deoxycholic-acid and Carcinoma--Non-Small-Cell-Lung

Metronomic chemotherapy has translated into favorable toxicity profile and capable of delaying tumor progression. Despite its promise, conventional injectable chemotherapeutics are not meaningful to use as metronomic due to the necessity of frequent administration for personalized therapy in long-term cancer treatments. This study aims to exploit the benefits of the oral application of carboplatin as metronomic therapy for non-small cell lung cancer (NSCLC). We developed an orally active carboplatin by physical complexation with a deoxycholic acid (DOCA). The X-ray diffraction (XRD) patterns showed the disappearance of crystalline peaks from carboplatin by forming the complex with DOCA. In vivo pharmacokinetic (PK) study confirmed the oral absorption of carboplatin/DOCA complex. The oral bioavailability of carboplatin/DOCA complex and native carboplatin were calculated as 24.33% and 1.16%, respectively, when a single 50mg/kg oral dose was administered. Further findings of oral bioavailability during a low-dose daily administration of the complex (10mg/kg) for 3weeks were showed 19.17% at day-0, 30.27% at day-7, 26.77% at day-14, and 22.48% at day-21, demonstrating its potential for metronomic chemotherapy. The dose dependent antitumor effects of oral carboplatin were evaluated in SCC7 and A549 tumor xenograft mice. It was found that the oral carboplatin complex exhibited potent anti-tumor activity at 10mg/kg (74.09% vs. control, P<0.01) and 20mg/kg dose (86.22% vs. control, P<0.01) in A549 tumor. The number of TUNEL positive cells in the tumor sections was also significantly increased during oral therapy (3.95% in control, whereas 21.37% and 32.39% in 10mg/kg and 20mg/kg dose, respectively; P<0.001). The enhanced anti-tumor efficacy of oral metronomic therapy was attributed with its antiangiogenic mechanism where new blood vessel formation was notably decreased. Finally, the safety of oral complex was confirmed by three weeks toxicity studies; there were no significant systemic or local abnormalities found in mice at 10mg/kg daily oral dose. Our study thus describes an effective and safe oral formulation of carboplatin as a metronomic chemotherapy.

Topics: Administration, Metronomic; Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Deoxycholic Acid; Lung; Lung Neoplasms; Male; Mice, Nude; Models, Molecular; Rats, Sprague-Dawley

A 53-year-old woman with an intraabdominal infection secondary to Candida albicans experienced hyperbilirubinemia after receiving amphotericin B in two different formulations--amphotericin B deoxycholate and amphotericin B lipid complex. Only a few case reports of amphotericin B-induced hyperbilirubinemia have been documented in the literature, each with different patterns of corresponding abnormalities in liver function tests. The unpredictable nature of this adverse effect warrants monitoring of bilirubin levels and liver function at baseline and potentially during therapy with amphotericin B, regardless of formulation, dosage, or duration of therapy.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Carcinoma, Non-Small-Cell Lung; Deoxycholic Acid; Drug Combinations; Female; Humans; Hyperbilirubinemia; Liver; Middle Aged; Phosphatidylcholines; Phosphatidylglycerols

To ascertain whether resistance to cis-diamminedichloroplatinum(II) (cisplatin) could be overcome, we determined the effects of amphotericin B (AmB), an antifungal agent, on cisplatin cytotoxicity, cisplatin-induced DNA interstrand cross-links formation, and cellular accumulation of cisplatin in human lung cancer cell lines, PC-9, PC-14, PC-7, and H69 and their corresponding respective cisplatin-resistant sublines PC-9/CDDP, PC-14/CDDP, PC-7/CDDP, and H69/CDDP in vitro. In PC-9/CDDP but not PC-9 cells, augmentation of cytotoxicity was observed when a nontoxic concentration (10 micrograms/ml) of AmB was combined with cisplatin, cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II), and cis-diammine(glycolato)platinum(II). Sensitizing effects of AmB of varying magnitudes on cisplatin cytotoxicity also were observed in all the other cell lines except PC-14. AmB-induced increases in cisplatin-induced interstrand cross-links formation were observed, the magnitudes of which corresponded to the magnitudes of AmB-augmented cisplatin cytotoxicity. Increased intracellular cisplatin accumulation was observed in the presence of AmB in all the cells that were sensitized to cisplatin by AmB. Therefore, the increases in cisplatin accumulation were considered to be responsible, at least in part, for the mechanism of the sensitizing effect. Further experiments using other human lung cancer cell lines showed that cells that were more resistant to cisplatin were more sensitized to cisplatin by AmB than cells that were cisplatin-sensitive.

Topics: Amphotericin B; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycholic Acid; DNA; DNA Adducts; Drug Resistance; Humans; Lung Neoplasms; Ouabain; Tumor Cells, Cultured