germanium and Carcinoma--Ehrlich-Tumor

The antitumor activity of the four metallocene compounds decaphenylstannocene [eta 5-(C6H5)5C5]2Sn(II), decabenzylstannocene [eta 5-(C6H5CH2)5C5]2Sn(II), decaphenylgermanocene [eta 5-(C6H5)5C5]2Ge(II), and decabenzylgermanocene [eta 5-(C6H5CH2)5C5]2Ge(II), containing the main group IV elements tin or germanium as the central metal atom and two pentasubstituted cyclopentadienyl ring ligands in sandwich arrangement, were tested against Ehrlich ascites tumor in female CF1 mice. The complexes caused cure rates of 40% to 90% of the animals treated over rather broad dose ranges. With both germanocene complexes, no strong dose-activity relationship was manifest. The toxicity of all four metallocenes was low, the LD10 values of both stannocenes being 460 and 500 mg/kg, and those of both germanocenes higher than 700 mg/kg. Regarding the isolated pentasubstituted cyclopentadiene ligands (C6H5)5C5H and (C6H5CH2)5C5H, these also exhibited antitumor activity which was less pronounced than that of the metal-containing sandwich complexes. Decasubstituted stannocene and germanocene compounds represent a new type of non-platinum group metal antitumor agents structurally differing from known inorganic and organometallic cytostatics.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Female; Germanium; Mice; Organometallic Compounds; Organotin Compounds; Solubility

The administration of IFN-containing sera (Ge-sera) obtained from Ge-132-treated mice (Ge-mice) or the passive transfer of macrophages (M phi) to mice bearing ascites tumors resulted in the inhibition of tumor growth. The cooperative role of Ge-sera and Ge-M phi in the display of Ge-132-antitumor activity was studied. When mice were pretreated with antimouse IFN gamma antiserum, no IFN-inducing or antitumor activities of the compound were detected. Cytotoxic activities were detected in peritoneal M phi of mice treated with Ge-sera, and passive transfer of these M phi to tumor-bearing mice resulted in the inhibition of tumor growth. When tumor-bearing mice were pretreated with substances toxic to M phi, no antitumor activity of Ge-sera was observed. However, Ge-132 antitumor activity was observed in mice depleted of T-cells, even though the antitumor effects of the compound itself were not demonstrable in T-cell-depleted mice. Therefore, a part of the antitumor activity of Ge-132 appears to be expressed as follows: Ge-132 stimulates T-cells to produce circulating lymphokine(s) which are inactivated by anti-IFN gamma treatment; activated M phi are generated from resting M phi by these lymphokine(s); the transplanted tumors are inhibited by these M phi.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Cytotoxicity, Immunologic; Female; Germanium; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Organometallic Compounds; Propionates

The antitumor activity of Ge-132 against a variety of allogeneic and syngeneic murine ascites tumors was first evaluated. The antitumor effects of Ge-132 were observed when mice inoculated with Ehrlich carcinoma (allogeneic) or RL male 1 leukemia (syngeneic) cells were treated orally. However, Ge-132 had no activity on a T-cell lymphoma (EL 4, syngeneic) or a methylcholanthrene-induced fibrosarcoma (Meth-A, syngeneic). The antitumor effect of Ge-132 in mice was related to the dose administered as well as the administration schedule. The antitumor activity of Ge-132 was next studied in mice pretreated with some blockers against immunocompetent cells. The antitumor efficacy of Ge-132 was not observed when tumor-bearing mice were treated with trypan blue and carrageenan or monoclonal anti-Thy 1.2 antibody. However, when natural killer cells were eliminated from mice bearing RL male 1 or Ehrlich ascites tumors by treatment with anti-asialo GM 1 antiserum, the antitumor efficacy of the compound was unchanged. These results suggest that Ge-132 is effective against certain ascites tumors regardless of whether the tumor is syngeneic or allogeneic. Further, its effect might be expressed through host defense mechanisms, including macrophages and/or T lymphocytes.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Germanium; Leukemia; Liver Neoplasms, Experimental; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Organometallic Compounds; Propionates; T-Lymphocytes

Sera from C57Bl/6 mice treated orally with Ge-132 exhibited antitumour activity against Ehrlich (allogeneic) and RL male 1 (syngeneic) ascites tumours in BALB/c mice. Sera obtained from mice 24 h after Ge-132 administration displayed the greatest antitumour effect and this was dose dependent. Sera prepared from mice 12, 36, or 48 h after Ge-132 treatment had no protective effect. Circulating interferon (IFN) was induced at 24 h after administration of Ge-132 but was not detected in the sera at 12, 36, or 48 h after administration. The antiviral activity of sera from Ge-132-treated mice was inactivated by treatments with trypsin, low pH, and anti-IFN gamma antiserum. The inactivated preparations of serum IFN induced by Ge-132 did not exhibit antitumour activity when administered to tumour-bearing mice. These results suggest that antitumour activity in the sera of Ge-132-treated mice may be expressed through activities of Ge-132-induced lymphokine(s), such as IFN gamma.

Topics: Animals; Carcinoma, Ehrlich Tumor; Dose-Response Relationship, Immunologic; Female; Germanium; Interferon-gamma; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms, Experimental; Organometallic Compounds; Propionates; Time Factors

Serum specimens from mice treated orally with Ge-132 (100 mg/kg) exhibited antitumor activity against Ehrlich (allogeneic) and RL 1 (syngeneic) ascites tumors in BALB/c mice. Sera obtained from mice 24 hours after Ge-132 administration displayed the highest antitumor effect and the antitumor activity was dose-dependent. Sera prepared from mice 12, 36 or 48 hours after Ge-132 treatment had no protective effect. Circulating interferon (IFN) was induced at 24 hours after administration. The antiviral activity of serum from Ge-132-treated mice was inactivated by treatment with trypsin, low pH, and anti-IFN-gamma antiserum. The inactivated preparations of serum IFN induced by Ge-132 did not show antitumor activity when administered to mice bearing Ehrlich ascites tumors. These results suggest that the antitumor activity in the sera of Ge-132-treated mice may have been expressed through IFN-gamma which was induced by Ge-132.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Germanium; Immunization, Passive; Interferon-gamma; Leukemia, Experimental; Macrophage Activation; Mice; Mice, Inbred BALB C; Organometallic Compounds; Propionates

In a murine model it has been shown that the antitumor activity of carboxyethylgermanium sesquioxide (Ge-132) can be depleted by administration of macrophage (M phi) blockers. In the present study, the role that M phi play in the antitumor activity of the compound was investigated. Oral administration of Ge-132 in mice was demonstrated to be effective in activating M phi (Ge-132-cytotoxic M phi), and the cytotoxic activity of these M phi appeared in the peritoneal cavity of mice 48 hours after the oral administration of the compound. Co-cultivation of RL male-1 leukemia or Ehrlich carcinoma cells with Ge-132-cytotoxic M phi in vitro resulted in marked suppression of the growth of tumor cells. The transfer of peritoneal exudate cells (PEC), or purified M phi fractions of PEC from Ge-132-treated mice to mice bearing Ehrlich or RL male-1 ascites tumors resulted in significant protection. However, when the cytotoxic M phi were depleted by carbonyl-iron treatment in vitro, no antitumor effect was demonstrated in mice bearing Ehrlich or RL male-1 ascites tumors. Macrophage fractions obtained from PEC of Ge-132-treated mice exhibited an inhibitory effect against certain tumors both in vivo and in vitro suggesting that the antitumor effect of Ge-132 observed in vivo resulted from the activation of M phi.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Cytotoxicity, Immunologic; Germanium; Leukemia, Experimental; Liver Neoplasms, Experimental; Macrophage Activation; Macrophages; Mice; Organometallic Compounds; Peritoneal Cavity; Propionates

The antitumor effect of an organic germanium compound, carboxyethylgermanium sesquioxide (Ge-132), was examined in mice using two systems: one, the ascitic form of Ehrlich carcinoma in DDI mice, and the other, the solid form of Meth-A fibrosarcoma in BALB/c mice. In the mice with Ehrlich ascitic tumors, a remarkable prolongation in life span was observed after intraperitoneal (i.p.) or per oral (p.o.) administration of Ge-132 (300 mg/kg), but not after intravenous (i.v.) injection of the same compound. Following i.p. or p.o. administration, cytotoxic macrophages (Mø) were induced in the peritoneal cavity after 48 h. although this was not the case after i.v. injections. When the in vivo effect of these in vitro active Mø was examined after adoptive transfer to mice bearing Ehrlich ascitic tumor cells, a significant antitumor effect was noted. In the mice bearing solid Meth-A tumors, i.v. injections of Ge-132 (100 mg/kg) were found to inhibit tumor growth remarkably, although i.p. and p.o. administrations did not have the same result. This inhibitory effect of Ge-132 by i.v. administration was explained by the continued augmentation of NK activity in peripheral blood, which was followed by the induction of specific killer cells appearing in the spleen. When the mice which had recovered from Meth-A tumor growth, following i.v. injections of Ge-132, were challenged with the same tumor on day 30, all mice were able to tolerate the challenge, but not a challenge of RL male 1 tumor cells. These observations may indicate that the differing antitumor effects of Ge-132 produced when different administration methods are used can be explained by the variation in effector cells induced by such different administration routes.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Drug Administration Schedule; Germanium; Infusions, Parenteral; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred BALB C; Organometallic Compounds; Propionates

Topics: Animals; Carcinoma, Ehrlich Tumor; Evaluation Studies as Topic; Female; Germanium; Helium; Kidney; Liver; Lymphoma, Non-Hodgkin; Mice; Mice, Inbred AKR; Neoplasms, Experimental; Radionuclide Imaging; Sarcoma 180; Selenium; Time Factors

Topics: Animals; Bone and Bones; Carcinoma, Ehrlich Tumor; Electric Conductivity; Electronics; Gallium; Germanium; Indium; Injections, Intraperitoneal; Intestines; Kidney; Lithium; Liver; Lung; Methods; Mice; Mice, Inbred Strains; Radioisotopes; Selenium; Semiconductors; Stomach