sodium-bicarbonate and Breast-Neoplasms

The purpose of this work is to investigate the effect of microenvironmental pH modulation on the in vitro dissolution rate and oral absorption of GDC-0810, an oral anti-cancer drug, in human.. The pH-solubility profile of GDC-0810 free acid and pH. Intrinsic solubility of GDC-0810 free acid was found to be extremely low. The pH. Incorporation of a basic pH modifier, sodium bicarbonate, in GDC-0810 NMG salt tablet formulations enhanced in vitro dissolution rate of GDC-0810 via microenvironmental pH modulation. The human PK data showed no statistically significant difference in drug exposure from tablets containing 5%, 10%, and 15% sodium bicarbonate.

Topics: Administration, Oral; Antineoplastic Agents; Area Under Curve; Biological Availability; Breast Neoplasms; Cinnamates; Drug Compounding; Drug Liberation; Drug Screening Assays, Antitumor; Excipients; Fasting; Female; Gastrointestinal Absorption; Healthy Volunteers; Humans; Hydrogen-Ion Concentration; Indazoles; Meglumine; Receptors, Estrogen; Sodium Bicarbonate; Solubility; Tablets

The extracellular pH (pHe) of many solid tumors is acidic as a result of glycolytic metabolism and poor perfusion. Acidity promotes invasion and enhances metastatic potential. Tumor acidity can be buffered by systemic administration of an alkaline agent such as sodium bicarbonate. Tumor-bearing mice maintained on sodium bicarbonate drinking water exhibit fewer metastases and survive longer than untreated controls. We predict this effect is due to inhibition of tumor invasion. Reducing tumor invasion should result in fewer circulating tumor cells (CTCs). We report that bicarbonate-treated MDA-MB-231 tumor-bearing mice exhibited significantly lower numbers of CTCs than untreated mice (P < 0.01). Tumor pHe buffering may reduce optimal conditions for enzymes involved in tumor invasion such as cathepsins and matrix metalloproteases (MMPs). To address this, we tested the effect of transient alkalinization on cathepsin and MMP activity using enzyme activatable fluorescence agents in mice bearing MDA-MB-231 mammary xenografts. Transient alkalinization significantly reduced the fluorescent signal of protease-specific activatable agents in vivo (P ≤ 0.003). Alkalinization, however, did not affect expression of carbonic anhydrase IX (CAIX). The findings suggest a possible mechanism in a live model system for breast cancer where systemic alkalinization slows the rate of invasion.

Topics: Animals; Breast Neoplasms; Carbonic Anhydrase IX; Carbonic Anhydrases; Female; Gene Expression Regulation, Neoplastic; Humans; Hydrogen-Ion Concentration; Mice; Neoplasm Invasiveness; Neoplastic Cells, Circulating; Sodium Bicarbonate; Xenograft Model Antitumor Assays

Gastrointestinal disturbances, such as nausea and vomiting, are considered amongst the main adverse effects associated with oral anticancer drugs due to their fast release in the gastrointestinal tract (GIT). Sustained release formulations with proper release profiles can overcome some side effects of conventional formulations. The current study was designed to prepare sustained release tablets of Capecitabine, which is approved by the Food and Drug Administration (FDA) for the treatment of advanced breast cancer, using hydroxypropyl methylcellulose (HPMC), carbomer934P, sodium alginate, and sodium bicarbonate. Tablets were prepared using the wet granulation method and characterized such that floating lag time, total floating time, hardness, friability, drug content, weight uniformity, and in vitro drug release were investigated. The sustained release tablets showed good hardness and passed the friability test. The tablets' floating lag time was determined to be 30-200 seconds, and it floated more than 24 hours and released the drug for 24 hours. Then, the stability test was done and compared with the initial samples. In conclusion, by adjusting the right ratios of the excipients including release-retarding gel-forming polymers like HPMC K4M, Na alginate, carbomer934P, and sodium bicarbonate, sustained release Capecitabine floating tablet was formulated.

Topics: Acrylic Resins; Alginates; Breast Neoplasms; Capecitabine; Chemistry, Pharmaceutical; Deoxycytidine; Drug Dosage Calculations; Female; Fluorouracil; Gastrointestinal Diseases; Glucuronic Acid; Hexuronic Acids; Humans; Hypromellose Derivatives; Methylcellulose; Sodium Bicarbonate; United States; United States Food and Drug Administration

The glycolytic nature of malignant tumors contributes to high levels of extracellular acidity in the tumor microenvironment. Tumor acidity is a driving force in invasion and metastases. Recently, it has been shown that buffering of extracellular acidity through systemic administration of oral bicarbonate can inhibit the spread of metastases in a mouse model for metastatic breast cancer. While these findings are compelling, recent assessments into the use of oral bicarbonate as a cancer intervention reveal limitations.. We posited that safety and efficacy of bicarbonate could be enhanced by dichloroacetate (DCA), a drug that selectively targets tumor cells and reduces extracellular acidity through inhibition of glycolysis. Using our mouse model for metastatic breast cancer (MDA-MB-231), we designed an interventional survival study where tumor bearing mice received bicarbonate, DCA, or DCA-bicarbonate (DB) therapies chronically.. Dichloroacetate alone or in combination with bicarbonate did not increase systemic alkalosis in mice. Survival was longest in mice administered bicarbonate-based therapies. Primary tumor re-occurrence after surgeries is associated with survival rates. Although DB therapy did not significantly enhance oral bicarbonate, we did observe reduced pulmonary lesion diameters in this cohort. The DCA monotherapy was not effective in reducing tumor size or metastases or improving survival time. We provide in vitro evidence to suggest this outcome may be a function of hypoxia in the tumor microenvironment.. DB combination therapy did not appear to enhance the effect of chronic oral bicarbonate. The anti-tumor effect of DCA may be dependent on the cancer model. Our studies suggest DCA efficacy is unpredictable as a cancer therapy and further studies are necessary to determine the role of this agent in the tumor microenvironment.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Bicarbonates; Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Dichloroacetic Acid; Disease Models, Animal; Female; Humans; Hydrogen-Ion Concentration; Lactates; Lung Neoplasms; Mice; Mice, SCID; Sodium Bicarbonate; Survival Analysis; Tumor Burden; Tumor Microenvironment

The external pH of solid tumors is acidic as a consequence of increased metabolism of glucose and poor perfusion. Acid pH has been shown to stimulate tumor cell invasion and metastasis in vitro and in cells before tail vein injection in vivo. The present study investigates whether inhibition of this tumor acidity will reduce the incidence of in vivo metastases. Here, we show that oral NaHCO(3) selectively increased the pH of tumors and reduced the formation of spontaneous metastases in mouse models of metastatic breast cancer. This treatment regimen was shown to significantly increase the extracellular pH, but not the intracellular pH, of tumors by (31)P magnetic resonance spectroscopy and the export of acid from growing tumors by fluorescence microscopy of tumors grown in window chambers. NaHCO(3) therapy also reduced the rate of lymph node involvement, yet did not affect the levels of circulating tumor cells, suggesting that reduced organ metastases were not due to increased intravasation. In contrast, NaHCO(3) therapy significantly reduced the formation of hepatic metastases following intrasplenic injection, suggesting that it did inhibit extravasation and colonization. In tail vein injections of alternative cancer models, bicarbonate had mixed results, inhibiting the formation of metastases from PC3M prostate cancer cells, but not those of B16 melanoma. Although the mechanism of this therapy is not known with certainty, low pH was shown to increase the release of active cathepsin B, an important matrix remodeling protease.

Topics: Animals; Breast Neoplasms; Cathepsin B; Cell Line, Tumor; Female; Humans; Hydrogen-Ion Concentration; Liver Neoplasms; Lung Neoplasms; Male; Melanoma, Experimental; Mice; Mice, Nude; Mice, SCID; Neoplasm Invasiveness; Prostatic Neoplasms; Sodium Bicarbonate

The extracellular (interstitial) pH (pHe) of solid tumours is significantly more acidic compared to normal tissues. In-vitro, low pH reduces the uptake of weakly basic chemotherapeutic drugs and, hence, reduces their cytotoxicity. This phenomenon has been postulated to contribute to a 'physiological' resistance to weakly basic drugs in vivo. Doxorubicin is a weak base chemotherapeutic agent that is commonly used in combination chemotherapy to clinically treat breast cancers. This report demonstrates that MCF-7 human breast cancer cells in vitro are more susceptible to doxorubicin toxicity at pH 7.4, compared to pH 6.8. Furthermore 31P-magnetic resonance spectroscopy (MRS) has shown that the pHe of MCF-7 human breast cancer xenografts can be effectively and significantly raised with sodium bicarbonate in drinking water. The bicarbonate-induced extracellular alkalinization leads to significant improvements in the therapeutic effectiveness of doxorubicin against MCF-7 xenografts in vivo. Although physiological resistance to weakly basic chemotherapeutics is well-documented in vitro and in theory, these data represent the first in vivo demonstration of this important phenomenon.

Topics: Animals; Breast Neoplasms; Cell Division; Doxorubicin; Female; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Mice; Mice, SCID; Neoplasm Transplantation; Sodium Bicarbonate; Survival Rate; Tumor Cells, Cultured

A novel inhibitor of dihydroorotate dehydrogenase (DHO-DH) has been discovered using data from the National Cancer Institute's in vitro drug screen. Upon analysis of cytotoxicity results from the sixty tumor cell lines used in this screen, the COMPARE program predicted that NSC 665564 was likely to have the same mechanism of inhibition as brequinar, a known potent inhibitor of DHO-DH. We validated this prediction experimentally using MOLT-4 lymphoblast and found the IC50 of brequinar (0.5 microM) and NSC 665564 (0.3 microM) were comparable and that this induced cytotoxicity was reversed by either uridine or cytidine. The enzyme target of NSC 665564 was shown to be identical to that of brequinar when incubation with each drug followed by a 1 h pulse with [14C] sodium bicarbonate resulted in cellular accumulation of [14C]N-carbamyl-L-aspartic acid and [14C]L-dihydroorotic acid, with concurrent marked depletion of CTP and UTP. The Ki's for NSC 665564 and brequinar were 0.14 and 0.24 microM, respectively, when partially purified MOLT-4 mitochondria (the site of DHO-DH) were used. These results show that mechanistic predictions obtained using correlations from the COMPARE algorithm are independent of structure since the structure of NSC 665564 is dissimilar to that of other established DHO-DH inhibitors.

Topics: Antineoplastic Agents; Aspartic Acid; Biphenyl Compounds; Breast Neoplasms; Carbolines; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Colonic Neoplasms; Dihydroorotate Dehydrogenase; Enzyme Inhibitors; Female; Humans; Kidney Neoplasms; Kinetics; Leukemia; Lung Neoplasms; Male; Melanoma; Mitochondria; Orotic Acid; Ovarian Neoplasms; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Prostatic Neoplasms; Ribonucleotides; Sodium Bicarbonate; Software; Tumor Cells, Cultured

Chemotherapy for liver metastasis of breast cancer has rarely been found effective. We devised a new regimen of chemotherapy for recurrent breast cancer mainly using ifosfamide. It was found clinically applicable and particularly effective for liver metastasis. The tumor decreased in size and the levels of various tumor-markers markedly decreased following drug administration. This treatment has made for longer survival for some patients. Side effects could be well controlled with steroid hormones and Na-bicarbonate.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bicarbonates; Breast Neoplasms; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Humans; Ifosfamide; Liver Neoplasms; Medroxyprogesterone; Medroxyprogesterone Acetate; Mitomycin; Mitomycins; Sodium; Sodium Bicarbonate