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Isoprinosine trial in herpes zoster. Effects on delayed cutaneous hypersensitivity
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DOUBLE-BLIND STUDY OF ISOPRINOSINE INFLUENCE ON IMMUNE P ~ T E R S IN SOLID TL~OR-BEARING PATIENTS TREATED BY RADIOTHERAPY. H. Fridman, Laboratoire d'I~aJnologie - R. Calle, Directeur Section M6dicale & hospitali~re Institut Curie - Paris. A. Morin - Laboratoires Delalande - 92400 Courbevoie Hundred and six patients of the InstitutCurie received Isoprinosine (53 patients) c r a placebo (53 patients) in a randomized double-blind trial to test the restoration of inm~me functions following curative radiotherapy. The distribution was as follows : 46 patients with breast cancer, 31 with mouth and neck cancer, 20 with cancer of the uterus. The immune status was assessed by the cotmts of lymphocytes, the percentage of E, EA rosettes and surface Ig-positive cells. Also, lymphoblastic transformation induced by mitogens and PPD and skin tests were measured. Nearly all patients sh~ved depressed i~mEme function following radiotherapy. Isoprinosine (or placebo) was then given with the following protocol : 3 g every day during the first month of therapy, then 3 g four days a week during the next 4 months. Inraune status was evaluated before radiotherapy, immediately thereafter and after I, 3 and 5 months of treatment. As a general rule, patients treated with Isoprinosine were more rapidly i~m~norestored than control patients. For instance, after 3 months of treatment, 64 % of Isoprinosine treated patients had a normal response as compared to 23 % of placebo treated patients (p < 0.05). Interestingly, at the end of the therapeutic trial 34 % of control patients were not immunorestored as compared to II % of treated patients. When breast cancer bearing patients are considered the ~ u n o r e s t o r a t i o n by Isoprinosine was even more significant after 3 months of treatment (71% as compared to 23 % in controls, p (0.01). It may therefore be concluded that Isoprinosine accelerates the restoration of the immune functions depressed by radiotherapy which may be of importance in the host defence against residual cancer.
25
Monocytes as the Possible Responding Cell Population in Augmentation of Phytohemagglutin Stimulation by Inosiplex Peter L. Jacobsen~ Deborah Greenspan~ and John S. Greenspan Department of Oral Medicine and Hospital Dentistry, University of California, San Francisco. San Francisco CA 94143, U.S.A. Inosiplex (Isoprinosine) was developed as an a n t i v i r a l agent but has come under wider investigation because of its incnunopotentiating properties. I t has been shown by various assays, including blast transformation with the mitogen phytohemagglutinin (PHA), to augment cell mediated immunity in v i t r o . This study addresses the p o s s i b i l i t y of a specific responding cell population among the peripheral blood lymphocytes that could account for the effect of inosiplex. Heparinized blood was obtained from 25 donors and the lymphocytes were separated on a Ficoll-Hypaque gradient. These cells were washed and 9 of the 25 samples were divided in half. One half (about 2xiO7 cells in 1.5 ml) was incubated with 5U mg of carbonyl iron f i l i n g s for 30 minutes to deplete the monocytes. A nonspecific esterase stain showed that the monocyte population was reduced from 18+5% to 1+1%, a concentration adequate to support PHA stimulation. Both the depleted lymphocytes (D) and nondepleted lymphocytes (ND) were plated at a concentration of 2xiO5 cells per microtiter well and cultured in essential medium supplemented with L-glutamine, p e n i c i l l i n , streptomycin, and 10% human AB serum. Inosiplex (ISOP) was added at a concentration of 250, 25, and 2.5 ~g/ml. PHA was used at a concentration of 3.3, 1.0, 0.33, and 0.1 ~g/ml. The ceils were incubated for 72 hours; then 3H-thymidine was added~ and incubation continued for 24 hours. The cells were then harvested and the amount of JH-thymidine incorporated was measured. As in other studies, the inosiplex at a concentration of 250 ~g/mg augmented the PHA stimulation by an average of 35_+15% over the PHA alone, at a l l doses except 0.1 ~g/ml. Inosiplex had no stimulating effect alone. Monocyte depletion alone increased the mitogenic stimulation by about 65+12% at a l l doses of PHA except 0.1 ~g/ml. I f ISOP 250 is added to D cells the PHA response is augmented by 32+20%. I t is therefore possible that inosiplex augments lymphocyte respose to PHA by f a c i l i t a t i n 9 the stimulatory effect of monocytes on lymphocytes.
24
DOUBLE-BLIND STUDY OF ISOPRINOSINE INFLUENCE ON IMMUNE P ~ T E R S IN SOLID TL~OR-BEARING PATIENTS TREATED BY RADIOTHERAPY. H. Fridman, Laboratoire d'I~aJnologie - R. Calle, Directeur Section M6dicale & hospitali~re Institut Curie - Paris. A. Morin - Laboratoires Delalande - 92400 Courbevoie Hundred and six patients of the InstitutCurie received Isoprinosine (53 patients) c r a placebo (53 patients) in a randomized double-blind trial to test the restoration of inm~me functions following curative radiotherapy. The distribution was as follows : 46 patients with breast cancer, 31 with mouth and neck cancer, 20 with cancer of the uterus. The immune status was assessed by the cotmts of lymphocytes, the percentage of E, EA rosettes and surface Ig-positive cells. Also, lymphoblastic transformation induced by mitogens and PPD and skin tests were measured. Nearly all patients sh~ved depressed i~mEme function following radiotherapy. Isoprinosine (or placebo) was then given with the following protocol : 3 g every day during the first month of therapy, then 3 g four days a week during the next 4 months. Inraune status was evaluated before radiotherapy, immediately thereafter and after I, 3 and 5 months of treatment. As a general rule, patients treated with Isoprinosine were more rapidly i~m~norestored than control patients. For instance, after 3 months of treatment, 64 % of Isoprinosine treated patients had a normal response as compared to 23 % of placebo treated patients (p < 0.05). Interestingly, at the end of the therapeutic trial 34 % of control patients were not immunorestored as compared to II % of treated patients. When breast cancer bearing patients are considered the ~ u n o r e s t o r a t i o n by Isoprinosine was even more significant after 3 months of treatment (71% as compared to 23 % in controls, p (0.01). It may therefore be concluded that Isoprinosine accelerates the restoration of the immune functions depressed by radiotherapy which may be of importance in the host defence against residual cancer.
25
Monocytes as the Possible Responding Cell Population in Augmentation of Phytohemagglutin Stimulation by Inosiplex Peter L. Jacobsen~ Deborah Greenspan~ and John S. Greenspan Department of Oral Medicine and Hospital Dentistry, University of California, San Francisco. San Francisco CA 94143, U.S.A. Inosiplex (Isoprinosine) was developed as an a n t i v i r a l agent but has come under wider investigation because of its incnunopotentiating properties. I t has been shown by various assays, including blast transformation with the mitogen phytohemagglutinin (PHA), to augment cell mediated immunity in v i t r o . This study addresses the p o s s i b i l i t y of a specific responding cell population among the peripheral blood lymphocytes that could account for the effect of inosiplex. Heparinized blood was obtained from 25 donors and the lymphocytes were separated on a Ficoll-Hypaque gradient. These cells were washed and 9 of the 25 samples were divided in half. One half (about 2xiO7 cells in 1.5 ml) was incubated with 5U mg of carbonyl iron f i l i n g s for 30 minutes to deplete the monocytes. A nonspecific esterase stain showed that the monocyte population was reduced from 18+5% to 1+1%, a concentration adequate to support PHA stimulation. Both the depleted lymphocytes (D) and nondepleted lymphocytes (ND) were plated at a concentration of 2xiO5 cells per microtiter well and cultured in essential medium supplemented with L-glutamine, p e n i c i l l i n , streptomycin, and 10% human AB serum. Inosiplex (ISOP) was added at a concentration of 250, 25, and 2.5 ~g/ml. PHA was used at a concentration of 3.3, 1.0, 0.33, and 0.1 ~g/ml. The ceils were incubated for 72 hours; then 3H-thymidine was added~ and incubation continued for 24 hours. The cells were then harvested and the amount of JH-thymidine incorporated was measured. As in other studies, the inosiplex at a concentration of 250 ~g/mg augmented the PHA stimulation by an average of 35_+15% over the PHA alone, at a l l doses except 0.1 ~g/ml. Inosiplex had no stimulating effect alone. Monocyte depletion alone increased the mitogenic stimulation by about 65+12% at a l l doses of PHA except 0.1 ~g/ml. I f ISOP 250 is added to D cells the PHA response is augmented by 32+20%. I t is therefore possible that inosiplex augments lymphocyte respose to PHA by f a c i l i t a t i n 9 the stimulatory effect of monocytes on lymphocytes.