[Monoclonal antibodies in the diagnosis and therapy of malignant tumors: current status amd future perspectives].
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Biomedical subjects
Publications and source records attributed to R Obrist.
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Accidental subcutaneous extravasation of several antineoplastic agents may provoke skin ulcerations for which there has been no simple and effective treatment. Since January 1983 we have treated all patients in our institution sustaining extravasation by a cytotoxic drug with a combination of DMSO and alpha-Tocopherole. During the first 48 hr after extravasation a mixture of 10% alpha-Tocopherole acetate and 90% DMSO was topically applied. The bandage was changed every 12 hr. So far eight patients with extravasation of an anthracycline or Mitomycin were treated on this protocol. No skin ulceration, functional or neurovascular impairment occurred in any of these patients. The only toxic effect observed by this treatment was a minor skin irritation. The combination of DMSO and alpha-Tocopherole seems to prevent skin ulceration induced by anthracyclines and Mitomycin.
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In an anonymous inquiry 101 consecutive tumour patients and their doctors were questioned on the use of treatment methods and preparations without proven efficacy. 32 patients stated they were using such preparations and methods. Three-quarters of the patients had adopted the following dietetic measures, in descending order of frequency: beetroot juice (34%), vitamins (22%), lactic acid or herbal products (9% each). Iscador (mistletoe extract) was used by 21%, and homoeopathic preparations by 6%. Patients' estimate of the total cost, in 69% of cases, was below 300 Swiss francs, but in one case it exceeded 1200. There was no difference in the use or non-use of the products in regard to the doctor's assessment of the prognosis, age, the therapeutic success according to established medical criteria, or the diagnosis and its correct appreciation by the patient. Male patients employed these methods or preparations significantly more often (43%) than female patients (22%); such patients also showed a higher incidence of severe suffering from side effects of chemotherapy (19% vs. 7%), especially nausea. The use of Iscador was known to the doctor in 71% of the cases, whereas the use of the other methods and preparations was known in only 25%.
Monoclonal antibodies (moab) are potentially useful carriers for the targeting of effector substances into tumors. Conjugation of the chemotactic peptide f-Met-Leu-Phe (fMLP) to tumor-directed antibodies yields compounds active in vitro and in vivo. The present experiments examine the conjugation of fMLP to four different moab iso- and idiotypes. Molar coupling rations and chemotactic activity are not dependent on the moab species used for conjugation.
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Two cases are reported of thrombocytopenia mediated by platelet-directed autoantibodies occurring in a patient with Hodgkin's disease in remission and a patient with non-Hodgkin lymphoma at the time of relapse. 0.5-1.5% of patients with malignant lymphoma have autoimmune thrombopenia, but few cases have been published. The detection of anti-platelet autoantibodies involves methodologic problems, and a specialized laboratory is needed for accurate diagnosis. Treatment is aimed at the malignant lymphoma, as steroids have little effect while the malignant disease is active. However, splenectomy may help even in these cases.
Corynebacterium parvum was administered intraperitoneally to 21 patients with epithelial ovarian cancer. Nineteen patients had surgically measurable disease and two received adjuvant therapy. Surgically confirmed responses were documented in six of 19 patients (31.6%), with two complete responses (10.5%) and four partial responses (21.1%). Three patients (15.8%) had stable disease, and 10 patients (52.6%) had disease progression. The mean survival of the patients who had a complete response was 35.5 months; the four patients who had a partial response the mean survival was 26.6 months, and of the nonresponders the mean survival was 12.6 months (p less than 0.02). The mean survival of the entire group was 18.2 months. Initial response and patient survival correlated with the amount of disease pretreatment. Thus six responding patients had less than or equal to 5 mm maximum diameter tumors, that is, minimal residual disease. Toxicity in the 86 courses of therapy included abdominal pain in 78% of cases, fever in 56%, nausea in 40%, and vomiting in 22%. Stimulation of cytotoxic lymphocytes resulted from the administration of C. parvum, which induced a significant increase of both intraperitoneal natural killer lymphocyte cytotoxicity and antibody-dependent cell-mediated cytotoxicity in six of nine patients tested; these two types of cytotoxicity correlated with response to therapy and may be partially responsible for the surgically documented tumor regression. While the clinical usefulness of intraperitoneal C. parvum is limited because of its toxicity, intraperitoneal immunotherapy may prove useful in patients with minimal residual ovarian cancer when more refined agents become available.
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The numbers of macrophages in peritoneal guinea pig hepatomas were significantly (P less than 0.005) elevated by the intraperitoneal injection of a covalent conjugate of the chemotactic peptide, formylmethionylleucylphenylalanine (fMLP), and IgG reactive with surface antigens on the hepatoma cells. These conjugates, which were previously shown to be chemotactic for guinea pig peritoneal exudate macrophages in vitro, increased the numbers of macrophages in the tumors approximately twofold when injected either in a single dose or in five doses. Although five injections of unconjugated fMLP were nearly as effective as the IgG-fMLP conjugates, free fMLP did not enhance the numbers of macrophages in tumors when injected as a single dose. Unconjugated IgG had no effect. The mean tumor weights were decreased in those groups of guinea pigs which received IgG-fMLP but statistical significance was not achieved due to tumor weight variability in all groups.
The clinical relevance of estrogen receptor determination is compared to the vast amount of preexistent knowledge on clinical variables that predict a response to hormonal manipulation. The indications for hormonal and/or cytostatic therapy are critically reviewed and the limits to present understanding outlined. The predictive value of estrogen receptor determinations and their influence on therapeutic choices are discussed.
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Availability of a chemically defined chemoattractant (fMLP) and of appropriate monoclonal antibodies may permit local manipulation of the inflammatory response to human tumors. fMLP has been conjugated with two monoclonal antibodies (OC125 and OC133) which react with human ovarian carcinomas. Conjugates retained the ability to bind to a human ovarian carcinoma line (OVCA433) judged by indirect immunofluorescence and by radioimmunoassay. The fMLP conjugate was maximally chemotactic for human blood monocytes and human peritoneal macrophages at protein concentrations of 300-900 micrograms/ml. Conjugates stimulated chemotaxis rather than chemokinesis. After incubation with an fMLP-antibody conjugate, antigen positive OVCA433 cells released chemotactic activity and attracted monocytes in vitro, whereas an antigen-negative ovarian cell line failed to do so. As monocytes can be important effectors of antibody dependent cell mediated cytoxicity, fMLP conjugates might increase monocyte concentrations at tumor sites and potentiate serotherapy for certain human neoplasms.
The arachidonic acid lipoxygenase products released into culture supernatants by the human myeloid cell line K562 were quantitated by high-performance liquid chromatography. During 2 hr of incubation, K562 cells spontaneously released a mean of 9 ng of 15-monohydroxyeicosatetraenoic acid, 35 ng of 5-monohydroxyeicosatetraenoic acid, and 87 ng of a partially resolved mixture of 11- and 12-monohydroxyeicosatetraenoic acid per 10(7) cells. The addition of 50 micrograms of arachidonic acid per ml to the cell cultures increased the quantities of monohydroxyeicosatetraenoic acids generated after 2 hr of incubation by 10- to 100-fold; changes in the ratios of these lipoxygenase products occurred over 24 hr of incubation. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate, at concentrations of 5 to 25 ng/ml increased arachidonic acid lipoxygenation 1- to 2-fold in cultures containing 50 micrograms of arachidonic acid per ml, and up to 20-fold in cultures not supplemented with arachidonic acid. The lipoxygenation of arachidonic acid was enhanced 2- to 9-fold for up to 24 hr after a 2-hr exposure of K562 cells to 12-O-tetradecanoylphorbol-13-acetate. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, blocked the effects of 12-O-tetradecanoylphorbol-13-acetate, suggesting that the monohydroxyeicosatetraenoic acids are the products of specific lipoxygenases rather than of nonenzymatic oxidative reactions. The capacities of phorbol esters to promote tumors in the mouse skin model corresponded to their respective capacities to enhance the lipoxygenation of arachidonic acid to 15- and 5-monohydroxyeico-satetraenoic acid but not to 11- and 12-monohydroxyeico-satetraenoic acid.
Corynebacterium parvum has been administered i.p. to 14 patients with advanced ovarian cancer. Two patients had responded completely to cytoreductive surgery and combination chemotherapy prior to immunotherapy, and one patient with residual disease had received only a single course of C. parvum due to i.p. catheter malfunction. Among the 11 patients with residual disease evaluable for response, from three to eight i.p. treatments with C. parvum produced surgically confirmed tumor regression in five patients (45%) with three partial responses and two complete responses of 5 and 12 months duration. All responders had (a) multiple tumor nodules less than 0.5 cm at the initiation of immunotherapy, and (b) severe abdominal pain and fever after C. parvum injection. Overall, 58 courses of immunotherapy were associated with abdominal pain (91%), fever (67%), nausea (52%), vomiting (31%), and hypotension that responded promptly to i.v. infusion of fluids (10%). Use of i.p. cathethers was associated with two episodes each of infection and intraabdominal bleeding. Administration of C. parvum i.p. has augmented the ability of human peritoneal cells to lyse human ovarian carcinoma cell lines in the presence of specific rabbit heteroantiserum. C. parvum administered i.p. has inhibited the growth of human ovarian carcinoma and may prove useful for modulating the activity of human effectors for antibody-dependent cell-mediated cytotoxicity.
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