- INTRODUCTION: THE FIRST MEDICAMENT THAT KILLS CANCER CELLS BUT NOT HEALTHY CELLS
- I. EFFICACY
- CASE REPORTS
- ANTIVIRAL PROPERTIES
- THE INHIBITION OF THE TUMORAL ANGIOGENESIS
- THE IN VIVO STUDIES
- MODULATION OF THE IMMUNE SYSTEM
- RADIOPROTECTIVE EFFECT
- TOXICOLOGIC STUDIES
- NORMALISATION OF THE METABOLISM
- THE EFFECT ON VARIOUS ENZYMES
- INTERACTION WITH OTHER DRUGS
- II. SAFETY
- III. QUALITY
Unusual for an anticancer agent NSC 631570 possesses some distinct immune properties (24, 44). In several immune target-effector systems NSC 631570 significantly amplified the malignotoxic activity of macrophages (231), lymphocytes and NK cells (47), and stimulates dendritic cells maturation in vitro (258). While the parameters like B-lymphocytes count, immune globulin concentrations, complement and acute phase proteins did not changed significantly, it can be postulated NSC 631570 modulates the cellular part of the immune system whereas the humoral part remains unaffected.
The incubation of peripheral lymphocytes of healthy blood donors with NSC 631570 resulted in the increase of lymphocytes with the T-helper phenotype, decrease of the lymphocytes with T-suppressor phenotype as well as increase of T-helper/T-suppressor ratio (7, 18).
NSC 631570 was administered to nine advanced stage cancer patients (4 with liver cancer, 4 with head and neck carcinomas, and one breast cancer). In three cases the tumors responded partially on the therapy, in one case a minimal response was noted, in 3 cases the disease was stabil, and in 2 cases the tumors did not respond on the treatment. After the therapy, the number of T-helper cells (CD4) as well as the CD4/CD8 ratio increased (13).
In eight oncological patients immune parameters were compared before and after the treatment with NSC 631570. It was revealed NSC 631570 affected basically the thymus dependant cells (T-cells). The number of rosette-forming T-lymphocytes was significantly higher after the treatment. No significant changes were observed in the humoral immune parameters (22).
In nine male lung cancer patients lymphocytes subpopulations were determined before and after the therapy with NSC 631570. The therapy resulted in increased total T-cells and reduced T-suppressor fraction. The helper-suppressor ratio normalized. There was no sign of the activation of NK cells, T-helpers as well as B-cells. The restoration of the cellular immunity correlated with the better clinical course of the disease (25).
The effect of NSC 631570 on the functional activity of monocytes from 20 patients with lung cancer or peritonitis was studied using nitro blue tetrazolium chloride test (NBT-test). The authors reported on the positive effect of NSC 631570 on the functional activity of the macrophages as well as antioxidant systems of monocytes and erythrocytes (46).
23 patients with various tumors were treated with NSC 631570 and the immune e parameters were evaluated before and after the therapy. The authors observed the increase of lymphocytes and the decrease of the blood sedimentation rate. Following immune changes were also noted: increase of T-lymphocytes, T-helpers, NK-cytotoxicity, phagocytic activity, normalisation of the T-helper/T-suppressor ratio, and occurance of large granular lymphocytes (48, 106).
NSC 631570 was effective in the therapy of recurring lung diseases in children from the Chernobyl area (202).
Dendritic cells are immune cells that act as messengers between the innate and adaptive immunity. Their main function is to process antigen material and present it on the surface to other cells of the immune system, thus functioning as antigen-presenting cells and are seen as the most potent population executing this function.
In the experiments with the mononuclears from the peripheric blood of healthy persons the effect of NSC 631570 on the phenotypic and functional properties of dendritic cells was studied. The most prominent induction of the expression of the cell surface molecules CD86 and HLA-DR was achieved with NSC 631570 at the lowest and highest concentration, 0.6 µg/mL and 10 µg/mL, respectively. Lipopolysaccharide as standard comparative agent induced similar increase of the cell surface receptors.
The proliferation index of the incubated lymphocytes was used as the indicator of the dendritic cells activity. After addition of NSC 631570 to the incubated dendritic cells, the lymphocyte proliferation index increased from 22.6% up to 32.30% at 0.6 µg/mL or 29.34% at 10 µg/mL, respectively. These values are similar to the one of 31.82%, i.e. proliferation index achieved at the incubation of lymphocytes with the phytohemagglutinin. The authors concluded dendritic cells incubated with NSC 631570 are strong stimulators of the lymphocyte proliferation. They postulate also NSC 631570 can take an important part in the immune therapy of cancer (268).
In the tests on alloimmunised mice NSC 631570 augmented the lytic activity of splenic lymphocytes by up to 48fold. The lytic activity of the IL-2 treated spleen cells and peritoneal exudate lymphocytes were also increased significantly by the addition of NSC 631570 to the assay medium (17, 66).
Human lymphocytes as well as guinea pig lymphocytes were activated more pronounced when incubated with Ukrain than with PHA. In rats NSC 631570 caused a clear increase of macrophages with NK-activity. A similar modulating effect on the macrophages was observed also clinically (49).
It was revealed in the tests on CBA mice and Wistar rats that NSC 631570 stimulates macrophages. As marker of this activity the enzyme chitotriosidase - a part of the native immunity was used (168).
In a study on intact and thymus-ectomised mice NSC 631570 augmented the endocrine function of thymus. After NSC 631570 administration, increased production of substances with thymosin-like activity was detected. Repeated administration of NSC 631570 caused a 2fold rise of T-cells in blood, a 4.5fold rise of large granulocytes and increase of the NK-activity of splenocytes. The production of interferon and antibodies after the antigen administration was increased as well (180).
The effect of well-known immune modulators interferon-gamma, NSC 631570 and pokeweed mitogen on the selective uptake of technetium-99m(99mTc)-labelled tumor necrosis factor (TNF) was studied in the intramuscular implanted murine embryonic carcinoma. The highest absolute tumor uptake of 99mTc- TNF was achieved when NSC 631570 was used, followed by IFN-γ and pokeweed mitogen (104).
In the experiments on BALB/c and F1 (BALB/c x C57BL/6J) mice it was revealed that NSC 631570 inhibits the allergic sensitization of animals against ovalbumin, expressed in the weakened IgE-reaction and decreased histamine release. The incubation of ovalbumin with NSC 631570 induced decreased antigenicity of this protein (84).
The immune modulating effect of NSC 631570 was studied in several studies in mice. Repeated subcutaneous injections of NSC 631570 to mice infected with the twofold LD50 of E. coli, S. aureus, or influenza virus increased the survival rate of the animals significantly (60, 87, 89).
When human lymphocytes were incubated with phytohemagglutinin (PHA) and NSC 631570, increased absorption of 3H-thymidin in the cells was observed. The authors point out the strong synergetic effect of NSC 631570 and phytohemagglutinin (76).
By means of the cell proliferation assay the mitogenic effects of PHA and NSC 631570 on human peripheral blood mononuclear cells (PBMC) were studied. It was revealed even a short pretreatment of the PBMC with NSC 631570 has a strong synergetic effect on the PHA-mitogenesis. Consequently, the cell stimulation parameters were much higher after combined stimulation than after using PHA alone (65).
In experiments with murine (CC57 Black/6) macrophages and rabbit G-actin, the effects of NSC 631570 and sanguinarine on phagosome-lysosome membrane fusion and actin cytoskeleton were studied. The most stimulating effect on the phagosome-lysosome fusion exerted sanguinarine at 10 µmol and NSC 631570 at 5 µmol. At the same dose NSC 631570 doubled the content of fibrillary actin in murine peritoneal macrophages. Moreover, NSC 631570 and sanguinarine induced the polymerisation of rabbit globular actin. These effects were dose-dependent. The authors suggest sanguinarine and NSC 631570 can alter intracellular membrane transport (231).