Radioiodinated
phospholipid ether analogues have shown a remarkable ability to selectively accumulate in a variety of human and animal
tumors in xenograft and spontaneous
tumor rodent models. It is believed that this
tumor avidity arises as a consequence of metabolic differences between
tumor and corresponding normal tissues. The results of this study indicate that one factor in the
tumor retention of these compounds in
tumors is the length of the alkyl chain that determines their hydrophobic properties. Decreasing the chain length from C12 to C7 resulted in little or no
tumor accumulation and rapid clearance of the compound in
tumor-bearing rats within 24 h of administration. Increasing the chain length had the opposite effect, with the C15 and C18 analogues displaying delayed plasma clearance and enhanced
tumor uptake and retention in
tumor-bearing rats.
Tumor uptake displayed by propanediol analogues NM-412 and NM-413 was accompanied by high levels of liver and abdominal radioactivity 24 h postinjection to
tumor-bearing rats. Addition of a 2-O-methyl moiety to the propanediol backbone also retarded
tumor uptake significantly. A direct comparison between
NM-404 and its predecessor,
NM-324, in human PC-3
tumor bearing immune-compromised mice revealed a dramatic enhancement in both
tumor uptake and total body elimination of
NM-404 relative to
NM-324. On the basis of imaging and tissue distribution studies in several rodent
tumor models, the C18 analogue,
NM-404, was chosen for follow-up evaluation in human
lung cancer patients. Preliminary results have been extremely promising in that selective uptake and retention of the agent in
tumors is accompanied by rapid clearance of background radioactivity from normal tissues, especially those in the abdomen. These results strongly suggest that extension of the human trials to include other
cancers is warranted, especially when
NM-404 is radiolabeled with
iodine-124, a new commercially available positron-emitting
isotope. The relatively long physical half-life of 4 days afforded by this
isotope appears well-suited to the pharmacodynamic profile of
NM-404.