Biomedical subjects

B U Sevin

Publications and source records attributed to B U Sevin.

At least 91 records · Page 5Linked to original sources

PubMed1992

The use of ATP bioluminescence assays in selecting a drug screen panel for chemosensitivity testing of uterine cancer cell lines.

The ATP bioluminescence assay has demonstrated a strong potential to become a clinical assay for chemosensitivity testing. Currently, chemotherapy of gynecologic cancers remains controversial and empirical. To optimize the patient's chance of survival and to justify related toxicities, the chemoregimen should be individualized and based on the patient's chemosensitivity profiles. This study was performed to identify a panel of active drugs against uterine cancer cell lines for possible use in future chemosensitivity testing. We used the ATP chemosensitivity assays to screen 12 common cytotoxic agents against six uterine cancer cell lines. Drug concentrations required for a 50% surviving fraction were defined as IC50s. When using an IC50 of 0.21 PPC (peak plasma concentration) as a cutoff value for sensitivity, the following 8 drugs were considered effective for uterine cancer cell lines: actinomycin D, Adriamycin, vinblastine, etoposide, 5-fluorouracil, methotrexate, cytosine arabinoside, and mitomycin-C. Meanwhile, 4 drugs, cisplatin, 4OH-Cytoxan, bleomycin, and Alkeran with mean IC50s of 2.1 +/- 0.7, 0.8 +/- 0.1, greater than 5.0, and 0.75 +/- 0.36 PPC, respectively, were considered inactive or partially active with higher IC50s than peak plasma concentrations. In conclusion, the above panel of promising drugs can be further tested in animal models or human cancer specimens for possible use in chemosensitivity testing of uterine cancer patients.

Adenocarcinoma↗

PubMed1992

Rationale of combining radiation and interferon for the treatment of cervical cancer.

The recent surge of interest in the mechanisms of action of biomodulators, also known as biological response modifiers, offers a new avenue of approach in the treatment of cancer. The in vitro antitumor activities of these agents, such as interferons, when combined with chemo- or radiotherapy, have generated enthusiasm among clinicians for developing clinical trials. In recent years many antineoplastic agents have been investigated as neoadjuvant or adjuvant therapy for patients with cervical cancer in an attempt to improve local control and to decrease incidence of metastasis. Normal tissue tolerance limits the potential combinations of standard cytotoxic chemotherapeutic agents with radiation. Interferon used as a radiomodulator has been studied mainly for the treatment of lung cancer with promising results. In this paper we report the rationale of combining interferon and radiation for the treatment of patients with cervical cancer.

Animals↗

PubMed1991

Long-term survival in stage III and IV ovarian cancer.

A total of 104 unselected, previously untreated patients with invasive stage III or IV ovarian cancer were operated on between 1977 and 1984. Nine patients were lost in follow-up, three died from non-malignant disease. Thirteen of the 92 eligible patients (15%) were observed to survive 5 years or longer. In the 13 long-term survivors, 4 had stage IV disease, 7 positive peritoneal cytology, 3 bowel resection, and 12 residual disease less than 2 cm after primary surgery. Retroperitoneal lymph nodes were involved in 6/9 cases. The majority of 5-year survivors (69%) received cis-platin-containing combination chemotherapy. 5/7 long-term survivors had positive second-look. At 5 years, life-quality in 9/13 patients who were free of disease, was high. It can be concluded that only patients with optimally resected stage III or IV ovarian cancer have a realistic chance of long-term survival. It is expected that increasing radicality n surgery for ovarian cancer together with platinum-based chemotherapy regimens may improve long-term survival in the future. In addition, further studies of new chemotherapeutic approaches are needed.

Adult↗

PubMed1991

Characterization of in vitro chemosensitivity of perioperative human ovarian malignancies by adenosine triphosphate chemosensitivity assay.

We report the in vitro chemosensitivity of primary and recurrent human ovarian tumor samples analyzed by adenosine triphosphate chemosensitivity assay. We defined sensitivity as a greater than or equal to 70% decrease in intracellular adenosine triphosphate versus control at 20% of the reported peak plasma concentration per agent tested. Twenty of 21 assays (95.24%) were completed successfully. Single-agent and combined dose-response patterns consisting of decreasing viability with increasing drug concentration were observed consistently. Thirteen primary tumors were assayed, with 15.4% sensitive to cisplatin, 7.7% sensitive to 4-hydroxycyclophosphamide and 53.8% sensitive to their combination. Seven recurrent tumors were assayed, with 14.3% sensitive to cisplatin, 28.6% sensitive to 5-fluorouracil, and 42.9% sensitive to their combination. Dose-response characteristics and in vitro sensitivity rates reported in this article are consistent with reports of patient response in the literature. We conclude that adenosine triphosphate chemosensitivity assay is an efficient and reliable instrument for the in vitro chemosensitivity assessment of human tumors and warrants further clinical investigation.

Adenosine Triphosphate↗

PubMed1991

Cell kinetic perturbations after irradiation and caffeine in the BG-1 ovarian carcinoma cell line.

The treatment of ovarian carcinoma includes maximum surgical removal of the tumor tissue followed by irradiation or chemotherapy. In this study, the effects of caffeine on cell cycle traverse have been studied over a 168-hr period after X irradiation in BG-1 cells, an ovarian carcinoma cell line. The results were obtained with dual-parameter flow cytometric measurements of DNA and nuclear protein, using propidium iodide and fluorescein isothiocyanate. After radiation alone, a dose-related arrest of cells in G2 phase and cell kill were observed. Irradiating BG-1 cells with 5 Gy produced an accumulation of the cells in G2 at 24-72 hr postirradiation. When G2 was divided into low nuclear protein (G2A) and high nuclear protein (G2B) compartments, there was a G2A peak accumulation at 24 hr and a G2B peak accumulation at 48-72 hr. The addition of 1 mM caffeine to the culture media, starting immediately postirradiation, prevented G2 arrest, promoting a rapid traverse of cells through G2A to G2B to G1, which was associated with diminished survival.

Caffeine↗

PubMed1991

In vitro enhancement of cis-platinum antitumor activity by caffeine and pentoxifylline in a human ovarian cell line.

Cell kinetic perturbations measuring DNA and nuclear protein with dual-parameter flow cytometry were studied in vitro after cis-platinum (DDP) treatment of a DDP-resistant human ovarian cell line (BG-1). Cell viability (trypan blue exclusion) and the cell's ability to replicate (replicating potential) are also reported. A dose-dependent G2 arrest and concomitant increase in cytotoxicity were observed. We also observed a marked increase in cytotoxicity of 2.5 micrograms/ml DDP with the addition of 1 mM of caffeine (CAF) or pentoxifylline (PTX). Additionally, the cells treated with DDP and CAF or DDP and PTX demonstrated a markedly diminished ability to replicate. Cell cycle perturbations, especially the G2-phase arrest, were markedly enhanced in the cells treated with DDP and CAF or DDP and PTX, when compared to that in cells treated with DDP alone. We conclude that the cytotoxicity of DDP is enhanced by CAF and PTX in vitro by inhibiting DNA repair during the S and G2 phases.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1991

The effects of Provera on chemotherapy of uterine cancer cell lines.

Even though progestin is commonly added to many chemotherapy regimens in the treatment of uterine cancers, its role is still unproven. Since progestin is antiproliferative, its tendency to arrest cells in G1 phase may interfere with cytotoxic mechanisms. The ATP chemosensitivity assay and flow cytometry were used to study the effects of a progestational compound such as Provera on three single agents and four drug combinations. Uterine cancer cell lines included progesterone-receptor (PR)-positive AE7 and ECC1 and PR-negative HEC1A, HEC1B, AN3, and SKUT1B. Provera selectively affected only PR-positive cell lines. It imposed an antiproliferative effect on drug-induced cell-cycle perturbations by reducing G2 and S blocks and minimizing G1 depletion. When using IC50s (concentrations required for 50% growth inhibition) of 0.5 as a cutoff for drug sensitivity and resistance, Provera significantly improved the IC50s of the drug-resistant subgroup from 1.95 +/- 0.36 to 0.71 +/- 0.19 (P = 0.009) but not those of the drug-sensitive subgroup (P = 0.13). In summary, Provera appeared to work independently from cytotoxic mechanisms. Its improvement of cytotoxicity was most pronounced in resistant cell lines bearing progesterone receptors.

Antineoplastic Agents↗

PubMed1991

Comparative evaluation of single and combination chemotherapy in uterine cancer cell lines.

Controversy over the chemotherapy of uterine cancers still exists. This study was designed to directly compare the efficacy of various chemotherapy combinations, CAP (Cytoxan, Adriamycin, cisplatin), CAF (Cytoxan, Adriamycin, 5-fluorouracil), MF (melphalan, 5-fluorouracil), CP (Cytoxan, cisplatin), to single agents, Adriamycin (DXR), Cytoxan (CYT), cisplatin (DDP), and carboplatin (CARBO). Five human endometrial cell lines and one sarcoma cell line were used: AE7, ECC-1, HEC1A, HEC1B, AN3, and SKUT1B. The ATP chemosensitivity assay was used to determine dose-response curves of various treatments. By using mean IC50's for comparison, CAF and MF were twice as effective in cell kill as CAP (P = 0.01, 0.03, respectively). There was however no significant difference between CAF, MF, and DXR (P = 0.12, 0.46, 0.34). When dose comparison is used, combinations CAP, CAF, and MF appeared to be 3 to 15 times more potent than DDP, CYT, or CARBO. In summary, Adriamycin remained the most effective single drug for uterine cancer cell lines. Its cytotoxicity was equivalent to that of combinations CAP, CAF, and MF.

Antineoplastic Agents↗

PubMed1991

Optimization of high dose-rate cervix brachytherapy; Part I: Dose distribution.

Computer controlled high dose-rate (HDR) brachytherapy afterloading machines are equipped with a single, miniaturized, high activity Ir-192 source that can be rapidly moved in fine increments among several channels. Consequently, by appropriate programming of source dwell positions and times, the dose distribution can be optimized as desired. We have explored the optimization potential of this new technology for two applications: (a) cervix brachytherapy, and (b) transvaginal irradiation. Cervix brachytherapy with a gynecologic ring applicator was simulated by 48 sources of relative activities ranging from 0.17 to 1.00 that were equally distributed between the tandem and the ring. The results confirmed that the optimized distribution of physical doses are superior to those achievable with standard brachytherapy sources and applicators. For example, with five-point optimization, the relative dose-rate in the rectum was only 47% of that in point A; for standard application the dose rate was 47% higher. For transvaginal application 27 sources of relative activities between 0.07-0.79 were placed in the ring and a single source of unit strength in the tandem. Using dose distribution homogeneity as an optimization criterion, the results (+/- 2.5%) were again superior to those obtained for commonly used double ovoid (+/- 15%), linear cylinder (+/- 27%), or a "T" source (31%).

Brachytherapy↗

PubMed1991

Comparative efficacy of short-term versus long-term cefoxitin prophylaxis against postoperative infection after radical hysterectomy: a prospective study.

We report the results of a randomized, double-blind comparison of short-term versus long-term cefoxitin prophylaxis against infections after radical abdominal hysterectomy with pelvic and para-aortic lymphadenectomy. Of 113 evaluable patients, 54 (47.8%) received short-term (three doses) and 59 (52.2%) long-term (12 doses) prophylaxis with intravenous cefoxitin (2 g per dose). No significant differences in demographics, preoperative risk factors, or clinical course were detected between the two groups; nor did we detect significant differences in the incidence of surgical-site-related infections (7.4 versus 5.1%, respectively, P = .61), postoperative urinary tract infection, or other febrile morbidity. We conclude that short-term and long-term cefoxitin prophylaxis are equally effective for the prevention of post-operative surgical-site-related infections after radical hysterectomy.

Adult↗

PubMed1990

Potentiation of cisplatin cytotoxicity by methylxanthines in vitro.

The ability of two supposed DNA-repair inhibitors to modulate cisplatin-induced cytotoxicity in a human ovarian cancer cell line (CAOV-3) and a human cervical cancer cell line (Me-180) was investigated using a short-term chemosensitivity assay based on bioluminescence of cellular adenosine triphosphate (ATP). Cisplatin concentrations bracketing the reported peak plasma concentration (2.5 micrograms/ml) were used and the 50% inhibitory concentrations were determined by linear regression of log-transformed survival data. At 2.5 mM, the methylxanthine caffeine enhanced cisplatin sensitivity 2.9-fold in CAOV-3 cells and 2.7-fold in Me-180 cells. At 2.5 mM, pentoxifylline, a closely related methylxanthine, increased cisplatin sensitivity 2.9-fold in CAOV-3 cells and 3.4-fold in Me-180 cells. Chemical modification of cisplatin-induced cytotoxicity by assumed inhibition of DNA-repair mechanisms may hold promise for clinical application in the treatment of gynecological cancer.

Adenosine Triphosphate↗

PubMed1990

Comparative chemosensitivity profiles in four human ovarian carcinoma cell lines measuring ATP bioluminescence.

cis-Platinum (DDP) and cyclophosphamide are commonly used for the treatment of ovarian cancer; however, survival remains poor. The degree of cytotoxicity of the standard antineoplastic agents DDP, 4-hydroperoxy-cyclophosphamide (4-OH-CTX), mitomycin C (MITOM C), vincristine (VCR), etoposide (VP-16), 5-fluorouracil (5-FU), cytosine arabinoside (ARA-C), and interferon (IF) in four representative ovarian cancer cell lines was studied using the ATP assay, which measures total cell kill. Cell lines CAOV-3, OVCAR-3, SKOV-3, and BG-1, which were derived from both pretreated and untreated patients, were exposed to six different concentrations for 90 min. On Day 7, intracellular ATP determinations were done. Sensitivity was defined as greater than or equal to 50% cell kill at 0.5 x peak plasma concentration as compared to controls. For 4-OH-CTX and ARA-C, 3 and 0.5 micrograms/ml were chosen as 0.5 x reference values. For each drug in each cell line, a highly reproducible dose-response relationship was observed. CAOV-3 cells were sensitive to all drugs except DDP, ARA-C, and IF, and OVCAR-3 cells to all except DDP and IF. SKOV-3 cells were resistant to all agents except VCR, and BG-1 cells to all except MITOM C and 5-FU. The apparent heterogeneic response to antineoplastic agents observed in the above cell lines underscores the importance of assessing individual patients' sensitivity profiles before treatment.

Adenosine Triphosphate↗

PubMed1990

Comparison of three tumor markers--CA-125, lipid-associated sialic acid (LSA), and NB/70K--in monitoring ovarian cancer.

The monitoring value of three tumor markers--CA-125, lipid-associated sialic acid (LSA), and NB/70K--alone and in combination has been studied in 152 patients with invasive, epithelial ovarian cancer. The sensitivity and specificity of CA-125 (90 and 92%, respectively) were superior to those of LSA (79 and 63%, respectively) and NB/70K (76 and 74%, respectively). CA-125 by itself showed equal or higher sensitivity as well as higher specificity than in combinations with either LSA or NB/70K. CA-125 predicted cancer at second-look in 87% of cases as did LSA and NB/70K in 70 and 57%, respectively. In patients with negative second-look, CA-125 predicted the disease status in 93% as did LSA and NB/70K in 54 and 63%, respectively. On the basis of these data, the value of simultaneous determination of LSA and NB/70K, in addition to the clinically established CA-125, seems to be limited. This is due mainly to the lack of specificity of LSA and NB/70K. However, the sensitivity and specificity of CA-125 in this study were in the upper reported range.

Antigens, Neoplasm↗

PubMed1990

Chemical enhancement of cisplatin cytotoxicity in a human ovarian and cervical cancer cell line.

While many advances have been made in the chemotherapy of gynecologic cancers, treatment failures remain a major clinical problem. A growing understanding of the mechanisms of tumor cell resistance to antineoplastic drugs provides a framework for the development of chemotherapy regimens containing agents capable of modulating tumor response. Using a short-term ATP bioluminescence assay we studied the ability of two methylxanthines (caffeine, pentoxifylline) and an inhibitor of ADP-ribosyl transferase (3-aminobenzamide) to enhance cisplatin cytotoxicity in gynecologic cancer cell lines. Our findings of significantly enhanced cisplatin-induced cytotoxicity with two different analysis techniques confirms the effectiveness of these agents. These results may have future clinical significance.

Adenosine Triphosphate↗

PubMed1990

Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.

There were 732 evaluable patients with primary, previously untreated, histologically confirmed stage I squamous carcinoma of the cervix with greater than or equal to 3-mm invasion. Of these, 645 had no gross disease beyond the cervix/uterus, had negative paraaortic lymph nodes, and had undergone a radical hysterectomy with pelvic lymphadenectomy. The 3-year disease-free interval (DFIs) for the 545 patients with negative pelvic nodes was 85.6%, and for the 100 with positive pelvic nodes, 74.4%. A large number of pelvic nodes involved with tumor was not correlated with a poorer prognosis; the DFIs were 72.1, 86.4, and 64.6% for one, two, and three or more positive pelvic nodes, respectively. DFI correlated strongly with depth of tumor invasion, both in absolute terms (mm) and infractional thirds. The DFI was 94.6% for less than or equal to 5 mm, 86.0% for 6-10 mm, 75.2% for 11-15 mm, 71.5% for 16-20 mm, and 59.5% greater than or equal to 21 mm. In fractional terms, the DFI was 94.1% for superficial third, 84.5% for middle third, and 73.6% for deep third invasion. With respect to clinical tumor size, the DFIs were 94.8, 88.1, and 67.6% for occult, less than or equal to 3 cm, and greater than 3 cm, respectively. The DFI was 77.0% for those with positive capillary-lymphatic spaces (CLS) and 88.9% for those with negative CLS. Tumor grade and parametrial status correlated with DFI. DFI was not significantly different for age, disease status of the surgical margins, tumor description (e.g., exophytic), quadrant involved with tumor, uterine extension, and keratinizing status of tumor cells. Clinical tumor size, CLS, and depth of tumor invasion were independent prognostic factors.

Carcinoma, Squamous Cell↗

PubMed1989

Continent urinary diversion in gynecologic oncology.

Pelvic exenteration is a salvage procedure used primarily for recurrent gynecologic carcinoma. Up to the present time, an ileal or colon conduit has been used for urinary diversion and the patient remains incontinent of urine. This is a preliminary report of nine patients with gynecologic carcinoma in whom a continent urinary diversion procedure was performed. A segment of distal ileum, the ascending colon, and part of the transverse colon are used to create the colonic reservoir. The segment of colon is opened along the tenia and folded onto itself. The walls of the ascending and transverse colon are anastomosed to detubularize this segment of bowel and eliminate the transient high pressure of the colon. Surgical staples are used for the anastomosis. The segment of ileum is tapered and three purse-string sutures (2-O silk) are placed at the level of the ileocecal valve to achieve continence. The short segment of ileum is then exteriorized as a stoma through which the patient catheterizes. Antirefluxing, non-tunneled ureterocolonic anastomoses are performed. The anterior wall of the reservoir is closed with absorbable staples. Postoperative urodynamic studies have shown maximum capacity of 750 ml and the area of continence to be at the ileocecal valve where the purse-string sutures are placed. All patients are continent and postoperative radiographs were negative for reflux. Follow-up was 6 to 12 months. The colonic reservoir is a capacious low-pressure system and warrants further clinical trials in patients with gynecologic cancer.

Colon↗

PubMed1989

Synergistic effects of cis-platinum and cytosine arabinoside on ovarian carcinoma cell lines, demonstrated by dual-parameter flow cytometry.

Ovarian cancer tends to remain confined to the peritoneal cavity even after widespread dissemination. In order to test the in vitro cytotoxic effect of cis-platinum (CP) and cytosine arabinoside (ara-C), a combination which, in theory, is particularly suitable for intraperitoneal (IP) administration, ovarian cancer cells were exposed to each drug alone and in combination and then sampled serially for 336 hr with cell counts and flow cytometry (FCM). We used dual parameter FCM analysis to study changes in DNA and nuclear protein simultaneously. There was good correlation between the degree of cell kill noted in the counts and the duration of observed cytokinetic disturbances in all the treated series. CP and ara-C alone produced temporary cytotoxic and cytokinetic changes. Together, the two agents produced an enhanced CP effect which lasted 336 hr and was accompanied by continued evidence of cell kill in the counts. We conclude that CP and ara-C in vitro act synergistically on ovarian cancer to achieve a high level of cell kill after a single simultaneous application.

Cell Count↗

PubMed1989

Carcinoma of the fallopian tube: clinical management.

From 1970 to 1986, 36 women were diagnosed to have primary fallopian tube cancer. Fifty-three percent of the patients were Stage III with a median adjusted survival of 27 months. Although varied adjunctive therapies were employed, none provided a clear survival benefit. Five "second-look" procedures were performed. Only one was negative, occurring in a Stage IIIC patient treated with combination chemotherapy. She has continued without evidence of disease 26 months following diagnosis. Recurrent disease was uniformly fatal, despite efforts at salvage therapy. Disease biology and response to therapy parallels that of similar stage epithelial carcinoma of the ovary.

Adult↗