Antibody-linked cytotoxic agents in the treatment of cancer: current status and future prospects.

Antibodies against tumor cell surface antigens have been used as selective carriers of anticancer drugs, which themselves lack selectivity. Although such antibodies have been demonstrated in tumor hosts, xenogeneic antitumor sera should provide larger yields of better-defined antitumor antibodies for therapeutic purposes. This review examined factors that influence the immune response to tumor-associated transplantation antigens (TATA) and the methods for rendering tumor cells more immunogenic. Consideration was also given to techniques for elimination of irrelevant immunoglobulin molecules. These could involve purification of both antitumor sera and TATA fractions for immunization, as well as tailoring of the immunization protocol. Various toxic agents that have been linked to antitumor globulins with retention of agent and antibody activity were tabulated: alkylating drugs, antibiotics, antimetabolites, cell surface agents, protein synthesis inhibitors, and unconventional anticancer agents that selectively convert nontoxic arsenicals or halides into cytocidal derivatives. The methods by which effective conjugates can be produced and their possible mode of action were described for the different types of agents. Several problems inherent in this modality of tumor therapy include: 1) the necessity of binding therapeutically effective amounts of antitumor agent, 2) ensuring of delivery of drug in active form to target sites, 3) avoidance of host reactions to foreign proteins, and 4) possible emergence of resistant tumor cell populations. Antibody-linked cytotoxic agents may find their greatest use in the eradication of small numbers of circulating tumor cells and micrometastases remaining after removal of primary tumors.

Suppression of an AKR lymphoma by antibody and chlorambucil.

A cell-surface localizing xenogeneic antibody against an AKR mouse lymphoma of spontaneous origin could be bound to chlorambucil without interference with either the alkylating activity of chlorambucil or the immunologic reactivity of the antibody. Exposure of the lymphoma cells to chlorambucil-bound antibody caused greater tumor inhibition both in vitro and vivo than did the synergistic effect of exposure seperately to the antibody and chlorambucil.

Production and characterization of xenogeneic antisera to a human renal cell carcinoma-associated antigen.

Antisera to human renal cell carcinomas were produced by the immunization of goats and rabbits with dissociated tumor cells and/or tumor homogenates from single donors. After absorptions with human red blood cells and homogenates of human liver, lung, spleen, and heart, all the immune sera reacted on immunofluorescence with the brush border of the proximal convoluted tubules of adult and fetal human kidneys and with the proximal convoluted tubular epithelia of rabbits, guinea pigs, rats, and mice. After further absorption with pooled normal human kidney homogenates, the immune sera on immunofluorescence showed cytoplasmic staining of smears and sections of 21 of the 22 human renal cell carcinomas tested. These sera did not show any staining of normal adult human tissues including normal kidney adjacent to the carcinomas, perirenal fibroblasts and peripheral blood leukocytes from the patients, human fetal kidneys, transplanted renal adenocarcinoma of BALB/c mice, and several human tumors tested, i.e., transitional cell carcinoma of the bladder, adenocarcinomas of the breast and colon, squamous cell carcinoma of the lungs, malignant lymphoma, and melanoma. Autoradiography of tissue sections with 131I-labeled antitumor globulins revealed greater localization of radioactivity in tumors than in adjacent normal kidney. Membrane immunofluorescence with the immune sera rendered tumor-specific after appropriate absorptions revealed tumor-associated antigens on the surfaces of all 5 human renal carcinoma cell lines tested.

In vivo suppression of EL 4 lymphomas by rabbit antitumor sera.

Three of more than 50 batches of rabbit antisera raised against the mouse EL 4 lymphoma could inhibit the growth of the tumor in the syngeneic C57BL/6J mice either after exposure of the tumor cells to the antitumor globulin (ATG) in vitro or after the administration of ATG in mice preinoculated with various numbers of EL 4 cells, even though the ATG was not cytotoxic to the tumor cells in the presence of complement. The outcome of immunotherapy with ATG in tumor-bearing C57BL/6J mice depended on the tumor load, the interval between tumor inoculation and the institution of therapy, the total dose, and the schedule of administration of ATG. Complete tumor suppression could be obtained in a proportion of mice preinoculated with 10(5) EL 4 cells, i.e., 10(4) times more than the minimum number of EL 4 cells necessary for 100% tumor takes. Whole-body irradiation (400 rads) or complement depletion of tumor host by cobra venom factor had no effect on tumor suppression by ATG. No evidence of immunity against the EL 4 lymphoma could be detected in EL 4-bearing mice that survived after serotherapy. Anti-EL 4 sera raised in goats and goat and rabbit antisera raised against a lymphoma in the AKR mice have, so far, failed to show any tumor inhibition.

Uptake of methotrexate linked to polyclonal and monoclonal antimelanoma antibodies by a human melanoma cell line.

[3H] Methotrexate [( 3H]MTX) was covalently linked to monoclonal antibody (MoAb) 225.28S against human melanoma, to a rabbit anti-human melanoma IgG absorbed either with human red blood cells (AHMGR) or with red blood cells and a variety of normal human tissues (AHMGR + T), or to normal rabbit IgG (NRG). Human melanoma M21 cells were incubated at 0 degrees C or 37 degrees C with 10 microM free MTX or 10 microM MTX linked to one of the above carriers. The order of net uptake of MTX during 6 hours was MTX-MoAb 225.28S greater than MTX-AHMGR greater than MTX-AHMGR + T greater than MTX-NRG greater than or equal to MTX. This order of uptake by the three antibody conjugates corresponded to the amount of conjugate bound at equilibrium at 0 degrees C and to the immunofluorescence titers. Binding sites for MoAb 225.28S were more efficient for internalization of MTX than were those for the two polyclonal antibody preparations. When M21 cells preloaded with MTX by incubation at a drug concentration of 1.0 or 10 microM were incubated in drug-free medium, the amount of cell-associated MTX rapidly declined to 1.8 pmol/mg protein, i.e., the level of intracellular dihydrofolate reductase (DHFR). However, when cells preloaded to a drug content of 112 pmol/mg protein by incubation with 10 microM MTX linked to AHMGR were transferred to conjugate-free medium, 65 pmol MTX/mg remained cell associated after 12 hours. The efflux was inhibited by chloroquine. Both the efflux medium and M21 cells after a 9.5-hour incubation period had MTX-containing catabolic fragments that inhibited DHFR.

Active immunoprophylaxis and immunotherapy in two mouse lymphoma models.

Injections of appropriate numbers of irradiated tumor cells produced antibodies against tumor cell-surface antigen(s) in both syngeneic tumor models studied: the early transplant generations of the spontaneous L2 lymphoma in AKR/J mice and the chemically induced EL 4 lymphoma in C57BL/6J mice. No antibody was detected in normal or nonimmunized tumor-bearing mice. Tumor inhibitory or enhancing activity was not demonstrated by these antibodies. Immunoprophylaxis or cell-mediated immunity against the L2 lymphoma was not observed after injections of irradiated L2 cells and/or BCG into AKR mice. However, injections of irradiated EL 4 cells alone were effective in immunoprophylaxis against as many as 10(6) EL 4 cells and in immunotherapy against 10(2) EL 4 cells per mouse. The addition of BCG injections made immunotherapy with irradiated EL 4 cells effective against a load of 10(4) EL 4 cells/mouse, though BCG alone was not effective for immunoprophylaxis against EL 4 cells. Resistance to EL 4 could be transferred with viable syngeneic peritoneal or nucleated spleen cells. In both tumor models, an ongoing delayed hypersensitivity reaction to BCG alone apparently did not inhibit bystander tumor cells even when tumor cells were mixed before inoculation with viable BCG. In neither tumor model were concanavalin A-coated tumor cells more potent for immunoprophylaxis than were irradiated tumor cells alone.

Immunochemotherapy of malignant melanoma with chlorambucil-bound antimelanoma globulins: preliminary results in patients with disseminated disease.

Thirteen consecutive patients with inoperable recurrent malignant melanoma were treated by immunochemotherapy with the use of chlorambucil noncovalently bound to goat or rabbit antihuman melanoma globulins. The next consecutive 11 patients fulfilling the criteria for admission into this study were treated with chemotherapy only, i.e., dimethyltriazenoimidazole carboxamide (DTIC). Follow-up was for a minimum of 29 months or until death. Two patients showing an objective response to immunochemotherapy had disease confined to lymph nodes and cutaneous sites; 5 others showed stabilization of cutaneous, nodal, and visceral disease, and 6 patients showed progression of their disease. The median survival of the responders and stabilizers was 20 months, but only 3.5 months for patients with disease progression. None of the 11 patients treated with DTIC had objective tumor regression, and all died within 11 months of the start of treatment with a median survival of 3 months. Immunochemotherapy significantly prolonged the survival compared to that in the DTIC-treated group (P less than 0.05). No hematologic or renal toxicity was detected after immunochemotherapy, but 2 patients in this group developed anaphylactic reactions. Skin reactivity tests to dinitrochlorobenzene and purified protein derivative were of no prognostic value

Imaging of human melanoma xenografts in nude mice with a radiolabeled monoclonal antibody.

External photoscanning with display of radioactivity data as a color-scaled image detected xenografts of human melanoma in male nude inbred mice of BALB/c background 48 hours after injection of 131I-labeled monoclonal IgG 225.28S that is specific for human melanoma. A 131I-labeled polyclonal goat IgG against human melanoma-associated antigens could also image the tumor, but with this preparation there was considerable localization of radioactivity in normal tissues, resulting in less satisfactory tumor definition. Labeled normal mouse IgG did not image the melanoma grafts. Assay of radioactivity in tissues of melanoma-grafted mice confirmed tumor-specific localization of the antimelanoma antibodies. The tumor:blood ratio of radioactivity was 6.55 with the monoclonal antimelanoma IgG and 0.45 with the polyclonal IgG.

Tumor and tissue distribution of a methotrexate-anti-EL4 immunoglobulin conjugate in EL4 lymphoma-bearing mice.

The uptake and tissue distribution of [3H]methotrexate [( 3H]MTX) at doses of 5 mg/kg i.p. either free or linked to anti-EL4 immunoglobulin G (AELG) or normal rabbit globulin (NRG) was studied in EL4 lymphoma-bearing C57BL/6J mice. When the uptakes of MTX-AELG, MTX-NRG, and free MTX were assayed as cell-associated 3H activity, comparison 3 hr after administration showed that uptake of MTX administered as the AELG conjugate was 2.5 times the uptake of MTX administered as the NRG conjugate and 6 times the uptake of MTX administered free. In contrast to the difference in the uptake of MTX-AELG and MTX-NRG by tumor cells, the pattern of uptake in all the other tissues studied was generally similar for the two conjugates. Conjugated MTX persisted in all tissues and serum and ascites fluid, whereas free MTX declined rapidly after reaching peak levels around 1 hr, except in EL4 cells where 45% was retained at 24 hr. The levels of intracellular MTX after administration of these three agents exceeded the intracellular dihydrofolate reductase level and correlated with the relative tumor-inhibitory effect in vivo of the agent (MTX-AELG greater than MTX-NRG greater than MTX).

Monoclonal antibodies to kidney and tumor-associated surface antigens of human renal cell carcinoma.

Three IgG1 monoclonal antibodies derived from BALB/c mice immunized with the Caki-1 human renal cell carcinoma (RCC) line react with antigens present in most human RCCs but restricted in their expression in normal adult tissues. Antibody DAL-K20 reacted with five of six RCCs and the lining epithelium of normal proximal and distal convoluted tubules. Antibody DAL-K29 reacted with eight of nine RCCs, with glomeruli, where it outlined the capillaries, and more weakly with prostatic glandular epithelium and the basal layer of the epidermis. K29 precipitated molecules with molecular weights of 118,000 and 150,000 from extracts of surface-labeled Caki-1 cells. Antibody DAL-K45 reacted with four of six RCCs but not with any normal adult tissue including kidney. It precipitated Mr 177,000 and 150,000 antigens. The three antibodies showed distinct patterns of reactivity with human tumor cell lines.

Targeting of methotrexate-containing liposomes with a monoclonal antibody against human renal cancer.

The potential of monoclonal antibody-linked small unilamellar vesicles containing methotrexate [(MTX)SUVs] in cancer chemotherapy was investigated. (MTX)SUVs prepared by probe sonication [50 +/- 20 (SD) nm in diameter] were linked covalently to Dal K29 (an IgG1 monoclonal antibody against human renal cancer), normal mouse IgG, or a nonspecific mouse myeloma IgG1. After incubation with a human kidney cancer cell line, CaKi-1, for 2 h, Dal K29-linked (MTX)SUVs showed 6 and 8 times more binding to CaKi-1 cells than nonspecific mouse myeloma IgG1-linked (MTX)SUV or (MTX)SUVs unlinked. After incubation with Dal K29-linked ([3H]MTX)SUVs, a higher amount of radioactivity was associated with CaKi-1 cells at 37 degrees C than at 4 degrees C. Membrane immunofluorescence revealed aggregation and capping of Dal K29-linked SUVs around CaKi-1 cells after incubation at 37 degrees C for 2 h and endocytosis at 4 and 6 h. Electron microscopic examination confirmed the aggregation of Dal K29-linked SUVs on the surface of CaKi-1 cells and their presence in endocytic vesicles at 4 and 6 h. After incubation with Dal K29-linked gold containing SUVs at 37 degrees C, gold-containing SUVs were seen on the surface as well as inside endocytic vesicle of CaKi-1 cells at 2 and 4 h. A colony inhibition assay showed that Dal K29-linked (MTX)SUVs were 5 and 40 times more potent than Dal K29-MTX and equimolar amounts of free untrapped MTX in inhibiting the growth of the target CaKi-1 cells but were not toxic to a human melanoma line (that did not react with Dal K29).

Radioimmunotherapy of human B-cell chronic lymphocytic leukemia in nude mice.

After i.v. or i.p. inoculation of 5 x 10(6) D10-1 cells, a subclone of an Epstein-Barr virus transformed human B-cell chronic lymphocytic leukemia (CLL) line, 100% of nude mice developed solid or ascites tumors and died within 17-60 days of tumor inoculation. There was significant tumor inhibition, including tumor cure, when these tumor-inoculated mice were treated with either unmodified or 131I (300 microCi)-linked Dal B02 (50 micrograms/mouse), a monoclonal antibody directed against surface-associated antigens on human CLL B-cells and several histological types of B-lymphoma cells. There was no significant difference between the antitumor activity of unmodified Dal B02 and 131I-linked Dal B02 when the treatment was given 3 days after i.p. or i.v. inoculation of 5 x 10(6) D10-1 cells. However, when the mice were treated 3 days after i.p. inoculation of 15 x 10(6) D10-1 cells, or 7 days after the i.v. inoculation of 5 x 10(6) D10-1 cells, 131I-linked Dal B02 was a more potent tumor inhibitor than was unmodified Dal B02 (P < 0.05 and P < 0.01, respectively). Two injections of 131I (500 microCi) linked to 100 micrograms of a Dal B02 F(ab')2 fragment preparation also prolonged the survival of i.p. or i.v. tumor-inoculated mice (P < 0.05 and P = 0.05, respectively). In nude mice with established s.c. xenografts of D10-1 cells, two injections of 131I (300 microCi) linked to 50 micrograms of Dal B02 led to complete tumor cure in 3 of 4, mice, but two injections of 50 micrograms of unmodified Dal B02 had no effect on the s.c. xenografts. Two injections of 131I (500 microCI) linked to 100 micrograms of Dal B02 F(ab')2 fragment caused significant tumor inhibition but no tumor cure. 131I (300 microCi) linked to 50 micrograms of a nonspecific IgG1 only led to minor tumor inhibition. A mixture of unmodified Dal B02 and 131I-linked nonspecific IgG1 was not a more potent tumor inhibitor than the 131I-linked nonspecific IgG1 preparation by itself. These results suggest that Dal B02 may be an effective carrier for the radioimmunotherapy of human B-cell CLL and other appropriate B-cell lymphomas, especially in the progressive phase of B-cell CLL, which is usually not amenable to currently available therapeutic modalities.

Role of 1q trisomy in tumorigenicity, growth, and metastasis of human leukemic B-cell clones in nude mice.

In order to investigate the association between various karyotypes of human tumor cells and biological behavior of tumors such as tumorigenicity, rate of growth, and the capacity to form metastasis, six chromosomally distinctive clones were isolated from an Epstein-Barr virus-transformed human chronic lymphocytic leukemic B-cell line which progressively grew and metastasized in irradiated nude mice. When inoculated into nude mice one clone (D10-1) with the karyotype of 46,XY,dup(1)(q11----q32) was more tumorigenic, grew faster, and produced more metastases than the other five clones. When mixtures of different clone-derived cells were grown in vitro or inoculated s.c. into nude mice the proportion of D10-1 cells was higher than their expected numbers in the cultures, s.c. tumors, and splenic and lymph nodal metastases. The growth and metastatic potential of the D10-1 clone were inhibited when cells from this clone were mixed with one or more clones that had slower growth. Duplication of 1q has been observed as a secondary aberration in human hematological malignancies and solid cancers. Our results demonstrate that duplication of the chromosome segment of 1q11----1q32 is associated with advantages in proliferation and metastasis formation.

Growth and spread in nude mice of Epstein-Barr virus transformed B-cells from a chronic lymphocytic leukemia patient.

Subcutaneous inoculation of Epstein-Barr virus (EBV) transformed peripheral blood B-lymphocytes (PBL) from an untreated chronic lymphocytic leukemia (CLL) patient produced progressively growing lethal tumors in 4 of 11 whole body irradiated (440 rads) nude mice. In one tumor bearing mouse there was splenomegaly and generalized enlargement of lymph nodes. Chromosomal analysis and membrane immunofluorescence revealed that cells in all the 4 s.c. tumors and a proportion of cells in the enlarged spleen and lymph nodes had human chromosomes and contained human kappa or lambda chains demonstrating that these were polyclonal human B-cells. Epstein-Barr virus associated nuclear antigen could be detected in 100% of cells in all the 4 EBV transformed B-cell lines in vitro and aliquots of cells from several s.c. tumors and metastatic lesions examined. Successful serial transplantation into irradiated nude mice was possible for at least 3 generations with one of the 4 s.c. tumors. During serial transplantation, spread of tumor cells to the spleen and lymph nodes could be detected in all the 3 passage mice investigated; however, there was no evidence in any mouse of dissemination of tumor cells into the bloodstream or into any organ other than lymph nodes and spleen. s.c. tumors also developed in a proportion of irradiated nude mice after inoculation of cells from two other s.c. tumors and the metastatic spleen and lymph nodes, but all these tumors regressed during the first or second transplant passage. Two % of PBL from the untreated patient and 4% of EBV transformed PBL maintained in vitro were found to have trisomy of chromosome 12 which is the most frequently reported anomaly associated with human CLL B-cells. It is highly probable that the cells with trisomy were derived from the leukemic clone of this patient. Cells with this trisomy predominated in most metastatic sites compared to the parent s.c. tumors. Inoculation of irradiated nude mice with EBV transformed PBL from this patient after chlorambucil therapy (100% metaphase plates with 46,XY,11q+ karyotype) or with EBV transformed PBL from 2 normal adults failed to produce any progressively growing tumor in a total of 12 irradiated animals observed greater than 300 days. Although there are several reports of EBV induced immortalization of CLL B-cells in vitro, we have not seen any previous report on the successful serial transplantation and dissemination of EBV transformed CLL B-cells in nude mice.

Delayed occurrence of restenosis in drug eluting stents: an evidence of delayed healing.

Drug eluting stents have made a significant impact on restenosis. However, there are concerns regarding delayed "catch-up" of restenosis. In this case report we present two such patients with delayed occurrence of restenosis after drug eluting stent implantation.

Dynamic Magnetic Resonance Imaging- a sensitive tool in managing consecutive exotropia.

BACKGROUND: Proper evaluation and accurate diagnosis are crucial in managing a case of strabismus. OBJECTIVE: Report a case of prolonged large angle complicated consecutive exotropia where dynamic Magnetic Resonance Imaging helped us to diagnose and simplify the management plan. CASE: A 19-year-old male presented with outward deviation of both eyes for last 16 years with right face turn, without diplopia and trauma. However, he had history of two consecutive squint surgeries, a month apart, at the age of 3 years. OBSERVATION: Visual acuity (best corrected) in the right and left eye was 6/36 and 6/6 respectively. Extraocular movements revealed minus (-) 4 adduction deficits in the left eye with right eye suppression. Prism Alternate Cover Test (PACT) showed 65 prism diopter (PD) base in (BI), for primary and near gazes with lateral incommitance and without any pattern. Forced Duction Test (FDT) showed restriction of the left lateral rectus. Dynamic Magnetic Resonance Imaging revealed posterior insertion of the left medial rectus with thinning of the tendinous insertion of the left lateral and medial rectus in neutral position. On adduction of left eye, there was slight increased bulk of the left medial rectus. Medial Rectus (MR) advancement 5.5 mm and Lateral Rectus (LR) recession 9mm was done. Repeat FDT showed improvement in resistance. After 3 month, the patient had excellent outcome with 5 PD primary position exotropia and 2 units of improvement in left eye adduction. CONCLUSION: Precise workup and appropriate investigation decreases the undue interventions with excellent outcome in a case of large angle consecutive XT. Keywords Consecutive exotropia; dynamic MRI; esotropia; medial rectus advancement; slipped muscle.

Use of anti-skeletal muscle antibody from myasthenic patients in the diagnosis of childhood rhabdomyosarcomas.

Rhabdomyosarcoma (RMS), a common soft tissue tumor in children, may often be difficult to distinguish from Ewing's sarcoma, neuroblastoma, and malignant lymphomas. Confirmation of the skeletal muscle origin of RMS depends partly on the demonstration of striations in tumor cells that are usually undetectable in poorly differentiated tumors. A number of tissue markers (e.g., myoglobin and desmin) are currently being used to establish the origin of RMS. However, most of these markers lack specificity and have relatively low sensitivity. We have investigated the specificity and sensitivity of anti-skeletal muscle antibody (ASMA) from patients with myasthenia gravis in the diagnosis of childhood RMS. Out of eight cases of childhood RMS (four embryonal and four alveolar) examined, two showed striations with hematoxylin and eosin and four with phosphotungstic acid hematoxylin. Myoglobin was detected in five tumors; only well-differentiated tumor cells contained myoglobin. Anti-desmin antibody and ASMA reacted with cells in all the eight tumors whether or not the tumor cells were well differentiated. Anti-skeletal muscle antibody did not react with nine lymphomas, four Ewing's sarcomas, four neuroblastomas, four osteogenic sarcomas, four lipomas, eight duct carcinomas of the breast, and eight squamous cell carcinomas of the lung. Eight leiomyomas and four leiomyosarcomas of the uterus were compared for their reactivity with anti-desmin antibody and ASMA. All the tumors stained with anti-desmin antibody and none with ASMA. The results show that ASMA is useful in the diagnosis of childhood RMS and is a more sensitive reagent than anti-myoglobin antibody. Unlike anti-desmin antibody, it can distinguish skeletal muscle tumors from smooth muscle tumors.

Synthesis of methotrexate-antibody conjugates by regiospecific coupling and assessment of drug and antitumor activities.

In order to increase the retention of drug activity, regiospecific coupling has been used to synthesize conjugates of methotrexate (MTX, 1) with normal rabbit IgG (NRG) and a mouse anti-human renal cancer monoclonal IgG (Dal K-20). MTX gamma-methyl ester (4) was produced either by selective esterification of MTX or by coupling of 4-amino-4-deoxy-N10-methylpteroic acid (2) with suitable glutamic acid derivatives. The MTX gamma-methyl ester (4) was then converted to the corresponding hydrazide 6. An amide-linked conjugate was formed when the MTX gamma-hydrazide (6) was converted to reactive acylating species 7 by using tert-butyl nitrite or trifluoroacetaldehyde, which were reacted with nucleophilic centers, presumably epsilon-amino groups, in native IgG. A hydrazone-linked conjugate was formed when MTX gamma-hydrazide (6) was reacted directly with IgG that had first been oxidized with periodate to form polyaldehyde IgG. The regiospecifically synthesized conjugates were somewhat more effective inhibitors in vitro of dihydrofolate reductase and of colony formation by human renal cancer (Caki-1) cells than were control nonregiospecific conjugates.

Induction of MHC class II expression in recipient tissues caused by allograft rejection.

MHC class II antigens (DR) are not commonly expressed on parenchymal cells of kidney and liver except when they are allografts undergoing rejection. The objective of this study was to determine whether allograft rejection can also induce DR upregulation in parenchymal cells of autologous recipient organs. Dogs had unilateral renal autografts to facilitate kidney sampling. All kidneys were tubular cell DR-negative. After 8-14 days each dog received a tubular cell DR-negative allograft. Tubular cell DR became positive in both allograft and autograft simultaneously, its onset and intensity correlating with blast cell infiltration and rejection in the allograft. Blast cells were first detected in the autograft after allograft nephrectomy, and then disappeared as autograft tubular cell DR diminished over the next 6-8 days. This was reproduced on repeat allografting. In 2 untreated dogs hepatocytes became positive on day 4, with no hepatic blast infiltrate. Four other dogs received cyclosporine immunosuppression. Allograft and autograft tubular cell DR, and hepatocyte DR, increased in all dogs, but were delayed while on CsA until onset of rejection despite transient earlier allograft blast infiltration. Downregulation in autograft and liver occurred together after allograft nephrectomy. An interferon-like substance appeared in plasma after allografting in association with the DR changes in native kidney and liver. Renal allorejection therefore induces upregulation of parenchymal DR expression in autologous liver and kidney of the recipient. It is probably mediated by an interferon-like substance derived from cells infiltrating the allograft. The effect is modified by CsA.

Radionuclide imaging of primary renal-cell carcinoma by I-131-labeled antitumor antibody.

A goat antibody against human renal-cell carcinoma reacted on immunofluorescence with renal-cell carcinomas from 20 patients, but not with normal adult human tissues, including kidney. After i.v. administration the I-131-linked antibody showed preferential tumor localization in six of seven patients with primary renal carcinoma. Labeled antitumor antibodies may have the specificity for tumor imaging that current radiopharmaceuticals lack.