digoxin and Uterine-Cervical-Neoplasms

Cisplatin and other platinum-containing drugs have played a crucial role in anticancer treatments for over 30 years. However, treatment with cisplatin may cause serious side effects, such as myelosuppression, nausea, ototoxicity, nephrotoxicity, and cell resistance processes. In addition, cardiotonic steroids, particularly digoxin, have recently been suggested to exert potent anticancer effects. Therefore, it is possible that the combined treatment of HeLa cells with cisplatin and digoxin can ameliorate the cytotoxic effects and decrease the side effects of cisplatin. In this study, we demonstrated that the interaction between cisplatin and digoxin had a synergistic effect on cervical cancer cells and a significantly positive cytotoxic and antiproliferative effect on this cell line compared to the control and single cisplatin treatments. Although a decrease in the Na,K-ATPase α1 subunit expression was observed in total extracts, its expression remains unchanged in the membrane, as does the Na,K-ATPase activity. The antiproliferative effect of the synergistic treatment appears to depend on Src kinase activation, indicating the possible involvement of the Scr-EGFR-ERK1/2 pathway in the antitumor effect. The inhibition of ERK1/2 provoked the same synergism with 1 μM cisplatin as that observed with 1 nM digoxin plus 1 μM cisplatin but not with 1 nM digoxin. Pretreatment with PP2 during combined treatment abolished the synergistic effect on the antiproliferative activity. Cisplatin and digoxin are already used in the clinical setting; therefore, this study opens possibilities for future clinical trials of combined treatments to improve treatment outcomes with a lower incidence of toxicity and side effects.

Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Cisplatin; Digoxin; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Phosphorylation; Proto-Oncogene Proteins pp60(c-src); Signal Transduction; Uterine Cervical Neoplasms

Drug delivery systems could be applied to locally treat cervical cancer, thus preventing the drawbacks of conventional therapy. In this study, anti-proliferative and anti-angiogenic effects of digoxin incorporated into poly(ε-caprolactone) implants were evaluated, aiming at the local treatment of cervical cancer. Implants were characterized, and the in vitro release profile of digoxin was demonstrated. Anti-proliferative and anti-angiogenic activities of digoxin were investigated by using chorioallantoic membrane and human cervix carcinoma (HeLa) cells, respectively. The chemical structure of digoxin and the semi-crystalline nature of poly(ε-caprolactone) were preserved after designing implants. The hydrophobicity of drug and polymer as well as the semi-crystalline structure provided a controlled diffusion of digoxin from implants. Digoxin released from implantable devices exhibited anti-proliferative activity against HeLa cells. The anti-angiogenic effect was also shown. Finally, implants composed of digoxin and poly(ε-caprolactone) could be applied as a therapeutic alternative to treat the early stage of cervical cancer, once they were able to locally control the release of this anti-angiogenic and anti-proliferative drug, minimizing its systemic side effects and toxicity.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Chickens; Chorioallantoic Membrane; Crystallization; Digoxin; Drug Carriers; Drug Delivery Systems; Drug Implants; Drug Liberation; Female; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Polyesters; Uterine Cervical Neoplasms

Digoxin is a phyto-estrogen capable of inducing hormonal effects. Use has been associated with increased risk of breast cancer, an estrogen-sensitive malignancy. The incidence of corpus uteri (uterus) cancer is also strongly increased with exposure to estrogens. Therefore, we evaluated whether digoxin use might also increase its incidence. In all women in Denmark, we identified digoxin users from 1995 through 2008 using a nationwide pharmacy registry system. Cancer occurrence was obtained from Danish Cancer Registry. Relative risk was determined using incidence risk ratios (RR) and 95% confidence intervals (CIs) relative to non-users after adjustment for age- and calendar-time. For ovarian and cervical cancers, RRs in users and non-users were similarly evaluated, these cancers representing gynecological cancers with weak or no associations to estrogen exposure. Of 2.1 million women, 104,648 (4.9%) had digoxin exposure and 137,493 6.5% had exposure to angina drugs but not digoxin during the study period. For uterus cancer, the RR was increased in current digoxin users (1.48, 95% CI: 1.32-1.65; N = 350). Incidence was marginally increased in former users. For ovary and cervix cancers, RRs in current digoxin users were 1.06 (95% CI: 0.92-1.22; N = 207) and 1.00 (95% CI: 0.79-1.25; N = 81), respectively. We examined risks in women using angina drugs but not digoxin to determine whether being under cardiac care affected risk. Among women using angina drugs only, RRs for uterus, ovary or cervix cancers were not statistically significant. We conclude that women currently using digoxin, a phyto-estrogen, have an increased risk of developing uterus cancers.

Topics: Adult; Aged; Aged, 80 and over; Angina Pectoris; Denmark; Digoxin; Female; Humans; Middle Aged; Ovarian Neoplasms; Phytoestrogens; Risk Factors; Uterine Cervical Neoplasms; Young Adult

A monoclonal antibody to digoxin enabled sandwich techniques to be used for the detection of hybridised digoxigenin labelled probes in cultured cells and paraffin wax sections. This system has greater flexibility than alkaline phosphatase conjugated polyclonal antidigoxigenin antibody and permits the use of alternative detector enzymes, such as horseradish peroxidase and fluorescence labels. The APAAP detection system that does not require the use of biotin can also be used in situations where endogenous biotin is a problem. The low level of background staining combined with precise substrate deposition of the amplified peroxidase system gives higher sensitivity and resolution. This permits localisation of closely adjacent chromosomal loci in interphase nuclei. The most sensitive peroxidase based digoxigenin detection system visualises two and a half to 12 copies of human papillomavirus (HPV) per nucleus. This system is also suitable for the analysis of low copy number HPV infection of cervical tissues.

Topics: Alkaline Phosphatase; Antibodies, Monoclonal; Biotin; Carcinoma in Situ; Cervix Uteri; Condylomata Acuminata; Digoxigenin; Digoxin; DNA Probes, HPV; Female; Fluorescent Antibody Technique; HeLa Cells; Humans; Interphase; Papillomaviridae; Uterine Cervical Neoplasms

Twelve couples (12 women and their male partners) presenting genital warts were investigated in order to evaluate the sexual transmission of human papillomavirus (HPV) in mutual partners and the localization of HPV DNA. Formalin-fixed, paraffin-embedded biopsy samples of 12 vulvar condylomata, and 12 penile condylomata from male partners were analyzed for the presence of HPV DNA-6, -11, and 16/18 by using in situ hybridization with digoxygenin labeled DNA probes. HPV DNA was identified in 9 women (75%) and in 9 men (75%). HPV-6 was frequently identified, being revealed in 42% of the vulvar specimens, in 67% of the cervical specimens and 58% of the penile specimens. Seven of 9 (77%) positive couples shared the same HPV DNA, and 2 couples harbored different HPV DNA types between the partners. The signal intensity of the HPV DNA was generally strong in superficial cell layers, weak in parabasal or basal cell layers. No malignant lesions resulted from the condyloma acuminatum caused by HPV-6 or -11. There were only mild dysplasia in the both sexes.

Topics: Condylomata Acuminata; Digoxigenin; Digoxin; DNA Probes; DNA Probes, HPV; DNA, Viral; Female; Humans; Male; Nucleic Acid Hybridization; Papillomaviridae; Penile Neoplasms; Uterine Cervical Neoplasms

Four evaluations of ambulatory medical care tasks were developed for use in quality assurance. The evaluations used medical records data and explicit criteria incorporating branching logic. They were implemented in eight general medicine provider groups in two teaching hospitals and six related health centers. Agreement with criteria among 316 provider responses to questionnaires varied from 57% to 100%. The percentage of cases with one or more variation from evaluation criteria, confirmed on peer review to have a deficiency in care, ranged by task from 6% to 42%, with substantial variation between sites. Physician reviewers from each site varied in leniency. Numbers of actions taken to correct deficiencies ranged by site and task from zero to six. Multisite evaluations revealed differences in performance and efforts to improve that are not apparent when each site conducts its own evaluations. More uniformly effective and impartial quality assurance is needed to correct some important deficiencies in care observed in this study.

Topics: Adult; Ambulatory Care; Blood Glucose; Breast Neoplasms; Digoxin; Evaluation Studies as Topic; Female; Follow-Up Studies; Group Practice; Hematocrit; Humans; Peer Review; Quality Assurance, Health Care; United States; Uterine Cervical Neoplasms

Topics: Administration, Oral; Adult; Biological Availability; Carcinoma, Squamous Cell; Digoxin; Female; Heart Failure; Humans; Injections, Intramuscular; Intestinal Absorption; Malabsorption Syndromes; Radiotherapy; Solutions; Tablets; Uterine Cervical Neoplasms