bropirimine and Colonic-Neoplasms

This investigation aimed to develop a biologically relevant murine model of colorectal liver metastases and determine if Kupffer cells (KC) and hepatic natural killer cells (hNKC) regulate tumor growth. The model involves the injection of murine colon adenocarcinoma 26 (MCA 26) tumor cells into the portal vein of female-specific pathogen-free BALB/c mice. Metastases developed in all animals, and the growth was limited entirely to the liver. To determine if KC and hNKC control the development of liver metastases, the in vivo function of these hepatic effector cells was modulated. Tumor growth was quantitated by the uptake of 125I into tumor DNA. Stimulation of the KC and hNKC produced a significant (P less than 0.01) dose-dependent decrease in 125I uptake in the liver in both treatment groups, which was associated with a significant improvement in survival (P less than 0.05). The in vivo cytotoxic function of the liver was inhibited with an intravenous injection of gadolinium chloride (for KC) or asialo GM1 antiserum (for hNKC). Inhibition of KC and hNKC cytotoxic function led to a significant (P less than 0.01) increase in 125I uptake in the liver and a significant decrease in survival (P less than 0.05).

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Division; Cell Line; Cell Survival; Colonic Neoplasms; Cytosine; Cytotoxicity, Immunologic; Female; G(M1) Ganglioside; Gadolinium; Immune Sera; Killer Cells, Natural; Kupffer Cells; Liver Neoplasms; Mice; Mice, Inbred BALB C; Propionibacterium acnes; Rectal Neoplasms

It is well documented that the antitumor activity of tumor necrosis factor (TNF) is improved by interferons (IFN's). Bropirimine (BP) is an immune response modifier which induces IFN. Both TNF and BP have the capacity to inhibit the growth of a transplantable colon tumor (CC531) in inbred WAG rats. In the present study their combined use was investigated in a one-week assay, with the tumor implanted under the renal capsule. The results indicate that BP, given on days 0 and 1, and 1 microgram TNF on days 0, 2 and 4 act additively, leading to an almost complete inhibition of tumor growth.

Topics: Animals; Colonic Neoplasms; Cytosine; Interferon Inducers; Male; Mice; Rats; Rats, Inbred Strains; Recombinant Proteins; Tumor Necrosis Factor-alpha

It is well documented that the antitumor capacity of tumor necrosis factor (TNF) can be enhanced by interferons (IFNs), notably IFN-gamma. The aim of this study was to investigate the efficacy of a combined treatment with TNF and the IFN-inducer 2-amino-5-bromo-6-phenyl-4-pyrimidinone (ABPP) on a transplantable colon carcinoma (CC531) in rats. The tumor was implanted under the kidney capsule of syngeneic rats; the tumors were removed a week after implantation and growth was assessed by weighing. The animals were treated with 1 microgram of TNF, given i.v. on days 0, 2, and 4; and with 250 mg/kg of ABPP, administered i.p. on days 0 and 1. The results of two separate experiments indicated that both TNF and ABPP had a significant inhibitory effect on tumor growth. Combined, the two agents were found to act additively. In the dosage used, TNF toxicity was mild, transient, and not influenced by ABPP.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Colonic Neoplasms; Cytosine; Drug Therapy, Combination; Interferon Inducers; Male; Rats; Rats, Inbred Strains; Tumor Necrosis Factor-alpha

ABPP (2-amino-5-bromo-6-phenyl-4-pyrimidinone) is a pyrimidinone with known interferon-inducing, natural killer (NK) cell activity enhancing, antiviral and antitumor properties in several animal species. Its effect on CC531, a dimethylhydrazine-induced, transplantable, weakly immunogenic adenocarcinoma of the colon in WAG rats, was studied. ABPP was found to have no direct cytotoxic effect on CC531 cells in vitro. When small cubes of tumor of equal weight were implanted under the renal capsule, administration of 250 mg/kg of ABPP i.p. on day 0 and +1 led repeatedly to significant (p less than 0.02 up to p less than 0.001) inhibition of tumor growth, when measured on day +7. Lower doses or a single dose of ABPP did not achieve this effect. Late administration (on day +6 and +7) of 250 mg/kg of ABPP in this model was found to have no effect on tumor growth when measured on day +13. When 5 X 10(5) tumor cells were injected in the portal vein, administration of 250 mg/kg of ABPP i.p. on day 0 and +1 reduced significantly (p = 0.002) the number of liver metastases, when counted on day +30. Survival in this group was significantly prolonged (p less than 0.01). However when ABPP was given on day +6 and +7, significantly more (p less than 0.02) metastases in the liver were counted on day +30. The results show a significant antitumor effect of ABPP against tumor CC531 in the subrenal capsule assay (SRCA) model as well as in the liver metastasis model when administered at the time of tumor inoculation. Late administration of ABPP did not inhibit tumor growth in the SRCA and significantly enhanced the development of liver metastases. The role of timing, tumor site, and the mechanisms by which this dual outcome of immunotherapy with ABPP is mediated are discussed. The results of these experiments may have important implications for the design of clinical studies with ABPP.

Topics: Animals; Antineoplastic Agents; Colonic Neoplasms; Cytosine; Dose-Response Relationship, Drug; Interferon Inducers; Killer Cells, Natural; Kupffer Cells; Liver Neoplasms; Male; Rats; Rats, Inbred Strains; T-Lymphocytes, Regulatory