mitoguazone and Breast-Neoplasms

New naphthalimidopropyl, bisphthalimidopropyl and bisnaphthalimidopropyl (BNIP) derivatives were synthesised and characterised. Their interactions with Calf Thymus DNA were studied by UV spectrophotometric analysis and a competitive Ethidium bromide displacement assay. Cytotoxicity was determined by MTT assay in a breast cell system (MDA-MB-231 and MCF-10A cells). All BNIPs exhibited strong DNA-binding properties and cytotoxic activity with IC(50) values in the range of 0.83-12.68 microM (24 and 48 h treatment). In addition, the uptake of BNIP derivatives within cancer cells was not via utilisation of the MGBG polyamine transporter. Put together the results confirm that the presence of the bisnaphthalimidopropyl and alkyl linker functionality are crucial for exerting DNA-binding and cytotoxic properties, hence demonstrating promise in their further development as potential anti cancer agents.

Topics: Breast Neoplasms; Cell Line, Tumor; DNA, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Imides; Magnetic Resonance Spectroscopy

Modulation of cancer chemotherapeutic drugs has been attempted to increase efficacy and overcome resistance to the chemotherapeutic agent. Studies have shown schedule-dependent interactions in combined use of chemotherapeutic drugs. Mitoguazone (MGBG), an old drug with possible modulating activity, was used in combination with gemcitabine, a relatively new cancer drug, in treating tissue cultured human breast cancer cells and mammary rat tumors. Tissue cultured BOT-2 cancer cells were first treated with varying concentrations of gemcitabine and MGBG, independently. Combinations of the two drugs were then used with different scheduled administrations. Marked synergistic activity was found between gemcitabine and MGBG when the MGBG was given first, followed by gemcitabine 24 hours later. A non-toxic dose of MGBG enhanced the toxicity of gemcitabine by eight orders of magnitude using MTT assays in the tissue cultured human breast cancer cell study. The sequential administration of MGBG and gemcitabine also increased the survival rate of rats bearing mammary tumors in our pilot animal study.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Division; Deoxycytidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Female; Gemcitabine; Humans; Mammary Neoplasms, Experimental; Mitoguazone; Rats; Survival Analysis; Tumor Cells, Cultured

Mitoguazone (methylglyoxal bisguanylhydrazone, methyl-GAG or MGBG) is a synthetic polycarbonyl derivative with activity in patients with Hodgkin's and non-Hodgkin's lymphoma, head and neck cancer, prostate cancer, and esophageal cancer. Mitoguazone has also recently been documented to have activity in patients with AIDS-related lymphoma. Among anticancer drugs, mitoguazone has a unique mechanism of action via interference with the polyamine biosynthetic pathway. Polyamines stabilize DNA structure by non-covalent cross-bridging between phosphate groups on opposite strands. In addition, mitoguazone causes uncoupling of oxidative phosphorylation. In this study, the ability of mitoguazone to induce apoptosis by inhibiting the polyamine pathway was assessed in three Burkitt's lymphoma cell lines (Raji, Ramos and Daudi) and one prostate carcinoma cell line (MPC 3). Additional evaluations were performed in two human breast cancer cell lines (MCF7 with wild-type p53 and VM4K with mutated p53) to determine whether the p53 tumor suppressor gene was required for efficient apoptosis induction. The present study demonstrated that mitoguazone induces apoptosis in all the different human cancer cell lines tested in a concentration- and time-dependent way, and triggers a p53-independent programmed cell death in the human breast cancer MCF7 cell line.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Burkitt Lymphoma; Genes, p53; Humans; Male; Mitoguazone; Prostatic Neoplasms; Tumor Cells, Cultured

Polyamines are considered to be important intracellular molecules for the proliferation of the cancer cells. In this study, effects of methylglyoxal bis(cyclopentylamidinohydrazone) (MGBCP), a potent inhibitor of the polyamine biosynthetic pathway, on the growth and cell cycle of T-47D human breast cancer cells were investigated. MGBCP dose-dependently inhibited the growth of T-47D cells, in which the contents of spermine, spermidine and putrescine decreased concomitantly. The gene expression of cyclin D1 was also repressed by the MGBCP treatment. The MGBCP-treated cells clearly exhibited morphological changes indicating the blebbing and chromatin condensation which are characteristic of apoptosis. Flow cytometric analysis showed hypo-diploid subpopulations due to apoptotic cells, and characteristic oligonucleosomal-sized DNA fragments were clearly observed for MGBCP-treated cells as the concentration of the drug was increased. These findings suggest that the inhibition of polyamine synthesis results in the repressions of cyclin D1 expression and cell cycle progression, eventually inducing apoptosis in these human breast cancer cells.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Division; Cyclin D1; DNA Fragmentation; Dose-Response Relationship, Drug; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Mitoguazone; Polyamines; RNA, Messenger; Time Factors; Tumor Cells, Cultured

SAMDC is a key enzyme in the biosynthesis of spermidine and spermine, 2 polyamines that are essential for cell proliferation. Inhibition of polyamine biosynthesis is often targeted as a therapeutic strategy to suppress cancer cell growth as these cells contain elevated levels of polyamines. We examined the effect of a new group of SAMDC inhibitors, CGP33829, CGP35753, CGP36958, CGP39937, and CGP48664, (obtained from Ciba-Geigy, Basel, Switzerland), and their parent compound, MGBG, on the proliferation of MCF-7 breast cancer cells. MGBG had minimal effects on the proliferation of MCF-7 cells up to 6 microM concentration. In contrast, CGP48664 and CGP39937, containing 2 aromatic rings that delocalize the pi electron system of the backbone of MGBG, were potent inhibitors with 50% growth inhibition at 0.5 microM concentration. Other CGP compounds were less effective in inhibiting cell growth. The ability of CGP48664 to inhibit MCF-7 cell proliferation was related to its ability to inhibit SAMDC and to consequently deplete spermidine and spermine levels in the cell. Exogenous spermidine and spermine could reverse the growth inhibitory effects of this compound. CGP compounds also increased the activity of ODC, another enzyme involved in polyamine biosynthesis. Northern blot analysis of mRNA from MCF-7 cells progressing in cell cycle after G1 synchronization did not show an increase in ODC mRNA level by CGP48664. These data demonstrate structure-activity relationships of a series of MGBG derivatives on cell growth, enzyme activities, and polyamine biosynthesis in a hormone-responsive breast cancer cell line and suggest potential application of SAMDC inhibitors as therapeutic agents.

Topics: Acetyltransferases; Adenosylmethionine Decarboxylase; Amidines; Antineoplastic Agents; Biogenic Polyamines; Breast Neoplasms; Cell Division; Enzyme Inhibitors; Estradiol; Female; Humans; Indans; Mitoguazone; Ornithine Decarboxylase; RNA, Messenger; Structure-Activity Relationship; Tumor Cells, Cultured

Methylglyoxal bis(guanylhydrazone) (MGBG) a structural analogue of spermidine produced a dose-dependent induction of cytosolic spermidine/spermine N1-acetyltransferase (N1-SAT) in the human breast carcinoma cell line, T47-D. Intracellular accumulation of MGBG was found to be saturable and the drug produced characteristic effects on intracellular polyamines, decreasing spermidine and spermine content, with concomitant increases in putrescine levels. The MGBG-induced increase in N1-SAT activity was potentiated by both tetronasin, a calcium ionophore, and felodipine, a calcium channel blocking agent. Only tetronasin was an active inducer of the enzyme when used alone. Both drugs influenced intracellular MGBG content but in opposite directions: tetronasin increased MGBG content while felodipine decreased it. Therefore, the potentiation of N1-SAT induction is not simply the result of increased intracellular accumulation of MGBG but is more likely to be related to the concentration of intracellular free calcium in these cells.

Topics: Acetyltransferases; Breast Neoplasms; Calcium; Carcinoma; Cytosol; Dose-Response Relationship, Drug; Enzyme Induction; Felodipine; Furans; Humans; Mitoguazone; Polyamines; Tumor Cells, Cultured

Topics: Breast Neoplasms; Cell Division; Female; Humans; Mitoguazone; Polyamines; Tumor Cells, Cultured

The Southwest Oncology Group has evaluated methyl-GAG on a weekly schedule among patients with metastatic breast cancer. Among 72 fully and partial evaluable patients, one complete and four partial responses were seen. Toxicity was similar to other trials with this compound except for thrombocytopenia which was more frequent and severe and probably related to tumor infiltrating marrow. In addition, one patient experienced recall dermatitis following methyl-GAG. This toxicity has not been previously reported with this compound. Methyl-GAG has minimal activity at this dose and schedule among heavily pretreated patients with breast cancer.

Topics: Adult; Aged; Breast Neoplasms; Drug Evaluation; Female; Guanidines; Humans; Middle Aged; Mitoguazone; Neoplasm Metastasis; Thrombocytopenia

Methyl-GAG was tested in organotypic cultures of malignant tumors of human and mice. In 3 cases, a reduction of the activity of two oxydoreductases (lactate dehydrogenase and NADH-diaphorase) after treatment with methyl-GAG was observed whereas in 19 other cultivated tumors no change of enzyme activity was induced by methyl-GAG. Electronmicroscopy revealed only minor structural alterations of tumor cells after application of methyl-GAG as compared with control cultures.

Topics: Animals; Breast Neoplasms; Cells, Cultured; Female; Guanidines; Histocytochemistry; Humans; L-Lactate Dehydrogenase; Mammary Neoplasms, Experimental; Melanoma; Mice; Mitoguazone; NADPH Dehydrogenase; Ovarian Neoplasms