minocycline and Carcinoma--Lewis-Lung

With the introduction of new drugs, the efficacy of chemotherapy in non-small-cell lung cancer has been improving. The combination of paclitaxel and carboplatin has shown activity in this disease but is far from curative.. The antiangiogenic agent regimen of TNP-470/minocycline was added to treatment with paclitaxel and carboplatin alone and in combination in animals bearing the Lewis lung carcinoma.. Administration of the antiangiogenic regimen prior to, during and after the cytotoxic therapy increased the tumor growth delay 1.6-fold and decreased the number of lung metastases to 20% of the number observed in the control animals. [14C]Paclitaxel, platinum from carboplatin and [14C]albumin levels were determined over a 24-h time course in tumors and normal tissues of animals bearing the Lewis lung carcinoma and pretreated with TNP-470/minocycline or not pretreated. There were higher levels of [14C]paclitaxel, platinum from carboplatin and [14C]albumin in the tumors and some normal tissues of the animals that had received TNP-470/minocycline compared with those that had not received TNP-470/minocycline, especially at the earlier time points. Administration of TNP-470/minocycline to animals bearing the EMT-6 mammary carcinoma increased the cytotoxicity of high-dose paclitaxel toward EMT-6 tumor cells and toward bone marrow CFU-GM. Administration of TNP-470/minocycline to animals bearing the EMT-6 mammary carcinoma also increased the cytotoxicity of carboplatin toward the EMT-6 tumor cells but did not affect the toxicity of carboplatin toward the bone marrow CFU-GM.. The addition of TNP-470/minocycline to treatment with paclitaxel and carboplatin resulted in increased antitumor activity and efficacy and further investigation of this combination is warranted.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Carboplatin; Carcinoma, Lewis Lung; Cell Survival; Colony-Forming Units Assay; Cyclohexanes; Drug Synergism; Drug Therapy, Combination; Female; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Minocycline; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Paclitaxel; Sesquiterpenes

TNP-740, minocycline, suramin and genistein have demonstrated antiangiogenic activity in various experimental systems. The effect of these agents alone and in two agent combinations on the number of intratumoral vessels and response to cytotoxic anticancer therapies was assessed in animals bearing the Lewis lung carcinoma. Treatment with each of the antiangiogenic agents alone and in two agent combinations decreased the number of intratumoral vessels visualized by CD31 or Factor VIII staining to 30% to 50% of the number in the untreated control tumors. In general, the antiangiogenic agents are more effective adjuvants to cytotoxic therapies when used as two agent combinations than as single agents. The most effective antiangiogenic combinations were: TNP-470/minocycline > TNP-470/genistein > TNP-470/suramin. The increases in the response of the primary tumor to cyclophosphamide, adriamycin, CDDP, BCNU, x-rays or 5-fluorouracil and the lung metastases occur to about the same level with the addition of antiangiogenic agents to the therapies. With the treatment combination TNP-470/minocycline/cyclophosphamide 40% of the animals were cured. The results of these studies indicate that antiangiogenic agents can be very useful additions to treatment regimens for solid tumors.

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Lewis Lung; Carmustine; Cell Division; Cisplatin; Cyclohexanes; Cyclophosphamide; Doxorubicin; Drug Synergism; Genistein; Isoflavones; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Minocycline; Neoplasm Invasiveness; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Random Allocation; Sesquiterpenes; Suramin

Although the antiangiogenic agent TNP-470 does not, in general, increase the cytotoxicity of anti-cancer therapies in cell culture, the antiangiogenic agents TNP-470 and minocycline individually and especially in combination have been shown to increase the tumor growth delay produced by several standard cytotoxic therapies in the Lewis lung carcinoma. In an effort to understand the mechanism by which the antiangiogenic agent combination TNP-470/minocycline potentiates the antitumor activity of cytotoxic therapeutic agents in vivo, the biodistribution of [14C]-cyclophosphamide and cis-diamminedichloroplatinum(II) was determined 6 h after cytotoxic drug administration in animals bearing Lewis lung carcinoma pretreated with TNP-470/minocycline and in animals without pretreatment. Higher levels of 14C and platinum were found in 9 tissues (including tumor) except blood in animals pretreated with TNP-470/minocycline. The increased drug levels in the tumors may be sufficient to account for the increased tumor growth delays observed previously. DNA alkaline elution of tumors from animals pretreated with TNP-470/minocycline showed increased DNA cross-linking by both cyclophosphamide and cis-diamminedichloroplatinum(II). The possible implications of these results are discussed.

Topics: Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Carmustine; Cell Hypoxia; Cell Survival; Cisplatin; Cyclohexanes; Cyclophosphamide; DNA, Neoplasm; Drug Combinations; Male; Melphalan; Mice; Mice, Inbred C57BL; Minocycline; O-(Chloroacetylcarbamoyl)fumagillol; Platinum; Sesquiterpenes; Tumor Cells, Cultured

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