Increased Preclinical Efficacy of Irinotecan and Floxuridine Coencapsulated Inside Liposomes Is Associated With Tumor Delivery of Synergistic Drug Ratios

Abstract

Whether anticancer drug combinations act synergistically or antagonistically often depends on the ratio of the agents being combined. We show here that combinations of irinotecan and floxuridine exhibit drug ratio-dependent cytotoxicity in a broad panel of tumor cell lines in vitro where a 1:1 molar ratio consistently provided synergy and avoided antagonism. In vivo delivery of irinotecan and floxuridine coencapsulated inside liposomes at the synergistic 1:1 molar ratio (referred to as CPX-1) lead to greatly enhanced efficacy compared to the two drugs administered as a saline-based cocktail in a number of human xenograft and murine tumor models. When compared to liposomal irinotecan or liposomal floxuridine, the therapeutic activity of CPX-1 in vivo was not only superior to the individual liposomal agents, but the extent of tumor growth inhibition was greater than that predicted for combining the activities of the individual agents. In contrast, liposome delivery of irinotecan:floxuridine ratios shown to be antagonistic in vitro provided antitumor activity that was actually less than that achieved with liposomal irinotecan alone, indicative of in vivo antagonism. Synergistic antitumor activity observed for CPX-1 was associated with maintenance of the 1:1 irinotecan:floxuridine molar ratio in plasma and tumor tissue over 16-24 h. In contrast, injection of the drugs combined in saline resulted in irinotecan:floxuridine ratios that changed 10-fold within 1 h in plasma and sevenfold within 4 h in tumor tissue. These results indicate that substantial improvements in the efficacy of drug combinations may be achieved by maintaining in vitro-identified synergistic drug ratios after systemic administration using drug delivery vehicles.

Dual Carfilzomib and Doxorubicin–Loaded Liposomal Nanoparticles for Synergistic Efficacy in Multiple Myeloma

“…The acquisition of drug resistance by multiple myeloma cells often requires that a combination of two or more drugs be prescribed to effectively promote cell death by synergistically disrupting different cellular mechanisms necessary for growth and survival (1). Although two drugs can demonstrate synergy, they are usually only synergistic, or exhibit the greatest synergy, at specific drug-to-drug molar ratios (2)(3)(4). Although the two drugs may be administered at the optimal drug ratio for synergy, this does not ensure that this ratio will be maintained at the tumor site due to differences in injection schedules, pharmacokinetic properties, metabolism, and nonuniform biodistribution (5)(6)(7).…”

“…To evaluate the therapeutic potential of NP[carfþdox], subcutaneous NCI-H929 tumor-bearing SCID mice were randomized into treatment groups when tumors reached a volume of 50 mm 3 and were intravenously injected with PBS (control), carf þ dox, or NP[carfþdox] at a dose of 1 mg/kg carfilzomib þ 0.8 mg/kg doxorubicin equivalents (1.8 mg/kg total drug) on days 1, 2, 8, and 9. Our results demonstrated that NP[carfþdox] significantly inhibited tumor growth inhibition (Fig.…”

Combination Chemotherapy in Cancer: Principles, Evaluation and Drug Delivery Strategies

“…During the course of the experiment, concentration and duration of administered drug(s) can be tightly controlled and the inhibition of tumor cell growth can be easily measured (Mayer & Janoff, 2007;Harasym et al, 2007;Chou et al, 2006). For the last two decades, in vitro experimentation with tumor-derived cell lines has been the most important resource for investigating molecular mechanisms of cancer pathogenesis (Mitchell et al, 2000).…”

“…Ultimately, one can only determine whether a new combination provides a statistically significant increase in a specific end point such as response rate, time to progression or survival . Preclinical drug interaction studies allow a more rational design of clinical combination chemotherapy protocols, which are generally based on the empiric assumption that maximal efficacy will be achieved by co-administering each drug at their maximum tolerated doses (MTDs) (Mayer & Janoff, 2007;Harasym et al, 2007;Mayer et al, 2006). This "more-is-better" philosophy applied to anticancer combinations may result in higher toxicity with minimal therapeutic benefit due to concentration-dependent drug interactions (Mayer et al, 2006;Ramsey et al, 2005).…”

“…The fundamentals of combination chemotherapy development have remained largely unchanged over the last decades. The general principles have been to: i) use drugs with nonoverlapping toxicities so that each drug can be administered at near-maximal dose; ii) combine agents with different mechanisms of action and minimal cross-resistance in order to inhibit the emergence of broad spectrum drug resistance; iii) preferentially use drugs with proven activity as single drugs and iv) administer the combination at early stage disease and at a schedule with a minimal treatment-free period between cycles but still allowing the recovery of sensitive target tissues (Mayer & Janoff, 2007;Harasym et al, 2007;Ramsey et al, 2005;Zoli et al, 2001). The advantages attributed to combination chemotherapy include improved patient compliance due to the reduced number of administrations, emergence of additive or synergistic interaction effects, ability to overcome or delay MDR and reduction of drug dose with consequent diminishing of toxicity to healthy tissues (Chou, 2010(Chou, , 2006Ramsey et al, 2005).…”