Toxicity of the mitochondrial poison dequalinium chloride in a murine model system.

Dequalinium chloride (DECA), a cationic, lipophilic mitochondrial poison, selectively targets the mitochondrial membrane of certain epithelial carcinoma cells, in which it inhibits cellular energy production. It has demonstrated potency as a cytotoxic agent specific for carcinomas and may provide a novel approach for cancer therapy, either as a single agent or as an adjunct to conventional chemotherapy. The purpose of this study was to determine the toxicity of DECA in the murine model. One hundred female BALB/c mice were divided into three schedule groups. Group one received a single intraperitoneal (ip) dose of DECA at 10, 15, 20, or 25 mg/kg of body weight. Group two received DECA at 6, 7, 8, 9, or 10 mg/kg ip every other day (QOD), and group three received DECA at 10, 11, 12, 13, or 14 mg/kg ip every 7 days. Over a 30- to 60-day period, acute and subchronic toxicities were evaluated on the basis of the following clinical parameters: respiratory distress, weight loss, and mortality. After a single ip administration, we found a maximum tolerated dose of 15 mg/kg and a lethal dose (LD50) of 18.3 mg/kg. Single ip doses of 20 and 25 mg/kg produced > 50% mortality. Histologic examination of the tissues revealed significant damage to the liver and kidneys, with pulmonary congestion occurring secondary to renal-hepatic failure. A cumulative assessment revealed that 60% of the animals tolerated 15 doses of 6 and 7 mg/kg QOD and that 100% tolerated 5 doses of 11 and 12 mg/kg (every 7 days). Higher DECA doses under either regimen induced severe toxic effects and mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of a human ovarian carcinoma cell line: UCI 101.

A new epithelial ovarian carcinoma cell line (UCI 101) has been established from the ascitic fluids and solid tumor of a patient with progressive papillary adenocarcinoma of the ovary shown previously to be refractory to combination chemotherapy consisting of cyclophosphamide, Adriamycin, and cisplatin as well as single-agent chemotherapy of taxol and high-dose cisplatin. The UCI 101 cell line grows well with an in vitro doubling time of 24 hr. The cell line expresses the B 72.3 (Tag 72), CA125, MH99 (ESA), and E29 (EMA) cell surface antigens and AE1/AE3 cytokeratins. This cell line overexpresses (as determined by immunocytochemistry) both p-glycoprotein and the epidermal growth factor receptor. The in vitro drug response to single agents including Adriamycin, cisplatin, dequalinium chloride, etoposide, 5-fluorouracil, taxol, and tumor necrosis factor was examined. Intraperitoneal transplantation of the cells into athymic mice resulted in foci of tumor on all peritoneal surfaces including the viscera and diaphragm ultimately leading to solid bulky disease with massive production of ascites. High levels of CA125 (> 500 units/ml) were detected in the serum of tumor-bearing mice. Cytogenetic analysis of cultured cells shows several marker chromosomes containing deletions, duplications, and translocations. Cytologic and histologic evaluation of the xenograft revealed morphological characteristics identical to those of the original tumor.

Effect of recombinant human tumor-necrosis-factor-alpha and dequalinium chloride on human ovarian-cancer cell-lines in-vitro.

Due to preferential uptake and retention, the small molecular weight lipophilic, cationic antimicrobial agent dequalinium chloride (DECA) displays potent in vitro and in vivo antitumor activity against carcinoma cells. The primary mechanism of DECA activity is directed against the mitochondria where it disrupts cellular energy production. One of the direct antitumor effects of tumor necrosis factor (TNF) is also targeted against the mitochondria. The ability of DECA to synergize this effect was examined in vitro against a panel of human ovarian cancer cell lines. The data from single agent and combined drug exposure were analyzed by the isobologram methods of Tsai et al (Cancer Res 49: 2390-2397, 1989). We demonstrate that TNF and DECA strongly synergize in vitro at clinically achievable doses for TNF and potentially clinically achievable doses for DECA. The degree of synergy varied with the cell line tested with UCI-101 being the least responsive and PA-1 cells displaying the greatest synergistic effect. DECA treatment also prolonged animal survival in mice bearing the PA-1 intraperitoneal ovarian carcinoma xenograft. Single agent DECA (5 mg/kg; qod) increased animal survival by 37% (p=0.002) whereas recombinant human TNF (0.5 mug/mouse; qod) increased survival by 12% (p=0.27) in those animals treated 3 days post tumor injection. Sequential DECA/TNF enhanced animal survival by 45% (p=0.0002) in similarly treated animals. DECA, as a mitochondrial poison is an agent capable of potentiating the effects of tumor necrosis factor against ovarian cancer cell lines.

Radical hysterectomy in the elderly patient: analysis of morbidity.

OBJECTIVE: This study compares the perioperative morbidity and mortality following radical hysterectomy of patients older than 65 years with a younger age group who underwent radical hysterectomy and pelvic lymphadenectomy for cervical carcinoma stage IB or IIA. STUDY DESIGN: A retrospective analysis of morbidity and mortality for the first 60 postoperative days was conducted. The study population of 45 women greater than 65 years of age with cervical cancer treated by radical hysterectomy was compared with a control population of 90 women less than 65 years treated similarly. RESULTS: In the elderly group, 31 of 45 and 12 of 15 were American Society of Anesthesologists Physical Status II and III respectively; 68/90 and 19/90 were American Society of Anesthesiologists status I and II in the younger age group (p = 0.001). Transfusions of greater than 2 units were required in 14% of the elderly and 35% of younger patients (p = 0.02). No statistical differences were observed between groups for other parameters examined. CONCLUSION: Age alone should not be a contraindication for radical hysterectomy in the elderly patient with American Society of Anesthesiologists Physical Status I to III.

[The gestrinone (R-2323) treatment of endometriosis]. / Tratamiento con gestrinona (R-2323) de la endometriosis.

Results of medical treatment with gestrinone are evaluated in 29 women with minimal (10), mild (9) and moderate (7) endometriosis. After a diagnostic laparoscopy, patients started gestrinone 2.5 mg/day 2 times a week per 6 months. Clinical evaluations and blood samples were performed at the end of the ist, 3rd and 6th month of treatment. A second look laparoscopy, in 26 out of the 29 patients, was performed within a month after discontinuation of the drug. Nineteen patients (73.1%) showed a diminishing in endometriosis score. Moreover, 2 of them presented with a normal pelvis at the time of the 2nd laparoscopy. Overall post treatment scores were significantly lower than pre treatment scores (6.1 +/- 6.9 versus 11.3 +/- 10.2 respectively, p < 0.025). Nineteen out of the 26 patients had amenorrhea, most of them (18) since the second month of treatment. Nineteen patients presented with dysmenorrhea at the beginning of the treatment and in 13 of them it disappeared during the first 3 months of the drug. Reversible elevation in serum transaminases was observed in 4 patients. Red blood cells count and platelet concentration increased at the end of the treatment. A clear pituitary suppression to basal levels was seen. No significant changes on androgen levels were appreciated. Seven patients achieved a spontaneous pregnancy, out of 22 that desired fertility (31.8%), all of them were clinical pregnancies.