Accessibility of circulating immunoglobulin G to the extravascular compartment of solid rat tumors.

We have measured the rate of influx (kin) of normal rat immunoglobulin G (IgG) from the blood into the fluid surrounding the cells of three syngeneic rat fibrosarcomas as well as rat skin, muscle, lung, and kidney. Also measured was the rate of efflux (kout) of IgG from the tumor and tissue back into the circulation. The value of kin ranged from 0.11 to 9.0% of the blood value (activity/ml blood) transferred/hr/g for the nonmalignant tissues and from 6.2 to 7.9% of the blood value transferred/hr/g for the three tumors. Dividing kin by the plasma volume of the tissue gave a measure of the permeability of the vascular bed of that tissue. This ratio was rather constant for the normal tissues studied; however, it was at least an order of magnitude larger in all three tumors, indicating that the vasculature of the tumors was very permeable to IgG. The interstitial fluid volume (IF) of the tumor and tissue was calculated. The IF of the three tumors contained approximately 0.5 ml of fluid per g, while the IF of normal tissues had values that ranged from 0.14 to 0.34 ml of fluid per g. Knowledge of the IF, kin, and kout allowed a calculation of the concentration of IgG in the fluid surrounding the cells of tumors and tissues. The concentration of IgG in the IF of the tumors was found to be 50% of the plasma concentration; this was larger than the concentration of IgG in the IF of normal tissues, where the values ranged from 9 to 28% of the plasma concentration. A model for Ab localization onto solid tumors was developed. The model was used to discuss the mechanism of localization as well as the physiological limits of drug- or isotope-coupled Ab localization.

Factors influencing localization of labeled antibodies in tumors.

Recent success with antibody to carcinoembryonic antigen makes it desirable to survey the practicality of producing other tumor-localizing antibodies for diagnosis and therapy. General procedures for reaching these goals are outlined. Experimental animal studies show some progress; detecting moderate-sized tumors by scanning appears a reasonable goal, but there is a basic lack of knowledge regarding the extent to which tumors express tumor-specific or associated antigens in vivo. This makes it difficult to evaluate the probability for success of different therapeutic proposals now under study. For organs not vital for the life and well-being of the patient, organ-specific antigens expressed on tumor may offer a target for immunological attack. Techniques for cloning antibody-producing cells promise more uniform and specific antibody preparations.

Preferential localization and rate of loss of labeled alloantibody from rat tumors and skin transplants carrying the corresponding alloantigen.

125I-Labeled rat histocompatibility antibody was prepared from sera of Buffalo rats immunized with a transplantable fibrosarcoma induced by methylcholanthrene in a Fischer 344 rat. After i.v. injection this antibody was shown to localize with high specificity in transplants of a second Fischer 344 tumor or Fischer 344 skin grafts onto immunosuppressed Buffalo rats. These represent conditions such that only tumor or skin grafts carry the corresponding antigen. In skin transplants localization at 24 hr corresponded to 80% and in tumor to 30% of the injected dose in tissue equal to 1% of the rat weight. However, rapid loss of the 125I label from the target tissues indicated that degradation of antibody fixed to target cells was rapid and that the half-time of the intact antibody was less than 2 days.

Endotoxin, epinephrine, and ellagic acid effects on the radiation-sensitized walker 256 rat carcinosarcoma.

A radiation exposure of 1500 R to the Walker 256 rat tumor was found to sensitize this tumor to the effect of a sublethal dose of endotoxin (Sarratia marcescens lipopolysaccharide) given 2 days later so that complete or almost complete destruction of the tumor resulted. Histological. study showed rapidly developing massive necrosis of tumor tissue. Tracer experiments with 131I-labeled antibody to rat fibrin indicated an absence of blood circulation in the treated tumor. These results suggest that the lesion may be secondary to blood coagulation occurring in the vascular bed of the tumor. Apparently identical lesions were also produced by epinephrine and ellagic acid, alone or in combination. It is known that even untreated tumors are often the site of fibrin deposition. Presumably radiation, by injury to tumor cells, enhances the release of coagulation-producing substances into the vascular bed. It is postulated that the effect of subsequent treatment with the drugs listed above is produced by circulatory stasis induced in the tumor. This may be associated with Hageman factor activation or release of platelet factor 3.