bleomycin-a6 and Lung-Neoplasms

From August 1993 to March 1994, 36 patients were enrolled for a phase I study of Boanmycin (Bleomycin A6) a new anticancer drug to determine it toxicity and maximal dose. Of the 36 cases, 16 were male and 20 female, age 20-62. Dose escalation was performed if a minimum of threed patients were fully evaluable for toxicity (2 weeks following drug administration) and if severe or life-threatening toxicity had not occurred. Dose of Boanmycin were escalated from 1 mg (0.5-0.7 mg/m2) to 12 mg(6.7-7.5 mg/m2) i. m. three times every week for two weeks. Surveillance of serum concentration of Boanmycin was conducted in six cases by microbiological analysis, and the pharmacokinetics parameters were obtained. Phase I study of Boanmycin showed that Boanmycin had no myelosuppression and cardiac toxicity, and its major adverse reactions were fever, gastrointestinal reactions and hardening at injection (by i. m. route). Rather than dose-related, fever was individual-related. There were mild myalgia, alopecia, skin rash, pigmentation in some patients. All adverse reactions resolved after discontinuation of therapy. There was no Boanmycin-related lethal complication, and the maximum tolerated dose was not obtainable. If patients have renal or lung disease, Boanmycin aggravate their renal and lung functions. Therefore we recommend that dose of Boanmycin for phase I clinical trial should be is 8-10 mg(5-6 mg/m2) i m or iv (iv can decrease local side effect) two-three times per week.

Topics: Adult; Antibiotics, Antineoplastic; Bleomycin; Breast Neoplasms; Female; Fever; Humans; Lung Neoplasms; Lymphoma, Non-Hodgkin; Male; Middle Aged

Boanmycin hydrochloride, a new antitumor agent, functions similarly to bleomycin, but has a shorter half-life and faster clearance in vivo. Therefore, it is used in clinical studies for lung squamous cell cancer. However, previous studies have shown that besides its antitumor effect, bleomycin also induces the generation of senescence fibroblasts, which secrete senescence-associated secretory phenotype factors that have protumorigenic potential, consequently altering the tumor microenvironment. Hence, it is critical to clarify boanmycin potential in remodeling the tumor microenvironment after the chemotherapy treatment of tumors. Bone is the favorite organ for lung cancer metastasis. Thus, in this study, lung fibroblasts and bone osteoblasts (OBs) were used to reflect the resident stromal cells in the primary lung and bone metastatic microenvironment, respectively. Lung fibroblasts (IMR90) and primary OBs were treated with 6.7 μl/ml boanmycin or bleomycin for 24 h and MTT was monitored from day 1 to day 9; senescence-associated β-galactosidase staining, which indicated the cell senescence, was performed on day 7; and well-established senescence-associated secretory phenotype factor interleukin-6 expression was detected on day 9. MTT data showed that boanmycin inhibited cell proliferation in both IMR90 and OBs. Moreover, senescence-associated β-galactosidase staining showed that in response to boanmycin, there were 90% senescence cells in IMR90 and 95% in OBs. However, in vehicle, there were only 40 or 30% senescence cells, respectively. Furthermore, quantitative PCR data also showed that the interleukin-6 expression was highly induced by boanmycin to six-fold in OBs. Boanmycin treatment for cancer chemotherapy has the remodeling ability to alter the tumor microenvironment and might contribute toward lung cancer relapse and metastasis on long-term treatment.

Topics: Animals; Antibiotics, Antineoplastic; beta-Galactosidase; Bleomycin; Cell Line; Cellular Senescence; Fibroblasts; Humans; Interleukin-6; Lung Neoplasms; Mice; Osteoblasts; Tumor Microenvironment

Boanmycin (bleomycin A6, BAM) was found to markedly inhibit the spontaneous pulmonary metastasis of Lewis carcinoma in mice. Compared at equitoxic doses (1/9 LD50), BAM was more effective than mitomycin. Minocycline (MNO) at 5 mg.kg-1 showed no inhibition on the growth of sc transplanted Lewis primary tumor; however, it markedly potentiated the antimetastatic effect of BAM. Treated with BAM (5 mg.kg-1) alone, the number of total metastatic foci and that of large foci (> 2 mm in diameter) in the lung were suppressed by 67% and 85%, respectively. When BAM was used in combination with MNO, the number of those foci was further reduced by 88% and 100%, respectively. By NAG enzyme assay, MNO was not cytotoxic and showed no synergism with BAM against PG cells, a cell line derived from a highly metastatic human giant cell carcinoma of the lung. Determined by ELISA with a monoclonal antibody, the expression of type IV collagenase in PG cells was remarkably inhibited by MNO. The intracellular free Ca2+ level in PG cells was reduced from 76.7 nmol.L-1 to 42.2 nmol.L-1 by MNO treatment. The study suggests that the combination of boanmycin and minocycline may be useful for control of tumor metastasis and the inhibition of type IV collagenase expression may be involved in the mechanism of minocycline potentiation.

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Carcinoma, Giant Cell; Carcinoma, Lewis Lung; Drug Synergism; Female; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Minocycline; Tumor Cells, Cultured