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Two patients with prior prostate surgery sustained peripheral nerve injuries after transurethral collagen injection for the treatment of urinary incontinence. In the first patient, brief lithotomy positioning caused a gluteal compartment syndrome and sciatic neuropathy. In the second patient, obturator neuropathy was due to leakage of collagen along the course of the obturator nerve. This is the first report of peripheral nerve injury in patients undergoing transurethral collagen injection.

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The mechanism by which tumors recur at sites of injection of retrovirus-infected fibrosarcoma cell lines was investigated. Previously, it was established that tumor recurrences reflect outgrowth of rare cells that lack viral antigens and are susceptible to superinfection with the homologous retrovirus. In the present study clones isolated from a retrovirus-infected cell line were evaluated as precursors for tumor recurrence. Under conditions of in vivo immunologic selection, a clone that contained a single abbreviated copy of the provirus formed variants that lacked the proviral gene. Tumor variants lacking the proviral gene grew progressively in both nonimmune and virus-immune male Sewall Wright strain 2 guinea pigs. Tumor recurrence could be prevented by superinfection of the virus-infected fibrosarcoma cell line or by superinfection of the precursor for tumor recurrence. Cell lines infected with retroviruses varied in frequency of tumor recurrence formation. This model may be useful in analyzing gene deletion as a mechanism of tumor escape from host immunologic attack.

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The metabolic and physical properties of tumor cells that are associated with their ability to resist or escape from immune attack have been investigated. The susceptibility of P815 murine mastocytoma cells to immune killing can be modulated. Culturing the cells with adriamycin or with hydrocortisone increases or decreases, respectively, the sensitivity of the cells to killing by antibody (Ab) plus complement (C); in addition, culturing the cells with mitomycin C or hydrocortisone increases or decreases, respectively, the sensitivity of the cells to killing by cytotoxic T lymphocytes (CTL). The susceptibility of the cells to Ab-C killing correlates with the ability of the cells to synthesize complex cellular lipids, but not DNA, RNA, protein, or carbohydrate. Further, tumor cells rendered sensitive to Ab-C killing by adriamycin are decreased in total lipid content and in their cholesterol/phospholipid mole ratio; hydrocortisone-treated resistant cells showed the opposite effects. The ability of tumor cells to resist CTL killing did not correlate with their total cellular lipid synthesis, but did correlate with the synthesis and composition of specific cellular phospholipids. In addition, tumor cells increased in sensitivity to Ab-C killing exhibited an increase in cell surface membrane fluidity, whereas cells increased in susceptibility to CTL attack showed an increase in their net negative cell surface charge density. These data show certain unique chemical and physical properties of tumor cells to be of fundamental importance for their ability to resist either humoral or cell-mediated immunologic attack; modulation of one or another of these cellular properties results in a change in the cells' susceptibility to immune killing by antibody plus C or by cytotoxic T lymphocytes.

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The effects of intralesional chemotherapy with 7 different drugs on line 10 hepatoma grown in strain 2 guinea pigs were compared with the sensitivity of line 10 tumor cells in vitro, using a micro modification of the tumor stem assay with capillary tubes. A modified method was used to evaluate the in vitro dose-response curves. The correlation for in vivo/in vitro resistance was found to be 100% and for in vivo/in sensitivity it was 80%.

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EA3H-C4hu treated with 2-mercaptoethanol (MSH) or dithiothreitol (DTT) were analyzed for residual chains and hemolytic activity. MSH treatment resulted in no loss of the chains of C4b and no loss of reactivity with a polyclonal anti-human C4 rabbit antibody, and the cells did not lose their ability to generate SAC4b2a. DTT-treated cells lost about 70% of the gamma-chain and over 95% of C4b activity; there was no loss of alpha' and beta chains or the ability to react with anti-C4 antibody. Kinetic studies indicated that the remaining 30% of the gamma-chains could not be removed by prolonged incubation with DTT, implying heterogeneity of cell bound C4b. The data also imply that the gamma-chain is important in the generation of SAC4b2a.

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Cells removed from asynchronous cultures during lag, log, and stationary phases of growth were found to differ in their sensitivity to antibody/complement-mediated killing. The human lymphoblastoid line, Raji, was relatively more susceptible to killing by human anti-HLA antibody plus rabbit complement during the lag and log phases of growth, while the human lymphoid cell line, PY, was relatively more susceptible to rabbit antilymphocyte serum or human anti-HLA plus rabbit complement during the log and late-log phases of growth. The mouse mastocytoma cell line, P815, was relatively resistant to killing by rabbit anti-P815 plus guinea pig complement during the middle log phase of growth. The variation in sensitivity of the three cell lines was dependent upon the concentration of antibody used to sensitize the cells but not due to differences in antigen expression, antigen density, or net synthesis of DNA, RNA, protein, complex carbohydrate, or lipid-containing macromolecules. These data suggest that the variability in susceptibility of the cells for complement-mediated killing is due to changes in physiological and/or physicochemical properties of the cells which either affect the ability of the cells to repair complement-mediated damage or nullify the activity of cell-bound complement.

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Human platelet membranes were isolated by the glycerol-lysis technique. When tested by a turbidimetric method in the presence of fibrinogen and calcium ions, the membrane vesicles exhibited patterns of reactivity to collagen. As with human platelet-rich plasmas, the aggregating effects of collagen were inhibited by preincubating the membrane suspensions with hemolytically active human C1q. Upon addition to platelet-rich plasma, the isolated membranes reduced collagen-provoked platelet aggregation. This inhibitory effect was partially suspended by prior incubation of the membranes with native C1q. The results show that the receptors for collagen and C1q are preserved during the membrane isolation procedure and support the competitive nature of inhibition by C1q of collagen-induced platelet aggregation.

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The immunogenicity of inbred strain 2/N guinea pig fibroblasts transformed to the malignant state in vitro by chemical carcinogens was evaluated with the use of a variety of in vivo and in vitro methods including delayed-type hypersensitivity skin and tumor transplantation tests and analysis of antibody production by immunofluorescence, complement fixation, and staphylococcal protein A binding tests. Neoplastic transformation was induced by direct treatment of cells in culture with benzo[a]pyrene, 3-methylcholanthrene, or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or by the host-mediated method by which fetuses were exposed to diethylnitrosamine or MNNG in vivo prior to cell culture. Rabbits and syngeneic guinea pigs were inoculated with unirradiated and X-irradiated clonally derived cells. Delayed hypersensitivity skin reactions to immunizing or other cells were equivalent in immunized or control guinea pigs, and no protection to tumor outgrowth from a challenge inoculum of immunizing cells was observed. Antibody activity induced in the sera of immunized guinea pigs was cross-reactive and removed by absorption with nontumorigenic cells. Rabbit antisera after absorption with fetal guinea pig cells were nonreactive with the specific immunizing or other culture cells. Chemical carcinogen-induced neoplastic transformation of guinea pig cells can, therefore, occur without formation of detectable, individually distinct cell surface tumor-specific neoantigens.

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The killing or lysis of nucleated cells, erythrocytes, bacteria, and other targets (e.g., liposomes) by antibody and complement is the result of complex series of actions and interactions between antibody, components of the complement system, and the cell. The complement attack mechanism has strict qualitative and quantitative requirements. For efficient activity, sufficient amounts of antibody must bind to the cell, the antibody must be of the complement-fixing type, and sufficient amounts of complement components must be activated and fixed to the surface of the target cells. Nucleated cells of different types differ in their sensitivity to the cytotoxic action of complement. This difference in sensitivity may be attributed to differences in metabolic properties and/or the chemical and physical composition of the cells. Since complement action occurs primarily on or in the cell membrane, the properties of the cell which may affect the outcome of complement-mediated attack should be linked to cell membrane function and integrity. The relationship between the susceptibility of nucleated cells to complement-mediated killing and the chemical and metabolic properties of the cells will be discussed in this review.

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Line-10 tumor cells cultured for 24 hr in lecithin-rich normal human plasma or with synthetic lecithin showed a 5- to 8-fold increase in their lecithin:sphingomyelin mole ratio without being affected in their total lipid content or cholesterol:phospholipid mole ratio. These cells were more sensitive to killing by antibody plus complement (C) than untreated controls. Line-10 cells that underwent a homogeneously catalyzed hydrogenation reaction were reduced 6-fold in their content of unsaturated fatty acid compared to controls; the lipid content of these cells was largely unaffected. These cells were more resistant to antibody-C mediated killing than controls. These modifications in cellular lipid and fatty acid composition could be reversed when the cells were recultured for 24 hr in serum-containing tissue culture medium; the cells regained control levels of susceptibility to antibody-C killing at this time. These results suggest that by manipulating the lipid or fatty acid composition of a tumor cell, either indirectly by changing the lipid composition of the environment in which the cell resides or by directly altering the chemical nature of a cellular lipid constituent, the susceptibility of the cell to humoral immune killing can be modulated.

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The failure of functionally purified C5gp to reconstitute the hemolytic complement (C) activity of C5-deficient human serum was studied. The lack of hemolytic activity of C5gp in this system could not be correlated with the failure of EAC1-3hu to bind and activate C5gp, but was related to the failure of EAC1-3hu5gp6hu to efficiently bind C7hu in a form that would lead to lysis when HuC8 and HuC9 were added. This failure was not observed with EAC1-3gp5gp6hu or EAC1-3hu5hu6hu, which could be lysed with any combination of human or guinea pig C7 through C9. The implications of these findings on the control of the lytic C attack mechanism by the initial components in the C cascade are discussed.

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Line-10 hepatoma cells from Sewall Wright guinea pigs are sensitive to killing by antibody plus human complement. Hormones that decrease the sensitivity of the cells to antibody-complement-mediated killing (insulin and hydrocortisone) were examined for their effects on the ability of the cells to synthesize and incorporate specific lipids into plasma membrane and intracellular membrane fractions. Cells that had been rendered resistant to antibody-complement-mediated killing following incubation for 1 hour with either of the hormones were enhanced in their incorporation of newly synthesized L-alpha-phosphatidyl serine, L-alpha-phosphatidyl choline, and triglycerides into the plasma membrane as well as L-alpha-phosphatidyl choline, L-alpha-phosphatidyl serine, and cholesteryl ester into mitochondria, endoplasmic reticulum, nuclear membrane, or microsomes; these cells were inhibited in cardiolipin synthesis. Cells cultured for 4 hours with hormone regained their sensitivity to antibody-complement-mediated killing and reverted to control levels in their ability to synthesize and incorporate lipids into plasma and intracellular membranes. These data suggest that agents that increase the resistance of the tumor cells to humoral immune killing stimulate the synthesis and incorporation of specific complex lipids into plasma membrane and intracellular organelles; these effects are generally opposite those observed after treatment with agents that increase the sensitivity of the cells to antibody-complement-mediated killing (metabolic inhibitors).

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The intense clinical interest in bleomycin as an anti-tumour agent has led to different methods of administration in an attempt to administer sufficiently high concentrations of the drug to the tumor. Therefore, a study was designed to determine the distribution and the therapeutic effect of a bleomycin emulsion and aqueous bleomycin after different routes of application. The tissue distribution of radioactively labelled bleomycin emulsion and aqueous bleomycin was determined in tumor-free CF 1 and tumor-bearing (EL 4, L 1210) C 57 Bl 6 and DBA 2 mice after local (s.c., i.t.) and systemic (i.v.) injection. The distribution studies for aqueous 57Co-bleomycin showed increased activity in the injection sites and the lymph nodes draining the injection sites after s.c. and i.t. injection compared to i.v. administration of the drug. In comparison to the aqueous local administration, the application of 57Co-bleomycin emulsion resulted in a disproportional increase of the 57Co-bleomycin concentration at the injection sites and in the draining lymph nodes. To prove the therapeutic relevance of the bleomycin tissue distribution tumor-bearing (line 10) strain 2 guinea pigs were treated with different modes of bleomycin. Animals with already lymphogenously metastasized tumors have been cured by means of low i.t. doses of the bleomycin emulsion. Guinea pigs treated with i.t. administration of aqueous bleomycin need, compared to the bleomycin emulsion, five times higher doses for tumor-free survival. Intravenously treated animals died either because of progressive tumor growth or because of toxic bleomycin effects. These findings made by animal experiments favor the i.t. treatment of head and neck carcinomas with a bleomycin emulsion.

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The well-known cytotoxic mode of action of bleomycin up to now has been clarified exclusively by intracellular processes. Our findings however indicate that an immunologic effect induced by bleomycin can also lead to the destruction of tumor cells.

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Line 10 guinea pigs hepatoma cells are resistant to killing by antibody and guinea pig complement. Metabolic inhibitors (adriamycin and actinomycin D) that increase the sensitivity of the cells to antibody-complement (C) killing were examined for their effects on the ability of the cells to synthesize and incorporate specific lipids into plasma membrane and intracellular membrane fractions. Drug-treated cells that had been rendered sensitive to antibody-C killing were inhibited in their incorporation of newly synthesized phosphatidylcholine and cholesteryl ester into the plasma membrane, as well as incorporation of phosphatidylcholine, cardiolipin, cholesteryl ester, and triglyceride into certain intracellular organelles including mitochondria, endoplasmic reticulum, nuclear membrane, or microsomes. Drug-treated cells recultured in the absence of the drug regained their ability to resist antibody-C killing and to synthesize and incorporate lipids into plasma and intracellular membranes. These data suggested that agents modifying the sensitivity of the tumor cells to humoral immune killing have a concomitant effect on plasma membrane and intracellular lipid synthesis.

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