POTENTIATION OF BOANMYCIN ANTITUMOR ACTIVITY BY CHEMOTACTIC PEPTIDE

Objective: Chemotactic peptide may interfere with the process of tumor growth, invasion and metastasis by activating and attracting leukocytes containing macrophages. fMLP (CHO-Met-II e-Phe) is one of the chemotactic peptides. Boanmycin (BAM), a single A6 component from the bleomycin complex, is effective against a panel of cancers in clinical trials. This study was set to investigate the antitumor activity of BAM in combination with chemotactic peptide fMLP. Methods: Cytotoxicity of BAM and fMLP to cancer cells was determined by MTT assay. Therapeutic effect was evaluated by using the model of subcutaneously transplanted hepatoma 22 in mice. Results were judged as that a CDI less than 0.85 was considered as synergism and one less than 0.75 as significant synergism. Results: BAM and fMLP showed no synergism in cytotoxicity to cancer cells. In all in vivo experiments, fMLP was administered peritumorally at the dose of 1 mg/mouse; no significant inhibition by fMLP alone on the growth of hepatoma 22 was found. Different settings of BAM and fMLP combination included: (1) BAM, administered peritumorally×3, was started 24 h after tumor inoculation. BAM (0.5 mg/kg) alone and BAM-fMLP combination inhibited the growth of hepatoma 22 by 26.6% and 64.7%, respectively (P<0.05, CDI=0.36) on day 13. (2) BAM, administered ip×3, was started 24 h after tumor inoculation. The growth of tumor in BAM (1 mg/kg) group was faster than that in BAM-fMLP combination group. On day 14, BAM (1 mg/kg) alone and BAM-fMLP combination suppressed the growth of tumor by 11% and 70.6%, respectively (P<0.05), CDI=0.42). (3) BAM, administered ip×3, was started 96 h after tumor inoculation. The growth of tumor in BAM (1 mg/kg) group was faster than that in BAM-fMLP combination group. On day 13, BAM (1 mg/kg) alone and BAM-fMLP combination suppressed tumor growth by 38.2% and 77.1%, respectively (P<0.05, CDI=0.51). As shown in all in vivo experimental settings, antitumor effect of BAM in combination with fMLP was much more potent than that of BAM alone. Conclusion: This experiment shows that chemotactic peptide fMLP may enhance the antitumor effect of BAM, which indicates that chemotactic modulation may play a positive role in cancer chemotherapy.

Synergistic Action of fMLP-boanmycin Combination on the Growth of Mouse Colon Carcinoma and Its Action Mechanisms

Objective： The inhibitory action of fMLP-boanmycin （BAM） combination on the growth of mouse colon carcinoma and its action mechanisms were observed in order to provide experimental proof for probing novel regimen of chemotactic modulation in combination with chemotherapy in the treatment of cancer. Methods： Cytotoxicity of BAM-fMLP combination to tumor cells was determined by MTT assay in vitro. Antitumor activity of BAM-fMLP combination was assessed in mice subcutaneously transplanted colon carcinoma 26. The amount of superoxide anion （O2 ·^-）released from fMLP stimulated macrophages was determined by NBT assay. The amount of nitric oxide （NO） was indirectly determined by Griess method. Results： BAM-fMLP combination had no synergistic effect on tumor cells（CDI〉0.85）, but BAM at the doses of 10μg/ml, 30μg/ml and 100μg/ml in combination with fMLP at the concentration 20μg / ml exhibited synergistic effect on tumor cells in the presence of macrophages（CDI〈0.75）, fMLP inhibited the growth of colon carcinoma 26 by 50.0% when it at dose of 1 mg/mouse was administered peritumorally. BAM （1 mg/kg, intraperitoneally, three times） alone and BAM - fMLP combination inhibited the growth of colon carcinoma 26 by 38.6% and 78.4%, respectively （CDI=0.71） on day 12. The amount of O2 ·^- released from fMLP 4.6×10^-7 mol/L （0.2μg/ml） stimulated macrophages which were treated by BAM in vitro increased significantly（P〈0.01）, fMLP 2.3×10^-6 mol/L （1μg/ml） could not stimulate macrophages to release NO, but may stimulate macrophages treated with BAM 10μg/ml and 100μg/ml to release NO significantly（P〈0.01）. Conclusion： The inhibitory action of fMLP-boanmycin combination on the growth of mouse colon carcinoma have synergism, which may associate with the increase of O2 ·^- and NO released by macrophages. Chemotactic modulation in combination with chemotherapy may be a novel regimen in the treatment of cancer.