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Biomedical subjects

B U Sevin

Publications and source records attributed to B U Sevin.

At least 73 records · Page 4Linked to original sources
PubMed1993

Taxol sensitizes human ovarian cancer cells to radiation.

Taxol is an exciting antineoplastic agent with a novel mechanism of action. This study was designed to explore the potential use of taxol as a radiation sensitizer. Three human ovarian cancer cell lines were used: BG-1, SKOV-3, and OVCAR-3. These cell lines were treated in the proliferative and confluent state with taxol doses of 0.0001X, 0.0005X, 0.001X, 0.005X, and 0.01X peak plasma concentration of taxol for 90 min and then irradiated either 24 or 48 hr later. Doses of cobalt60 were 0, 2, 5, 8, and 10 Gy. ATP bioluminescence assays were performed on Day 7 after irradiation. Survival data was fit to the linear-quadratic model and mean inactivation dose D was calculated. Data analysis with t test and analysis of variance was performed. Taxol was found to have a significant radiosensitizing effect on all cell lines. Proliferating cells were more sensitive to taxol, radiation, and the combination than confluent cells. Treatment of proliferating cells with taxol 48 hr prior to irradiation had a greater radiosensitizing effect than treatment 24 hr prior to irradiation. In summary, taxol is a potent radiosensitizer in ovarian cancer cell lines and should be considered for further study.

Adenosine Triphosphate↗
PubMed1993

Radical hysterectomy for stage IB adenocarcinoma of the cervix: the University of Miami experience.

The treatment of adenocarcinoma of the cervix has traditionally followed that of squamous cancer. A 25-year review of 88 radical hysterectomies for Stage IB adenocarcinoma of the cervix at the University of Miami/Jackson Medical Center (UM) is compared to over 1600 cases reported in the literature. Adenocarcinoma represented 10.4% of 978 radical hysterectomies performed at UM from July 1965 to December 1990. In a survey of the literature, patients with Stage IB cervical adenocarcinoma treated by radical surgery alone had a statistically better 5-year survival than those treated by radiation alone (79% vs 67%, respectively; P < or = 0.05). Furthermore, no additional benefit was achieved by combining the two therapeutic modalities. The corrected 5-year survival at UM is 81% for Stage IB adenocarcinoma of the cervix treated with radical hysterectomy, a number consistent with the cumulative data base. Radical surgery is an acceptable primary therapy in Stage IB adenocarcinoma of the cervix.

Adenocarcinoma↗
PubMed1993

The role of DNA index as a prognostic factor in early cervical carcinoma.

The value of DNA index as a prognostic factor in early cervical cancers was investigated. A total of 124 patients who underwent radical hysterectomy for stages IB-IA cervical cancers from 1/1982 to 12/1985 were included. Paraffin blocks were available in only 98 patients for the analysis. After dewaxing, rehydrating, and enzyme disaggregation, cells were subjected to dual parameter flow cytometry. Tumor DNA index was calculated and the results were correlated with 5-year survival, stage, grade, tumor size, nodal metastasis, surgical margins, and lymphovascular invasion. There were 1% hypoploid, 7.3% diploid, 72.9% aneuploid, 16.7% tetraploid, and 2.1% hyperploid. At the end of 5 years, there were 69 alive and 27 dead patients with mean DNA indices of 1.50 +/- 0.3 and 1.70 +/- 0.3, respectively. t Test analysis revealed that mean DNA index of deceased patients was significantly higher than that of alive ones (P = 0.008). Survival analysis demonstrated the prognostic significance of DNA index 1.70 (P = 0.017). Median survival of patients with DNA index of 1.70 or greater was 36 months in contrast to 73.5 months for those with DNA index less than 1.70. Multivariate analysis subsequently confirmed DNA index of 1.70 as an independent prognostic indicator with a hazard ratio of 2.05.

Carcinoma↗
PubMed1993

Taxol as a radiation sensitizer: a flow cytometric study.

Taxol is an exciting antineoplastic agent with a novel mechanism of action. Taxol has been shown to prolong the G2/M phase of the cell cycle. This cell cycle perturbation has been the explanation given for the radiation-sensitizing effects seen with taxol in vitro. The aim of this study is to evaluate the cell kinetics of the BG-1 human ovarian cancer cell line after treatment with nontoxic doses of taxol and radiation (RT). This cell line was treated in the proliferative state for 90 min with 5 nM taxol and then irradiated 48 hr later with 2 Gy of Cobalt60. Flow cytometric evaluations of cell cycle perturbations were performed at 24-hr intervals from 0 through 216 hr. ATP cell viability assay was performed in parallel to obtain survival data. Survival data was fit to the linear-quadratic model and mean inactivation dose D was calculated. Data analysis with t test was performed. At this nontoxic dose of taxol no cell cycle perturbations as compared to control were seen. Radiation sensitization was still found. Sensitizer enhancement ratio was 2.3 at 10% survival. The RT-related G2/M block peaked at 24 h after RT and then resolved. The combination of taxol and radiation resulted in a large prolonged block in G2/M that did not resolve through the duration of the experiment. In summary, taxol sensitized cells to radiation at a dose that was not cytotoxic and that did not cause cell cycle perturbations.

Cell Survival↗
PubMed1993

Adenosquamous carcinoma of the cervix: prognosis in early stage disease treated by radical hysterectomy.

The prognosis of adenosquamous carcinoma of the cervix compared to the pure cell types of this disease is a controversial issue. Survival rates vary widely among published series, with some authors finding the prognosis to be much worse and others finding it to be equal. We have studied a group of 290 patients, all of whom had the diagnosis of stage IB or IIA cervical cancer, and all of whom were treated by radical hysterectomy and bilateral pelvic and paraaortic lymphadenectomy. The pathology specimens were reviewed for every case. Median follow-up for all living patients was 73 months. Forty-five patients (15.5%) had adenosquamous histology, 220 (75.9%) had squamous cell, and 25 (8.6%) had adenocarcinoma. By X2, there was no significant difference among the three groups with regard to race, economic status, number of grade 3 lesions, number with positive pelvic lymph nodes, number with positive margins, stage distribution (IB vs IIA), or number of recurrences. Using Student's t test, there was no significant difference between any combination of two groups with regard to mean patient age, mean depth of invasion, or mean tumor size. Estimated disease-free survival and overall survival were not different among the three cell types. We conclude that for early stage cervical cancer treated by radical hysterectomy, the adenosquamous cell type does not carry a worse prognosis than either of the pure cell types.

Adenocarcinoma↗
PubMed1993

Characteristics of the combination paclitaxel plus doxorubicin in breast cancer cell lines analyzed with the ATP-cell viability assay.

Preliminary clinical data show promising activity regarding the combination of paclitaxel (Taxol) (TAX) and doxorubicin (Adriamycin) (ADR) in the treatment of breast cancer. This combination needs both further preclinical and clinical investigations to better understand the drug interaction, and to optimize the dose and schedule of these drugs. This study was done to evaluate the combination effect of TAX and ADR in three human breast cancer cell lines. The ATP-Cell-Viability Assay was used to evaluate the chemosensitivity profiles and to obtain dose response curves. For quantitation of synergism and antagonism the median-effect principle was applied and the corresponding combination index values were calculated. Drug synergism/antagonism was shown to be dose-related; synergism was enhanced at higher fractions affected. From this preclinical data, we have concluded that TAX-ADR is highly effective and partly synergistic in vitro. In spite of severe initial toxicities in early clinical trials in metastatic breast cancer patients, further clinical studies appear to be justified in order to define a tolerable dosage.

Adenosine Triphosphate↗
PubMed1993

Cell cycle perturbations of platinum derivatives on two ovarian cancer cell lines.

Cisplatin continues to be one of the most commonly used cytotoxic agent. Problems of drug resistance and nephrotoxicity have generated interest in new platinum derivatives. In this study, we used flow cytometry to study their effects on cell kinetics and to see if the extent of cell cycle perturbations can be used to determine relative potency. The following four platinum derivatives were tested: cisplatin, carboplatin, 254S, and NK121 on two human ovarian cancer cell lines: BG1 and CAOV3. Flow cytometric analysis revealed a dynamic spectrum of cell kinetic perturbations, which included sequential S-G2 block, concomitant S-G2 block, and a dominant S block with abolition of G2 block. Platinum derivatives NK121, 254S, and CARBO induced an average of 54.5 +/- 5.6, 21.2 +/- 5.5, and 2.5 +/- 2.8% more S-G2 blocks than cisplatin, respectively. When comparing the severity of S-G2 blocks and requiring a p-value of 0.05, the order of increasing potency was: cisplatin, carboplatin, 254S, and NK121.

Carboplatin↗
PubMed1993

In vitro evaluation of the novel chemotherapeutic agents U-73,975, U-77,779, and U-80,244 in gynecologic cancer cell lines.

U-73,975 (U-73), U-77,779 (U-77), and U-80,244 (U-80) are analogs of the potent antitumor compound CC-1065. This class of drugs act as alkylating agents binding to DNA preferentially. Using the ATP-chemosensitivity assay, this study was designed to compare the potencies of U-73, U-77, and U-80 with cisplatin (DDP) or adriamycin (DXR) in 10 gynecologic cancer cell lines. The mean IC50s were: U-73, 0.173 +/- 0.115 ng/ml; U-77, 0.650 +/- 0.209 ng/ml; U-80, 3.0 +/- 3.0 ng/ml; DDP, 4.40 +/- 2.83 micrograms/ml; and DXR, 0.286 +/- 0.040 micrograms/ml. U-73 appears the most potent analog, being 10(3) to 10(4) times more cytotoxic than DDP and DXR. U-77 and U-80 were somewhat comparable, demonstrating approximately 10(2) to 10(3) greater potency than DDP and DXR. All the cervical, endometrial, and ovarian cell lines were sensitive to U-73, with decreasing sensitivity to U-77, U-80, DXR, and DDP in that order. U-73 as well as the other analogs appear promising chemotherapeutic agents.

Adenosine Triphosphate↗
PubMed1992

Microinvasive carcinoma of the cervix.

BACKGROUND: Microinvasive carcinoma of the cervix (MIC) has been poorly defined in the past and is still a focus of persistent controversy. In 1985, the International Federation of Gynecology and Obstetrics (FIGO) defined Stage IA as "preclinical invasive carcinoma, diagnosed by microscopy only," subdividing it into Stage IA1 or "minimal microscopic stromal invasion," and Stage IA2 or "tumor with invasive component 5 mm or less in depth taken from the base of the epithelium and 7 mm or less in horizontal spread." In 1974, the Society of Gynecologic Oncologists (SGO) defined MIC as any lesion with a depth of invasion of 3 mm or less from the base of the epithelium, without lymphatic or vascular space invasion. METHODS: To assess the risk of lymph node metastasis and treatment failures, pathologic material and clinical data on 370 patients with Stage I carcinoma of the cervix, who were treated by radical hysterectomy and pelvic-aortic node dissection, were reviewed. Histopathologic analysis of tumors was based on a uniform format, including measurement of the maximum depth of invasion, the width and length of the horizontal tumor spread, invasive growth pattern, cell type, tumor grade, and lymphatic or vascular space involvement. RESULTS: Of the 370 patients, 110 had a depth of invasion of 5 mm or less. Of these, 54 patients fulfilled the SGO definition of MIC; 42, the new FIGO Stage IA2 definition; and 27, both definitions. None of the patients with MIC, as defined by either the SGO or the new FIGO Stage IA2, had lymph node metastases or tumor recurrence. These data support the conclusion that MIC, defined by either the SGO or FIGO definitions, have a low risk for lymph node metastasis or recurrent carcinoma. A review of the literature indicated a recurrence rate for Stage IA2 of 4.2%. In addition to depth of invasion, lymph vascular space invasion is a better predictor of lymph node metastasis and recurrence than the surface dimension. CONCLUSIONS: The authors recommend adoption of the SGO definition of MIC. Patients with a depth of invasion of 3 mm or less without lymph vascular space invasion safely can be treated conservatively.

Carcinoma↗
PubMed1992

In vitro evaluation of a novel chemotherapeutic agent, Adozelesin, in gynecologic-cancer cell lines.

Adozelesin is a derivative of an extremely cytotoxic compound, CC1065. This entirely new class of drug binds preferentially to DNA and facilitates alkylation reaction. In the present study, we used the adenosine triphosphate (ATP) chemosensitivity assay to compare the cytotoxic potency of Adozelesin with that of common chemotherapeutic agents in ten gynecologic-cancer cell lines. Flow cytometry was also used to study its effects on cell-cycle kinetics. The mean drug concentrations required to produce a 50% reduction in ATP levels as compared with controls [IC50] were: Adriamycin, 0.17 +/- 0.06 microM; 4OH-Cytoxan, 18 +/- 3 microM; cisplatin, 17 +/- 7 microM; 5-fluorouracil, 183 +/- 116 microM; and Adozelesin, 11.0 +/- 5.4 pM. Thus, Adozelesin was 10(4) - 10(7) times more potent than Adriamycin, cisplatin, 5-fluorouracil, and Cytoxan. Cell kinetics studies revealed significant S and G2 blocks such as those previously reported for other alkylating agents.

Adenocarcinoma↗
PubMed1992

Spectrum of cell-cycle kinetics of alkylating agent adolezesin in gynecological cancer cell lines: correlation with drug-induced cytotoxicity.

Adolezesin is an analog of CC-1065. These compounds are among the most potent alkylating agents known to date. Currently Adolezesin is undergoing phase I clinical trials at several cancer centers in the USA. While the cytotoxic effects of Adolezesin have been addressed elsewhere, its effects on cell-cycle kinetics have not been reported. Flow cytometry was performed on five human gynecological cancer cell lines: AN3, AE7, BG1, HEC1A, and SKUT1B. Exposure to Adolezesin (U73975, Upjohn Co.) was done at near confluency at 0, 0.1, 0.2, 0.5, 1 and 5x, with x = 10 pg/ml as reference concentration, for 90 min. Cell samples were taken by trypsinization at 0, 24, 48, 72, 96, and 168 h for flow cytometry. The ATP chemosensitivity assays were performed on the above cell lines to establish dose/response curves. Flow-cytometric analyses revealed that there was a spectrum of cell-cycle perturbations, which included biphasic S and G2 blocks, reverse dose-dependent G2 blocks, and a sequential relationship of S and G2 blocks. This study demonstrated that the cell kinetic response to Adolezesin depended on several variables such as cell lines, drug sensitivity, concentrations, and sampling time. Because of this multivariable dependence and the lack of correlation with cytotoxicity, it would be difficult to use cell kinetic pertubations to predict chemotherapeutic response.

Adenosine Triphosphate↗
PubMed1992

Ovarian metastases in stage IB carcinoma of the cervix: a Gynecologic Oncology Group study.

Surgical and pathologic findings at laparotomy for radical hysterectomy in 990 patients with clinical stage IB carcinoma of the cervix were analyzed to determine the frequency of metastases to the ovary. Ovarian spread was identified in 4 of 770 (0.5%) patients with squamous carcinoma and 2 of 121 (1.7%) with adenocarcinoma. No patients with adenosquamous carcinoma (n = 82) or other histologic types (n = 17) had ovarian metastases. Although the frequency of metastases was greater among patients with adenocarcinoma, this was not statistically significant (p = 0.19, Fisher's exact test). All 6 patients with ovarian metastases had other evidence of extracervical disease. Three underwent radical hysterectomy and bilateral salpingo-oophorectomy. Of these, one patient received extended field radiotherapy and died of disease 18 months after diagnosis. Two patients, one treated with combination chemotherapy and one with no adjunctive therapy, are alive without evidence of disease at 59 and 62 months, respectively. Three patients underwent exploratory laparotomy with salpingo-oophorectomy and lymphadenectomy without hysterectomy. All three patients died of disease at 2, 3, and 30 months; the first and last patient received adjunctive radiotherapy. Not all patients underwent oophorectomy. Of 347 patients with at least unilateral ovarian preservation, no postoperative pelvic radiotherapy, and no gross extracervical disease or metastasis to the paraaortic nodes, pelvic recurrence developed in 16. There was no excess of pelvic recurrences in patients with adenocarcinoma (0/41) or adenosquamous carcinoma (1/29, 3.4%) when compared with those with squamous carcinoma (15/270, 5.6%). This suggests no excess of occult ovarian metastases in nonsquamous tumors of the cervix. There is no evidence in these data of an increased risk of ovarian preservation in patients with stage IB carcinoma of the cervix with no gross extracervical disease.

Adenocarcinoma↗
PubMed1992

Chemosensitivity to the new anthracycline pirarubicin and other chemotherapeutic agents in primary and recurrent ovarian tumors in vitro.

We analysed the in vitro sensitivity of 50 fresh gynecologic cancer specimens to the new anthracycline-analogue pirarubicin (Pira). Nine endometrial and cervical tumors were excluded from the evaluation in this study. The in vitro sensitivities of 41 ovarian cancer specimens to Pira were evaluated with the adenosine triphosphate chemosensitivity assay (ATP-CSA). The results were compared to the sensitivity of drugs used in gynecologic oncology: Adriamycin, cisplatin, and the metabolite of cyclophosphamide, 4-hydroxycyclophosphamide (4-HC). Sensitivity (S) is defined as > or = 70%, partial sensitivity as 50-69% ATP decrease compared to controls at 20% of the peak plasma concentration. In vitro response is defined as S + PS. Twenty-two primary ovarian tumors were assayed, with 77% response to Pira, 12% to Adriamycin, 29% to cisplatin, and 38% to 4-HC. In 19 recurrent ovarian tumors, Pira showed 53% response; Adriamycin, 25%; cisplatin, 8%; and 4-HC, 67%. The in vitro data are partly consistent with reported data from the literature. Pira reveals a significantly higher degree of cytotoxicity compared to the three drugs listed above. The IC50 of Pira is less than 20% of the peak plasma concentration achievable in patients and is significantly lower compared with the IC50s of other drugs. We conclude from our in vitro data that Pira is more active than Adriamycin, cisplatin, and 4-HC.

Adenosine Triphosphate↗
PubMed1992

Comparison of U-73,975 and cisplatin cytotoxicity in fresh cervical and ovarian carcinoma specimens with the ATP-chemosensitivity assay.

U-73,975 (U-73), a closely related synthetic analogue of the antitumor agent CC-1065, acts by binding tightly in the minor groove of DNA. A comparison was made between the cytotoxicity of U-73 and cisplatin (DDP) on 11 fresh cervical and 7 fresh ovarian carcinoma specimens. The ATP-chemosensitivity assay as previously described (Sevin et al. Gynecol. Oncol. 31, 191-204, 1988) was used to determine the cytotoxic effect of U-73 and DDP. IC 50s were calculated using regression analysis. The mean IC 50s for U-73 and DDP were 519 pg/ml and 2918 ng/ml, respectively, for the cervical carcinoma specimens and 324 pg/ml and 2649 ng/ml, respectively, for the ovarian carcinoma specimens. Significance comparing U-73 and DDP for cervical and ovarian tissue was demonstrated with P < 0.001. U-73 was 4000 times as cytotoxic per unit of mass as DDP on cervical carcinoma compared to over 8000 times for ovarian carcinoma. Based on these in vitro data, U-73 appears to be a very promising antitumor agent for cervical and ovarian carcinoma.

Adenosine Triphosphate↗
PubMed1992

Determination of hormonal response in uterine cancer cell lines by the ATP bioluminescence assay and flow cytometry.

Although progesterone receptor status has been shown to correlate with response to hormonal therapy, not all progesterone receptor-positive patients respond to this treatment and additional biologic assays are needed to help better predict clinical response to hormonal therapy. This study explored the potential of the ATP bioluminescence assay and flow cytometry as biological assays of hormonal response. Five uterine cancer cell lines were used: AE7, ECC-1, HEC1A, AN3, and SKUT1B. Cells were exposed to Provera or tamoxifen at 0.1, 0.2, 0.5, 1, 2, and 5X (X equal to peak plasma concentrations: 1.0 micrograms/ml Provera and 0.1 micrograms/ml tamoxifen). For correlation, estrogen and progesterone receptors were determined by the standard dextran-coated charcoal method. Only AE7 and ECC-1 were positive for progesterone receptors (501 fmol/mg AE7, 194 fmol/mg ECC-1) and the rest were negative (less than 8 fmol/mg). Tamoxifen exerted no inhibition to the above cell lines. Meanwhile, Provera exerted dose-response inhibition on both AE7 and ECC-1 cell lines. The effects of accumulation of G0-G1 phase and reduction of S, G2 cells (P less than 0.05), but not on the HEC1A cell line (P = 0.4). These changes confirmed the antiproliferative property of Provera. Further studies are needed to establish the role of the ATP bioluminescence assay and flow cytometry as biological assays of hormonal response.

Adenocarcinoma↗
PubMed1992

The use of ATP bioluminescence assay and flow cytometry in predicting radiosensitivity of uterine cancer cell lines: correlation of radiotoxicity and cell cycle kinetics.

Radiotherapy remains an important part of uterine cancer treatment. This study was designed to evaluate the potential of the ATP bioluminescence assay and flow cytometry for predicting radiosensitivity. Correlation of these two modalities revealed important insights into the relationship of radiotoxicity and cell kinetic effects. Six human uterine cancer cell lines were used: AE7, ECC1, HEC1A, HEC1B, AN3, and SKUT1B. Doses of cobalt 60 were 0, 1, 2, 5, 8, and 10 Gy. The ATP bioluminescence assays were performed on Day 7. Cell samples were taken at 0, 24, 48, 72, 96, and 168 hr for flow cytometry. The linear-quadratic model was used to fit survival data and mean inactivation dose D was calculated. Among parameters such as D, alpha and beta coefficients, and surviving fraction at 2 Gy (SF2), both D and SF2 correlated best with survival data. Radiation effects on the cell cycle did not correlate with D and revealed two distinct patterns: either a G1 accumulation with mild G2 block or a G1 depletion and severe G2 block. The S cells consistently demonstrated a biphasic pattern with an initial reduction followed by an accumulation. In summary, the ATP assay was shown to have potential in the study of radiosensitivity. Radiation-induced cell kinetics appeared to vary with intrinsic cellular differences and, thus, could not be used to predict radiosensitivity.

Adenosine Triphosphate↗
PubMed1992

Comparative evaluation of pirarubicin and adriamycin in gynecologic cancer cell lines.

Pirarubicin (PIRA) has been shown to have improved potency with less cardiac toxicity in several phase I and II clinical trials in Japan and Europe. Since Adriamycin (DXR) remains one of the most potent drugs in treatment of gynecologic cancers, this derivative has the potential to become an important chemotherapeutic agent. In this study, we compared the performance of these two drugs against a panel of 10 gynecologic cancer cell lines. The ATP chemosensitivity assays were used to determine dose-response curves. Flow cytometry was used to study cell kinetic response to both drugs. Using an IC50 value of 0.2 micrograms/ml as a cutoff for drug sensitivity, 4 cell lines, ECC1, HEC1B, BG1, and SKOV3, were considered resistant to DXR. By comparing IC50s, PIRA was 3.4 +/- 0.4 times more potent than DXR (P = 0.05). The other 6 cell lines, AN3, AE7, HEC1A, CAOV3, SKUT1B, and ME180, were considered sensitive to DXR. In this group of cell lines, PIRA was 1.6 +/- 0.3 times more potent than DXR (P = 0.5). Both PIRA and DXR elicited a spectrum of cell kinetics. By comparing the magnitude of G2 blocks at 0.1 micrograms/ml, PIRA was approximately 2-5 times more potent than DXR in SKUT1B, HEC1A, and BG1 cell lines. PIRA also displayed a reverse dose-response pattern of G2 block so that at high dose, cell cycle kinetics would mirror those of untreated controls. This observation supports the presence of a resistant tumor subpopulation and the concept of tumor heterogeneity.

Antibiotics, Antineoplastic↗