Nontoxic suramin treatments enhance docetaxel activity in chemotherapy-pretreated non-small cell lung xenograft tumors.
OBJECTIVE
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 microM 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.
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College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA.
Wientjes
Trini S-S
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Jessie L-S
JL
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001973:Bromodeoxyuridine / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage; D013498:Suramin / Q000008:administration & dosage / Q000494:pharmacology*; D043823:Taxoids / Q000008:administration & dosage; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D013498:Suramin; D016190:Carboplatin; D001973:Bromodeoxyuridine; D017239:Paclitaxel