatic prostate cancer: a drug with limited efficacy J. Clin. Oncol. 14 1626–1636
M. R. Mirza E. Jakobsen P. Pfeiffer B. Lindebjerg-Clasen J. Bergh C. Rose (1997) ArticleTitleSuramin in non-small cell lung cancer and advanced breast cancer. Two parallel phase II studies Acta Oncol. 36 171–174
A. Falcone E. Pfanner I. Brunetti G. Allegrini M. Lencioni C. Galli G. Masi R. Danesi A. Antonuzzo M. Tacca ParticleDel P. F. Conte (1998) ArticleTitleSuramin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in metastatic colorectal cancer patients resistant to 5-FU+LV-based chemotherapy Tumori 84 666–668
M. Hussain E. I. Fisher D. P. Petrylak J. O’Connor D. P. Wood E. J. Small M. A. Eisenberger E. D. Crawford (2000) ArticleTitleAndrogen deprivation and four courses of fixed-schedule suramin treatment in patients with newly diagnosed metastatic prostate cancer: A Southwest Oncology Group study J. Clin. Oncol. 18 1043–1049
L. Miglietta L. Canobbio C. Granetto M. Vannozzi M. Esposito F. Boccardo (1997) ArticleTitle. Suramin/epidoxorubicin association in hormone-refractory prostate cancer: preliminary results of apilot phase II study J. Cancer Res. Clin. Oncol. 123 407–410
R. J. Motzer E. Dmitrovsky W. H. Miller W. P. Tong D. F. Bajorin H. I. Scher G. J. Bosl (1993) ArticleTitleSuramin for germ cell tumors. In vitro growth inhibition and results of a phase II trial Cancer 72 3313–3317
B. L. Rapoport G. Falkson J. I. Raats M. Wet Particlede B. P. Lotz H. C. Potgieter (1993) ArticleTitleSuramin in combination with mitomycin C in hormone-resistant prostate cancer. A phase II clinical study Ann. Oncol. 4 567–573
R. Dreicer D. C. Smith R. D. Williams W. A. See (1999) ArticleTitlePhase II trial of suramin in patients with metastatic renal cell carcinoma Invest. New Drugs 17 183–189
S. P. Howard S. J. Park L. Hughes-Davies C. N. Coleman B. D. Price (1996) ArticleTitleSuramin increases p53 protein levels but does not activate the p53-dependent G1 checkpoint Clin. Cancer Res. 2 269–276
S. T. Palayoor E. A. Bump B. A. Teicher C. N. Coleman (1997) ArticleTitleApoptosis and clonogenic cell death in PC3 human prostate cancer cells after treatment with gamma radiation and suramin Radiat. Res. 148 105–114
L. Qiao J. G. Pizzolo M. R. Melamed (1994) ArticleTitleEffects of suramin on expression of proliferation associated nuclear antigens in DU-145 carcinoma cells Biochem. Biophys. Res. Commun. 201 581–588
Acknowledgments
This work was supported in part by research grant R01CA97067 from the National Cancer Institute, DHHS, and by a grant from Aventis Inc.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lu, Z., Wientjes, T.SS. & Au, J.LS. Nontoxic Suramin Treatments Enhance Docetaxel Activity in Chemotherapy-Pretreated Non-Small Cell Lung Xenograft Tumors. Pharm Res 22, 1069–1078 (2005). https://doi.org/10.1007/s11095-005-6038-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-005-6038-1