Low-Dose Suramin Enhanced Paclitaxel Activity in Chemotherapy-Naïve and Paclitaxel-Pretreated Human Breast Xenograft Tumors

Abstract

We reported induction of broad-spectrum chemoresistance by acidic and basic fibroblast growth factors and chemosensitization by their nonspecific inhibitor suramin at nontoxic and subtherapeutic doses. This study evaluated whether low-dose suramin enhances paclitaxel activity in chemotherapy-naïve and paclitaxel-pretreated human MCF7 breast xenograft tumors in mice. Suramin, 10 mg/kg, and/or paclitaxel, 15 mg/kg, were administered intravenously, twice weekly for 2 to 3 weeks. In addition to conventional end points [tumor size change, median survival time (MST)], we also used clinically relevant end points [partial (PR) and complete response rates (CR); progressive disease (PD); stable disease (SD); time to tumor progression (TTP)]. In chemotherapynaïve mice, the control and suramin groups showed identical TTP (3 days) and MST (21 days). Single-agent paclitaxel produced 47% PR and 24% CR, and prolonged both TTP and MST to 73 days. The addition of suramin further improved the total response rate to 100% with a dramatically greater 63% CR, shortened the time to attain PR and CR, and prolonged TTP and MST to >136 days. In the paclitaxel-pretreated group, single-agent paclitaxel resulted in 67% SD and 33% PD, whereas the combination produced 50% PR and 50% SD. Suramin also significantly enhanced the apoptotic effect of paclitaxel in tumors. In conclusion, suramin improved the activity of paclitaxel in both chemotherapy-naïve and paclitaxel-pretreated animals, without enhancing host toxicity (<10% body weight loss in all groups). These data have led to the initiation of phase I/II trials of paclitaxel and low-dose suramin combination in advanced metastatic breast cancer patients.

Pathophysiologic Effects of Vascular-Targeting Agents and the Implications for Combination with Conventional Therapies

“…The combination of AIAs and chemotherapy can increase apoptosis. This has been seen in tumors in vivo (167)(168)(169)(170)(171)(172)(173)(174)(175) as well as with tumor and endothelial cells in vitro (72,176,177); this latter effect probably explains the decrease in MVD seen after such combination therapy (72,165,167,172,174,(178)(179)(180). A decrease in MVD might be expected to decrease drug delivery, and in fact, two studies have shown that treatment with TNP-470 can reduce the uptake of temozolomide in rat glioma models (181,182).…”

Intravital Microscopic Characterization of Suramin Effects in an Orthotopic Immunocompetent Rat Model of Pancreatic Cancer

“…The ability of suramin to decrease proliferation rates in vitro has been demonstrated in several types of cancer cells, including cells derived from stomach cancer, esophageal cancer, breast cancer, and nonsmall-cell lung cancer. [21][22][23][24] The anti-angiogenic effect of suramin has been analyzed both in vitro and in vivo and documented in the chick chorioallantoic membrane assay and in a bFGF-induced model with gel sponges subcutaneously implanted in mice. 25,26 Our group showed recently the inhibitory effect of suramin on tumor growth, metastasis, and angiogenesis in a orthotopic nude mouse model of pancreatic cancer.…”

Nontoxic Suramin as a Chemosensitizer in Patients: Dosing Nomogram Development

“…We reported that suramin, at a dose that delivers plasma concentration between 10 and 50 mM, significantly enhances the therapeutic efficacy of chemotherapy (doxorubicin, paclitaxel, docetaxel, mitomycin) against well-established subcutaneous or metastatic human xenograft tumors (breast, prostate, bladder) in immunodeficient mice, without enhancing the host toxicity (1Y3, 18,19). We further found that this chemosensitizing effect of suramin was diminished at higher doses/ concentrations (20), presumably due to cell cycle perturbations.…”