Intratumoral distribution of two consecutive injections of chimeric antibody G250 in primary renal cell carcinoma: implications for fractionated dose radioimmunotherapy.

Tumor uptake of the chimeric G250 (cG250) monoclonal antibody (mAb) in patients with primary renal cell carcinoma (RCC) is among the highest reported in solid tumors. However, as observed in other tumor types, the intratumoral distribution of the antibody is highly heterogeneous, which may limit the efficacy of radioimmunotherapy. A number of highly dynamic physiological factors have been postulated that may contribute to heterogeneous tumor uptake of antibodies. Their impact on tumor uptake of antibodies may vary from one tumor region to another as well as from one day to the next. Here, we report on a clinical study that was designed to investigate whether the pattern of mAb cG250 uptake within RCC tumors is altered with subsequent injections. Ten patients with a clinical diagnosis of primary RCC were studied. Nine days before surgery, patients received 125I-cG250 (5 mg of cG250, 50 microCi of 125I), followed by a second injection of 131I-cG250 (5 mg of cG250, 3.5 mCi of 131I) 4 days later. Postsurgery, the tumor was cut into (1-cm) thick slices. Slices were imaged on a gamma camera, and the slice with the most pronounced heterogeneity in 131I-cG250 distribution was selected and cut into 1-cm3 cubes. Each cube was analyzed for 121I-cG250 and 131I-cG250 uptake, and the 131I/125I ratio was determined. For each tumor slice, the distribution patterns of both isotopes were reconstructed and compared with each other. All tumors analyzed showed a heterogeneous distribution of both isotopes throughout the tumor slice; focal uptake in some areas of a tumor reached very high levels (up to 0.19% injected dose/g), whereas other tumorous areas of the same slice showed much lower uptake (as low as 0.0047% injected dose/g). Remarkably, in all tumors, the distribution pattern of both injections was identical: without exception, in all samples analyzed (n = 692), the uptake of 125I-cG250 was similar to 131I-cG250 uptake. Overall, the 131I/125I ratio was 1.64+/-0.31 (mean+/-SD). The constant 131I/125I ratios, observed in all tumor samples investigated, indicate that the tumor parameters governing cG250 mAb uptake were not altered significantly within the time period studied. In addition, the results of this study suggest that multiple radiolabeled antibody injections, administered within short time periods, will target the same areas within a tumor and, thus, will not solve the problem of heterogeneous tumor uptake of antibody.

The value of dynamic hepatic scintigraphy and serum aminoterminal propeptide of type III procollagen for early detection of methotrexate-induced hepatic damage in psoriasis patients.

Oral methotrexate (MTX) is a highly effective drug for the treatment of severe psoriasis. A limitation of this treatment is its potential hepatotoxicity. In the present prospective study the value of dynamic hepatic scintigraphy (DHS) and serum aminoterminal propeptide of type III procollagen (PIIINP) were investigated as screening methods for early detection of MTX-induced hepatic damage. These relatively non-invasive procedures were compared with the liver biopsy classification, until now the gold standard to assess MTX-induced liver damage. Twenty-five MTX patients were studied. The mean cumulative MTX dose was 3.9 g (range 0.2-11.1 g). Twenty-one patients had a normal liver histology (grade I), three patients had steatosis (grade II), and one patient mild fibrosis (grade IIIA). Seven additional patients with non-MTX related hepatic cirrhosis were included as disease controls. DHS showed a clear-cut separation between the portal contribution of the MTX patients with grade I liver histology, and that of all other patients. A portal contribution larger than 52% was associated with a > 95% chance of normal liver histology. If this cut-off value had been used to postpone the liver biopsy, this would have resulted in at least a 55% reduction in the number of biopsies in patients with a normal liver histology. DHS appeared to be very promising as a screening test to differentiate between the presence or absence of MTX-induced hepatic damage, but appeared not suitable to grade the severity of hepatic damage. Although a global relationship was demonstrated between serum PIIINP concentration and hepatic damage, single measurements in individual patients were not reliable. The combination of PIIINP measurements with DHS had only a limited additional value above DHS alone. The present study indicates that DHS has great promise for the detection of early MTX-induced hepatic damage. Pending further studies, regular liver biopsies remain mandatory for the safe prolonged use of MTX in psoriasis patients.