TO THE EDITOR:

The recent paper by Min et al. (1), extending earlier work by Delmon-Moingeon et al. (2) and Madar et al. (3,4), is an elegant presentation of the potential use of tetraphenylphosphonium (TPP) as a tumor probe for PET (1). Min et al. contend that the specificity of TPP for tumor imaging would not be compromised by accumulation in inflammatory lesions, which is a problem with ¹⁸F-FDG imaging (1). As noted by the authors, TPP is a delocalized lipophilic cation, much like the ^99mTc-labeled myocardial imaging agents sestamibi and tetrofosmin, which are also used for tumor imaging. The selective accumulation of this class of compounds in tumors (and the heart) is related to the highly negative inner mitochondrial membrane potential in these cells (2).

However, Min et al. (1) fail to mention that lipophilic cations, such as TPP, sestamibi, and tetrofosmin, are transport substrates for the multidrug resistance transporter P-glycoprotein (5–7). Multidrug resistance refers to a phenotype in which a tumor is inherently resistant or develops resistance to a variety of structurally unrelated chemotherapeutic agents, including such common drugs as anthracyclines, taxanes, and vinca alkaloids. The prevalence of P-glycoprotein overexpression varies greatly among tumor types. Tumors that overexpress P-glycoprotein will show lower accumulation of these tracers than will P-glycoprotein–negative tumors, because of active efflux of the tracer. Indeed, the ∼10% false-negative rate observed in scintimammography with sestamibi and tetrofosmin could actually be a true-negative rate because of multidrug resistance. This reduces the sensitivity of such a tracer for tumor detection, though the tracer may still be useful for tumor characterization.

Thus, in proposing an agent that may be more specific for tumors, they have sacrificed sensitivity. Although there is often a trade-off between sensitivity and specificity in nuclear medicine, in this instance the trade-off could have been predicted from the literature.