© The Author 2006. Published by Oxford University Press.
EDITORIAL |
Respecting Cancer Drug Transportability: A Basis for Successful Lead Selection
Correspondence to: Edward A. Sausville, MD, PhD, Marlene & Stewart Greenebaum Cancer Center, University of Maryland, 22 South Greene Street, Baltimore, MD 21201 (e-mail: esausville{at}umm.edu).
Tirapazamine is a prodrug that yields a DNA-directed alkylating agent after activation in hypoxic tumor cells. The basis for its development was its selective activation in that fraction of the tumor cell population that is most refractory to radiation and conventional chemotherapeutics (1). Yet the actual level of clinical activity attributable to tirapazamine has been modest (2). Therefore, a reexamination of the basis for the drug's action is timely if this general strategy is to be further improved. Recent studies on the mechanisms allowing cancer cells to proliferate and function in a hypoxic environment have led to the conclusion that persistent activation of hypoxia-inducible factor, with the attendant downstream activation of angiogenesis and glycolytic activity, is a crucial difference in behavior of cancer cells compared to normal cells (3). Accordingly, strategies for the design of treatments predicated on this difference are of enormous interest.
In this issue of JNCI, Hicks et al. (4) describe the measurement of transport of tirapazamine analogs through HT29 colon cancer multicellular layers, the anoxic cytotoxic potency of these compounds as determined by clonogenic assay, and their plasma pharmacokinetics in animals. The authors have also modeled oxygen diffusibility in a tumor microvascular network. These collective results allowed them to generate a spatially resolved pharmacokinetic/pharmacodynamic (PK/PD) model that, critically, includes estimates of compound diffusion capacity and tumor O2 content. The authors present evidence of wide variation in the diffusion coefficients for individual members of the tirapazamine analog series. Overall, their results indicate that low intrinsic transport of drugs into hypoxic regions can be a clear barrier to achieving a response to the analogs in the xenograft models. Indeed, when they accounted for differences in the diffusion coefficients of individual agents, xenograft activity of the series was much better predicted by the performance of the analogs in the PK/PD model than by the agents' plasma pharmacokinetics and intrinsic activity in hypoxic cells. The implication of this study for the development of tirapazamine analogs and other drugs in humans is that, unless the diffusion and drug transport properties of an agent are optimized, what looks good in tissue culture experiments will likely look less promising when applied to the human milieu.
The experiments of Hicks et al. (4) are of import for a number of reasons. From a strategic perspective, much effort has gone recently into defining novel agents that address molecular targets underlying the "hallmarks" of malignancy. Yet clear differences in efficacy are emerging among the different molecularly targeted agents. For example, erlotinib appears to convey a survival advantage in non-small-cell lung cancer (5), whereas gefitinib does not (6), although both drugs ostensibly target the epidermal growth factor receptor. Similarly, bevacizumab (an antibody) and sunitinib (a small molecule) have different spectra of activity in renal neoplasms, even though both agents target the vascular endothelial growth factor (VEGF) receptor (7,8). Contributing to these differences in clinical outcome may be prominent pharmaceutic or pharmacologic differences among the agents. Yet researchers selecting candidate compounds for further development have often lacked the tools to illuminate pharmaceutical features which would predict optimal performance characteristics in living organisms.
Optimizing pharmaceutics is a "Rodney Dangerfield" aspect of the drug discovery business, garnering less respect in academic currency than does the initial identification of a compound acting against a target. Moreover, the skill sets to optimize pharmaceutic properties are often not known or available, even in large pharmaceutical companies. The approach outlined by Hicks et al. (4) must be considered, therefore, as a methodologic advance of potentially great interest. Although in this case a defining feature activating the tirapazamine series is hypoxia, one can imagine other types of variables that could be incorporated into versions of this model, such as the level of expression of a drug transporter or of a drug-metabolizing enzyme. A key message of the article by Hicks et al. (4) is that, in addition to having action against an important molecular target, most useful drugs will be characterized by having optimized pharmaceutics in the tumor microenvironmental milieu.
In fact, to be a valuable oncology drug an agent must meet several challenges. In addition to interacting with an important target, the drug must run the gauntlet of several membrane-delimited compartments, including gastrointestinal mucosa (for chronically administered drugs) and endothelial and tumor cell membranes; it must survive hepatic and renal elimination mechanisms, at least for a while, although often not too long lest there be untoward host toxicity; and plasma protein binding, if present, must not be too strong. Finally, on reaching the tumor vascular bed, the agent must contend with tumor cells that are variably disposed in relation to blood vessel architecture, a feature modeled in the study of Hicks et al. (4).
Numerous targeting strategies have recently been pursued to improve the potential localization of a drug to tumors (9). These include design of polymeric or nanoparticle-based "packaging" systems, which are proposed to target tumors through the enhanced permeability and retention effect of tumors (9); matrix-dependent protease or pH-dependent drug release mechanisms from prodrug forms; and nutrient-targeted [e.g., folate (10)], antibody-targeted, or peptide-targeted means of finding a stromal (11), neovascular (12), or tumor cell surface–based (13) binding molecule. Yet these strategies will now have to be reconsidered in light of the information presented by Hicks et al. (4) because, without a consideration of effects on drug diffusibility allowing for facile tumor permeation, these strategies may also founder. Moreover, by adding a targeting moiety to a recognized "warhead," the favorable features allowing the action of the parent molecule may be unintentionally altered.
What molecular features allow optimal diffusion of small molecules? In the current study (4), the octanol:water partition coefficient of the analog series was important. However, that is not the only important variable. The presence of drug metabolizing enzymes in the tumor or its supporting vascular stroma, the presence of efflux mechanisms from tumor cells, and the presence of "off-target" binding sites with partial affinity for the drug are all likely to influence the transportability of the agent, from the drug's point of view. From the tumor's point of view, interstitial fluid pressure has already been identified as a key variable that influences the capacity of small-molecule drugs as well as macromolecules to enter tumor compartments (14,15), and this attribute may be approachable in part through the use of VEGF antagonists.
The bottom line is that we do not, in general, know a priori how to optimize those aspects of drug structure that will impart optimum performance in a pharmaceutical sense. The importance of the observations of Hicks et al. (4) is that they offer a clear methodology for beginning to intelligently select for compounds with desirable features. This methodology is particularly relevant to cancer drugs because agents proposed for use in other therapeutic contexts do not have to contend with the disordered and heterogeneous vasculature of tumors. Generalizing from the specific example of tirapazamine analogs presented in the study of Hicks et al. (4) to the broader universe of compounds with additional mechanisms of action is now a challenge that can profit from consideration of their approach. A more systematic application of this method to other categories of both classical and molecularly targeted anticancer drugs would be of great interest and broad value to the "drug-discovering" research community, as well as the patients who will participate in clinical trials with molecules triaged by this information.
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