Abstract The title compound (VI) and its lipophilic derivatives (IXa) and (IXb) are synthesized after the structural feature of mycobacterial cell walls for the purpose of modifying and possibly enhancing the immunostimulating activity of the muramyl dipeptide which is the minimum requisite for the activity.
4-Amino-1-(o-, m-, or p-nitrophenyl)-1H-pyrazolo [3, 4-d] pyrimidine (Io, Im, or Ip), and 41 kinds of their derivatives were synthesized and the compounds were screened for antitumor activity against Ehrlich carcinoma. Antitumor activity was found in 4-elaidamido-1-(o-nitrophenyl)-1H-pyrazolo [3, 4-d] pyrimidine (VIIIo) and 4-oleamido-1-(p-nitrophenyl) compound (IXp).
The antitumor effect of human fibroblast interferon (HuIFN-beta) was examined using a nude mouse-human tumor xenograft group. Eight subcutaneously transplanted tumors--one line each of ovarian carcinoma, laryngeal carcinoma, carcinoma of the nasopharynx and hepatoma, and two lines each of lung carcinoma and melanoma--were used. HuIFN-beta at 1 X 10(5) IU/mouse was injected subcutaneously around the tumor or into the tumor itself. In the former case, statistically significant growth-suppressive effects were observed in one lung carcinoma (PC-12) and both melanomas (AM-1 and SK-14), but no effect was seen on the other five tumors. Further studies were made to ascertain the effects of intratumoral injections. Increased growth inhibition was observed in both melanomas (AM-1 and SK-14), but not in lung cancer (PC-12). Complete regression was seen in 3 of 8 mice carrying SK-14. The sensitivity of tumors to HuIFN-beta was correlated to the inhibitory effect of HuIFN-beta on cell division detected by histological observation.
Abstract Die Verbindung (IVa) wird entsprechend dem Formelschema dargestellt, hieraus werden mit Aminen 41 Amidderivate (IVb) synthetisiert und auf ihre Antitumor‐Wirkung am Ehrlich‐Carcinom geprüft.
Daily intratumor injection of human fibroblast interferon (HuIFN-beta) resulted in significant growth inhibition of human gliomas transplanted into nude mice. Light and electron microscope examinations were conducted to estimate the efficacy of HuIFN-beta. A 29-day daily treatment with HuIFN-beta induced complete regression of oligodendroglioma KG-1--a slowly growing tumor line positive for S-100 protein and negative for glial fibrillary acidic protein (GFAP)--in 9 out of 10 mice receiving 6 X 10(5) IU and 6 out of 9 given 1 X 10(5) IU. In mice with glioblastoma multiforme TMIMS-583, which showed more rapid growth and was positive for GFAP, dose-dependent growth inhibition was observed during 23 days of HuIFN-beta administration. Pathological changes of TMIMS-583 induced by HuIFN-beta were characterized by a decrease of the metaphase tumor cells, by enhanced degeneration of tumor cells with stromal reaction and round cell infiltrates, and by prominence of multinuclear giant cells containing glial filaments. Tumor weights were well correlated with the number of tumor cells in the metaphase (r = 0.89).
The mode of action of the direct antiproliferative effect of human fibroblast interferon (HuIFN-beta) on tumor cells was analyzed in vitro with a human malignant melanoma cell line, HMV-1. HuIFN-beta inhibited the growth of HMV-1 cells in a time-dependent fashion (50%-inhibition concentration: less than 50 IU/ml). Its action was cytostatic. DNA synthesis was inhibited before the antitumor effect appeared, and apparent dose-dependent inhibitions of RNA and protein synthesis were induced. An increase of cell protein content was seen with the occurrence of growth inhibition. Increase of cell volume and prolongation of doubling time were seen from the second day after the addition, which corresponded well with the effects of HuIFN-beta on the cell cycle (the accumulation of cells in the S phase). These results indicate that the direct antitumor effect of HuIFN-beta on HMV-1 cells may result from cell cycle retardation mediated through obstruction of DNA synthesis.
The antitumor effects of human fibroblast interferon (HuIFN-beta) on three lines of human malignant melanoma (AM-1, SK-14, SK-2) were studied using a nude mouse-human tumor xenograft system. The sensitivity of melanoma to interferon in relation to melanin productivity was investigated. Intratumoral administration of 6 X 10(5) IU of HuIFN-beta significantly inhibited proliferation of AM-1 and SK-14, but did not inhibit that of SK-2. The sensitivity to HuIFN-beta was in the order of SK-14, AM-1 and SK-2, and was well correlated with the susceptibility of cell division observed histologically. Although these tumors differ in production of melanin, difference in sensitivity to HuIFN-beta due to melanin productivity was not clear. The relationship between the antitumor effect and the administration method was studied with SK-14, which was the most sensitive to HuIFN-beta. Antitumoral activities depending on the routes of administration were in the order of intratumoral, peritumoral-subcutaneous and intraperitoneal. Intratumoral and subcutaneous administrations of high doses brought about complete disappearance of the tumor cells or decrease in size of the tumor mass.
The biological and immunological characteristics of TC-13, an antitumor protein-bound polysaccharide, were studied. TC-13 had no direct cytocidal effect on Ehrlich carcinoma, but it induced antitumor resistance in mice whose tumors were regressed by TC-13. TC-13 changed the electrophoretic pattern of serum proteins of mice after its ip administration, causing a slow increase of the LB component and a rapid increase of the X component. TC-13 augmented the delayed-type hypersensitivity reaction to tumor homogenate, anti-SRBC antibody formation and the cytocidal activity of macrophages in an antibody-dependent system, but it had little or no effect on blast formation of spleen lymphocytes or carbon clearance. These results and comparative studies with other immunomodulators suggest that TC-13 is a unique polysaccharide having properties intermediate between those of lentinan, a simple-structured homologous polysaccharide from basidiomycetes, and lipopolysaccharide, a cell-surface component from bacteria.
DMG, a degraded D-manno-D-glucan with a host-mediated antitumor activity did not significantly enhance nor inhibit the development of suppressor cells for either the antibody-forming response or the delayed hypersensitivity reaction to sheep red blood cells. Cyclophosphamide (CY), which inhibited the generation of suppressor cells, was combined with DMG in treatment of murine syngeneic tumors to obtain a higher antitumor activity. The antitumor activity of the combination against MH134 hepatoma was synergistically higher than that of either component alone. A marked antitumor effect of the combination treatment against MM46 mammary carcinoma was also shown. High levels of antitumor delayed hypersensitivity reactions were observed with this combination therapy. The possible roles of DMG and CY in this combination therapy are discussed.
