Anti‐tumor effects of recombinant human macrophage colony‐stimulating factor, alone or in combination with local irradiation, in mice inoculated with lewis lung carcinoma cells

Abstract

Recombinant human (rhu) macrophage colony-stimulating factor (M-CSF) was evaluated for efficacy, either alone or in combination with local X-irradiation (LR), in mice inoculated subcutaneously (s.c.) with Lewis lung carcinoma (LLC) cells. The size of the primary tumor and numbers of lung metastases, 21 days after tumor inoculation and 15 days after the start of treatment, were reduced by 87% in tumor-bearing mice treated with 20 micrograms/dose M-CSF s.c. twice a day for 5 days. LR (800 cGy) to the tumor once a week for 2 weeks had a moderate anti-tumor effect and enhanced the anti-tumor effect of M-CSF. Hematological parameters, including nucleated cellularity in peripheral blood, femoral marrow, spleen and peritoneal exudate, as well as marrow and splenic granulocyte-macrophage progenitor cells, and numbers of splenic Thy 1.2+ cell and peritoneal mast cells, were perturbed in LLC-bearing mice, and were influenced by treatment with M-CSF and LR. Treatment with M-CSF plus LR, but not with either agent alone, was associated with a significant, although slight, enhancement in survival time for LLC-bearing mice. Inability to obtain a better survival-enhancing effect appeared to be related to the limited treatment, since the anti-tumor effects of M-CSF were more notable early on in disease progression and were related to the dose of M-CSF used. The effects of M-CSF were most probably indirect ones on the host immune system. M-CSF, in combination with LR, may be of benefit in the treatment of human tumors that have metastatic potential.

In vivo studies with Interleukin-12 alone and in combination with monocyte colony-stimulating factor and/or fractionated radiation treatment

“…All of the combination therapies reduced the percent of vascularized metastases, indicating either a growth inhibition (or delay) of the seeded colonies or a delay in the time of implantation of the metastasis compared to the controls. These results concur and extend those of Lu et al (1991) that M-CSF is effective in enhancing the response of the Lewis lung carcinoma to radiation therapy.…”

Immunostimulatory human urinary protein.

“…Although cytokines, interleukin la (10), interferons ,B (11) and y (12), tumor necrosis factor (13), granulocyte/ macrophage colony-stimulating factor (14), have been reported to increase the resistance of mice toward some pathogens, it is unlikely that they account for the biological activity of HGP.43, because their molecular masses are much lower. Since M-CSF, which was shown to have antitumor effects (15), is a 90-kDa disulfide-bonded homodimer (16), we tested M-CSF in our Listeria infection model and found it had no effect. It, therefore, appears that HGP.43 is distinct from cytokines.…”

Antitumor effects of human recombinant macrophage colony-stimulating factor against rat brain tumors

“…This is, to our knowledge, the first report on the antitumor effects of M-CSF on rat gliomas, although similar effects of M-CSF in vivo against some other tumors, e.g. melanoma [23,24], sarcoma [24], leukemia/lymphoma [25], ovarian-carcinoma [26] and lung cancer [17] have been reported. The doses of M-CSF which showed significant antitumor effects in these studies were wide-ranging and corresponded to less than 1/10 of [26] to 3 or 5-fold [17,25] the dose that showed antitumor effects in our study.…”

“…melanoma [23,24], sarcoma [24], leukemia/lymphoma [25], ovarian-carcinoma [26] and lung cancer [17] have been reported. The doses of M-CSF which showed significant antitumor effects in these studies were wide-ranging and corresponded to less than 1/10 of [26] to 3 or 5-fold [17,25] the dose that showed antitumor effects in our study. However, it has also been reported that the administration of M-CSF, at nearly twice the dose used here, achieved virtually no antitumor effect [24].…”

“…Human M-CSF is functional in nonprimate species [15,16] and native and recombinant human and mouse M-CSF are biologically active when administered to mice, rats and non-human primates [17]. Macrophage colony-stimulating factor has also been demonstrated to increase the tumoricidal activities of macrophages in vitro [18][19][20][21][22] and in vivo [17,[23][24][25][26]. As tar as we are aware, however, the in vivo effects of M-CSF on glial tumors have tlot been studied.…”