The role of insulin-related substance in Hodgkin's disease.

An insulin-related growth-promoting substance was detected in the serum of a patient with Hodgkin's disease who suffered from severe hypoglycaemia, as well as in the supernatant of homogenized spleen tissue of the same patient. Low concentrations of this substance enhanced DNA synthesis of short-term-cultured spleen tumour cells obtained from the same patient, while the addition of anti-insulin antiserum interfered with that effect. Moreover, the preincubation of this insulin-related substance with the anti-insulin antiserum abrogated its stimulatory effect on tumour cell proliferation. Both insulin and the insulin-related substance bound to patients splenocytes to a similar extent. The data suggest that the insulin-related substance, found in this particular case of Hodgkin's disease, plays a role in tumour progression by an autocrine mechanism.

Reversal of human myeloid leukemia cells into normal granulocytes and macrophages: activity and intracellular distribution of catalase.

The activity and intracellular distribution of catalase was studied in culture human myeloid leukemia cells before and after induction of differentiation with tunicamycin. Activity of catalase was increased 5-fold in acute myeloid leukemia cells (AML) and 3-fold in chronic myeloid leukemia cells in comparison with normal granulocytes. Tunicamycin induced differentiation of HL-60 line and primary AML line characterized by increase in phagocytic cells and changes to resemble mature myeloid cells. Fc receptors were also induced in cells after tunicamycin treatment. Induction of differentiation with tunicamycin decreased high activity of catalase in cultured leukemic cells. The results of digitonin titration experiments showed that in control granulocytes and differentiated leukemic cells most of the catalase activity is present in subcellular particles distinct from mitochondria or lysosomes. In contrast, the catalase activity in undifferentiated cells is present in the same compartment as the other cytosolic markers.

Electrophoretic distribution and dissociation into subunits of lactate dehydrogenase derived from human myeloid leukemia cells before and after induction of differentiation.

The electrophoretic distribution of lactate dehydrogenase (LDH) isoenzymes, Michaelis constant, reaction with substrate, and dissociation into subunits with guanidine hydrochloride was examined in undifferentiated and differentiated human myeloid leukemia cells. Differentiation was induced with 1/microgram/ml tunicamycin. Undifferentiated cells did not display phagocytic ability, and less than 5% of these cells had Fc receptors. After exposure to tunicamycin for 40 hr, 40% of these differentiated cells had Fc receptors, and 35% showed phagocytic activity after 160 hr. The majority of the LDH activity in the undifferentiated cells was found in fraction 3, and following differentiation almost a 50% reduction in LDH activity was observed in this fraction. In addition, LDH 3 isoenzyme levels were found to be greater in patients containing a high percentage of undifferentiated cells than in patients containing a high percentage of differentiated cells. Differentiated cells displayed LDH isoenzyme fraction pattern, Michaelis constant, and reaction with substrate similar to those found in the normal granulocytes. Differences in the dissociation of LDH into subunits with guanidine hydrochloride were found between undifferentiated and differentiated acute myeloid leukemia (AML) cells. Treatment with 0.75 M guanidine hydrochloride caused complete inactivation of LDH derived from normal differentiated cells, whereas similar treatment caused complete inactivation of LDH derived from AML or normal granulocytes. LDH isoenzymes derived from normal granulocytes and differentiated AML cells were also more sensitive to guanidine hydrochloride depression of fluorescence intensity. The sedimentation constant for single peak LDH at 5.5 M guanidine hydrochloride was calculated as 1.65 sec for differentiated and 1.70 sec for undifferentiated cells. The molecular weight of the polypeptide subunits for undifferentiated cells was 30,000 and for differentiated cells was 39,000. The apparent parallel between leukemic cells after induction of differentiation and normal granulocytes indicates that the leukemic cells retain their maturation potential when exposed to an inducer of differentiation.

[Positive feedback mechanisms by which immunoproliferative tumors stimulate their own growth]. / O mehanizmu pozitivne povratne sprege kojom imunoproliferativni tumori podsticu vlastiti rast.

Based on clinical findings of patients with some proliferative tumors and experimental data, a hypothesis of positive feedback mechanism by which tumor stimulates its own growth has been formulated. In some patients with Hodgkin's disease and non-Hodgkin's lymphomas, i.e. leukemias, the high levels of substances immunologically cross reactive with insulin (SICRI), low glycemic values and increased values of growth hormone were found in the blood. These findings were in correlation with the status and stages of the disease. In a more advanced stage of the disease, the concentration of insulin-like substances was higher and glucose levels were lower in patients in remission. The high correlation was found between the increased SICRI levels of insulin-like substances showed faster growth. It is certain that some tumor cells excrete these substances. In mice with melanomas, high concentrations of these substances, growth hormone and low glucose levels were found in the blood. On the basis of these findings a hypothesis was formulated about positive feedback mechanism by which tumors stimulates their own growth. Tumor excretes SICRI which decreases glucose concentration in the blood. Hypoglycemia is a stimulation for the pituitary to release growth hormone into the blood. This hormone probably stimulates protein synthesis and replication of tumor cells contributing to increased SICRI excretion, etc. The final results of this positive feedback mechanism is faster growth of tumor and death of host.

Correlation of substance(s) immunologically cross-reactive with insulin, glucose and growth hormone in Hodgkin lymphoma patients.

The levels of substance(s) detectable by insulin specific radioimmunoassay (RIA), glucose and growth hormone (GH) were determined in the blood of patients suffering from Hodgkin lymphoma. In the relapse phase of the disease, the levels of substances immunologically cross-reactive with insulin (SICRI) were elevated and glucose concentrations were below normal. In these patients the basal and hypoglycemia-induced levels of GH in blood were strongly elevated. Contrary to this, both SICRI and glucose levels were normal in the blood of patients in remission, and GH levels were significantly reduced compared to those measured in patients in relapse.

Hormonal changes in patients with haematological malignancies.

Levels of immunologically reactive insulin (IRI), growth hormone (GH), thyroxine, cortisol and ACTH in sera of patients with various haematological malignancies were determined. IRI and GH levels were increased in 80% of the patients regardless of the type of disease. IRI was more elevated in relapse than in remission. Cytostatic treatment returned IRI serum levels to normal. Thyroxine, ACTH and cortisol in serum were higher in only two percent of the patient with haematological malignancies.

[Combined cytostatic therapy in the treatment of acute leukemias]. / Kombinovana citostatska terapija u lecenju akutnih leukemija

It was analysed 66 patients with different types of acute leukaemias treated on haematological department of Internal Clinics Mylitary Medical Academy during 1969-1974 years with combination chemotherapy. At 35 patients with acute lymphoblastic leukaemias it was obtain complete remission at 60%, and partial remission at 28,5%. Without the response was 11,4% patients. At 20 patients with acute myeloid leukaemias were induced only partial remission at 4 0% patients, and 60% patients were without the therapeutic response. The survival of patients with acute leukemias is presented. 88,4% patients with acute lymphoblastic leukaemias survived to two years, and 61,5% patients with acute myeloid leukaemias survived only to three months. None of the patients with acute myeloid leukaemias survived over one year.