Improved detection of hepatic lesions using MoAb B72.3 and a modified 111In labelling technique in patients with recurrent colon cancer.

In this study, the clinical usefulness of 111In-SCN-Bz-diethylenetriaminepentaacetic acid (DTPA) monoclonal antibody (MoAb) B72.3 in patients with recurrent colorectal carcinoma was evaluated. In previous studies with radiolabelled MoAb B72.3, metastatic liver lesions in patients with colon cancer appeared as areas of either increased (hot lesions) or decreased (cold lesions) activity, and extrahepatic lesions appeared as areas of increased activity. Eleven patients were enrolled in this study, and 12 MoAb imaging study results were correlated with computed tomography/magnetic resonance imaging findings. The improved detection rates (number of hot lesions) in MoAb imaging were 48% (14/29) for hepatic metastases and 60% (6/10) for extrahepatic metastases. This represents a significant improvement in the rate of detection of metastatic disease of the liver in patients with recurrent colon cancer when compared to the rate in previous reports. Seventeen clinically unsuspected hepatic and extrahepatic areas of increased uptake were also identified on MoAb studies, and two of these areas were confirmed as metastatic disease at surgery. The rate of detection of extrahepatic metastases with 111In-SCN-Bz-DTPA MoAb B72.3 was also compared and found to be equal to the detection rates with other radiolabelled immunoconjugates. No major adverse side effects were noted during the administration of the MoAb. Four of nine patients tested had a positive anti-mouse antibody (HAMA) response 3 months after injection. These preliminary data indicate that this 111In-labelled immunoconjugate of MoAb B72.3 demonstrates an improvement in hepatic lesion detection rate than did previously reported preparations in patients with recurrent colon cancer.

Estrogen receptor binding affinity and uterotrophic activity of triphenylhaloethylenes.

Radiohalogenated estrogens have considerable potential for estrogen receptor-directed imaging and therapy for cancers which contain such receptors. In an effort to evaluate the potential of the triphenyl ethylene structure for such purposes we have synthesized 3 series of 2-halosubstituted triphenylethylenes containing oxygen functions in the 4 position of both aromatic rings attached to carbon 1 of the ethylene and tested their uterotrophic activity and competition for rat uterine low salt extractable, "cytosol" estrogen receptor. Most active, both as competitors for estradiol binding to estrogen receptors and by their ability to stimulate uterine growth are the 1,1-bis-4-hydroxyphenyl derivatives although the 1,1-bis-4-acetoxyphenyl derivatives also show good receptor affinity and demonstrate uterotrophic activities. However, since uterine cytosol contains enzymes which hydrolyze the acetates to the free phenols even during the incubation in the cold used for the competitive binding studies, a significant portion of the competition shown by the diacetates is probably due to their hydrolysis products, the free phenols. The 1,1-bis-4-methoxyphenyl derivatives are weak competitive binders and demonstrate uterotrophic activity only when administered at the higher, 20 micrograms, doses. Comparing the relative activities of various halogens at the 2 position, in each series the bromo and chloro derivatives generally were of similar activity and significantly more active than the corresponding iodo derivative. The non-halogen substituted derivatives were very good competitors for estrogen receptor binding but less active with regard to uterine growth stimulation, providing evidence that in vivo the vinyl halides would appear to be relatively stable to simple dehalogenation. Since they show reasonably good apparent affinities for the estrogen receptor and apparent in vivo stability, reflected by estrogenic activity, these halogen substituted triphenylethylene derivatives appear to be promising substrates for investigations of estrogen receptor directed imaging and therapy.

The synthesis of non-steroidal estrogen receptor binding compounds labeled with 80mBr.

Estrogen receptor (ER) binding radiopharmaceuticals have potential for use in the diagnosis and treatment of cancers of the female reproductive system. Two triphenylethylene derivatives based on the structure of hydroxytamoxifen 4, a high ER binding metabolite of tamoxifen 5, have been prepared: 1-(4-dimethylaminoethoxy)phenyl]-1-(4-hydroxy)phenyl-2-bromo-2-phenyl ethylene 2 and 1,1-bis (p-hydroxyphenyl)-2-bromo-2-phenylethylene 3. Both 2 and 3 bind strongly to the ER. Compound 3 has been labeled in modest yield by direct bromination with 80mBr, which was produced by the 83Kr (d,n alpha) reaction. Radiolabeled 22, a dimethoxy precursor of 3, has been prepared in yields ranging between 40 and 60% by a bromination destannylation reaction.

Potential tumor- or organ-imaging agents XXIV: chylomicron remnants as carriers for hepatographic agents.

This paper describes the possible utility of plasma lipoproteins for the site-specific delivery of diagnostic agents. The class of lipoproteins known as chylomicrons was selected for this preliminary study, since they are known to be rapidly metabolized and taken up by the liver. Cholesteryl iopanoate (II), an iodinated analogue of a normal constituent of the hydrophobic core of chylomicrons, was synthesized from cholesterol and iopanoic acid (I) and subsequently radiolabeled with ioidine-125. Whereas intravenous administration of II in physiological saline resulted in the appearance of approximately 31% of the dose in the liver at 0.5 hr, prior incorporation of II into chylomicrons resulted in an almost threefold (87%) increase in the liver accumulation of II in the same time period. A more gradual appearance of II in steroid-secreting tissues was consistent with the association of II with high-density lipoproteins following administration.

Potential tumor- or organ-imaging agents. 23. Sterol esters of iopanoic acid.

A series of sterol esters of iopanoic acid was synthesized and evaluated for their potential to selectively localize in liver and steroid-secreting tissues for possible application in either computed tomography or nuclear medicine imaging. Unlike free iopanoic acid (1), which was rapidly cleared following intravenous administration to rats, cholesteryl iopanoate (2) was found to accumulate in liver, adrenal cortex, and ovary. At 24 h, the ovary was found to contain the highest concentration of 2. The ability of 2 to accumulate in the above tissues was attributed to its resistance to hydrolysis. Pregnenolone iopanoate (3) and dehydroepiandrosterone iopanoate (4), on the other hand, were shown to reach unusually high concentrations in the adrenal cortex within 0.5 h of administration but declined to much lower levels by 24 h. Lipid extraction of tissues showed 3 and 4 to be susceptible to in vivo hydrolysis, which undoubtedly was a major factor in their clearance from adrenal tissue.

Potential organ- or tumor-imaging agents. 22. Acyl-labeled cholesterol esters.

A series of cholesteryl phenylalkanoic esters was synthesized in which the acyl moiety served as the carrier for radioiodine. Tissue distribution studies in rats revealed that several of these radioiodinated esters selectively accumulated in steroid-secreting tissues, such as the adrenal cortex and ovary. Furthermore, this selective uptake was shown to correlate with the stability of these esters to in vivo hydrolysis. An unexpected finding was the unusually high propensity of some of these esters to localize in the ovary and thus afford a possible approach to ovarian imaging agents.