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Papers by hoa nguyen

Research paper thumbnail of Cell Cycle Perturbations of Platinum Derivatives on Two Ovarian Cancer Cell Lines

Cancer Investigation, 1993

Cisplatin continues to be one of the most commonly used cytotoxic agent. Problems of drug resista... more 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.

Research paper thumbnail of Comparative evaluation of single and combination chemotherapy in uterine cancer cell lines

Gynecologic Oncology

Controversy over the chemotherapy of uterine cancers still exists. This study was designed to dir... more 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.

Research paper thumbnail of Notice of retraction. The impact of National Health Service Corps physicians in the lowering perinatal mortality rate in Dade County, Florida

Obstetrics and Gynecology

Research paper thumbnail of The impact of National Health Service Corps physicians in the lowering perinatal mortality rate in Dade County, Florida

Obstetrics and Gynecology

In some parts of Dade County, Florida, perinatal mortality rates have revealed serious problems i... more In some parts of Dade County, Florida, perinatal mortality rates have revealed serious problems in the delivery of health care to poor pregnant women. From 1982-1985, the reported perinatal mortality rates varied from 32-36 per 1000 live births, more than double the national average. Under the leadership of the Primary Health Care Consortium of Dade County (a federation of community health centers and other primary care providers), National Health Service Corps obstetricians and pediatricians served inner-city, medically needy patients as part of a coordinated perinatal plan from 1987-1989. Data on fetal and neonatal deaths, collected from census tracts adjacent to the community health centers, were used to study the impact of Corps obstetrician and pediatrician placement. The respective perinatal mortality rates were compared with those of 1986 as historic controls. Within a year, the overall perinatal mortality rate was reduced by 45%. As a result, an estimated 320 lives were saved between 1987-1989. This public health achievement represents a measurable impact due to assignment of National Health Service Corps physicians and can be used as a working model to reduce perinatal mortality in medically underserved communities in the United States.

Research paper thumbnail of Radical hysterectomy for invasive cervical cancer: A 25‐year prospective experience with the Miami technique

Cancer

Background. The Miami modification of the traditional Wertheim-Meigs radical hysterectomy was use... more Background. The Miami modification of the traditional Wertheim-Meigs radical hysterectomy was used to treat Stage IB-IIA cervical cancer in a 25-year prospective study involving 978 patients.

Research paper thumbnail of Radical hysterectomy for stage IB adenocarcinoma of the cervix: the University of Miami experience

Research paper thumbnail of Cell cycle perturbations of platinum derivatives on two ovarian cancer cell lines

Cancer Investigation

Cisplatin continues to be one of the most commonly used cytotoxic agent. Problems of drug resista... more 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.

Research paper thumbnail of Preliminary experience with a modified Tenckhoff catheter for intraperitoneal chemotherapy

Journal of Surgical Oncology

This study reports our preliminary experience with a modified Tenckhoff catheter for intraperiton... more This study reports our preliminary experience with a modified Tenckhoff catheter for intraperitoneal chemotherapy, primarily designed to be larger, longer, and have more perfusion holes. There were 137 catheters implanted in 125 ovarian cancer patients from June 1988 to December 1990, among which 116 were actually used for intraperitoneal chemotherapy. A total of 559 cycles of intraperitoneal chemotherapy was given with a range of 1 to 16 uses per catheter. There were seven infections (6.0%), four inflow obstructions (3.4%), three bowel perforations (2.6%), and one leakage (0.8%). Among patients with catheter infection, three had delayed bowel perforation. Although the incidence of inflow obstruction was reduced from 5.5 to 3.4%, the improvement did not reach statistical significance. The frequency of delayed bowel perforation and infection were similar to the literature experience of other catheters. An unused catheter should be removed to avoid this serious complication. Further study is needed to evaluate fully the performance of this catheter system.

Research paper thumbnail of Chemosensitivity to the new anthracycline pirarubicin and other chemotherapeutic agents in primary and recurrent ovarian tumors in vitro

Gynecologic Oncology

... MD, PH.D.,2 JAMES P. PERRAS, PH.D., ROBERTO ANGIOLI, MD,+ ANDREA BAIBL, HOA ... in drug refra... more ... MD, PH.D.,2 JAMES P. PERRAS, PH.D., ROBERTO ANGIOLI, MD,+ ANDREA BAIBL, HOA ... in drug refractory cancer, in Important advances in oncology (VT DeVita, S. Hellman, and S ... Salmon, SE, Alberts, DS, Durie, BGM, Meyskens, FL, Jones, SE, Soehnlen, B., Chen, HSG, and ...

Research paper thumbnail of In vitro potentiation of radiation cytotoxicity by recombinant interferons in cervical cancer cell lines

Cancer

This investigation, which evaluates the combination of radiation and interferon, bridges two clin... more This investigation, which evaluates the combination of radiation and interferon, bridges two clinical treatments of cancer. Radiation therapy (RT) is an integral part of cervical cancer treatment; interferons (IFN), however, are classified as modifiers of biologic response. The authors evaluated the radiation-modulation effects of recombinant alpha-IFN and beta-IFN on two different human cervical cancer cell lines: ME-180 and SiHa. The radiation sensitivity based on the cell growth rate (logarithmic growth phase versus confluence) was also evaluated. Control cells and cells pretreated with either alpha-IFN or beta-IFN were exposed to RT at doses of 0, 2, 5, 10, and 15 Gy. The pretreated cells received IFN at doses of 100, 500, 1000 and 5000 IU/ml for 24 hours. The adenosine triphosphate bioluminescence assay was used to measure the surviving fractions after 7 days of incubation. The data were analyzed using the linear-quadratic model and the radiosensitivity index D. The combined effects of IFN and RT on cytotoxicity were evaluated using the synergistic interaction formula for anticancer agents. The ME-180 and SiHa cell lines had the same mean inactivation D values of 13.2 when radiated at confluence. Irradiation of ME-180 and SiHa cells in the logarithmic growth phase resulted in mean inactivation D values of 7.5 and 10.2, respectively. Enhanced radiosensitivity was observed in all IFN-RT combinations. Synergism was observed in the majority of experiments. Recombinant alpha-IFN and beta-IFN potentiate the radiotoxicity of two cervical cancer cell lines. ME-180 cells were less sensitive to IFN alone than were SiHa cells, but they showed higher a radiosensitizing effect from both IFN. Proliferating cells were more sensitive than confluent cells to RT by itself and to RT-IFN combinations.

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

Journal of Cancer Research and Clinical Oncology

Adolezesin is an analog of CC-1065. These compounds are among the most potent alkylating agents k... more 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.

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

Gynecologic Oncology

The ATP bioluminescence assay has demonstrated a strong potential to become a clinical assay for ... more 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.

Research paper thumbnail of Radiosensitization of uterine cancer cell lines by cytotoxic agents

Research paper thumbnail of Rationale of combining radiation and interferon for the treatment of cervical cancer

Oncology

The recent surge of interest in the mechanisms of action of biomodulators, also known as biologic... more 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.

Research paper thumbnail of The role of DNA index as a prognostic factor in early cervical carcinoma

Research paper thumbnail of National survey of ovarian carcinoma. I. A patient care evaluation study of the American College of Surgeons

Cancer

The Commission on Cancer of the American College of Surgeons recently finished a national survey ... more The Commission on Cancer of the American College of Surgeons recently finished a national survey of patients with ovarian cancer patients. The goal was to compare the patterns of care over a 5-year period. Data were collected from 25 consecutive patients whose disease was diagnosed first at 904 hospitals with cancer programs in 1983 and 1988. There was a total of 12,316 patients, of whom 80% were 45-85 years old. Contrary to popular belief, only 8.2% of patients were nulliparous; 85% of patients had one to five children. Of significance, 18.2% of patients with ovarian cancer had undergone a previous hysterectomy with ovarian preservation. Primary surgical treatment was used in 94.9% of patients and consisted of: oophorectomy, 81.9%; hysterectomy, 55.1%; and omentectomy, 59.0%. However, only 12-25% of patients had biopsies of the diaphragm, paracolic gutters, colon, small bowel, pelvic and paraaortic lymph nodes, and cul-de-sac to permit adequate surgical staging. The primary surgeons were: gynecologic oncologists, 21%; obstetrician-gynecologists, 45%; general surgeons, 21%; and others, 13%. These data indicate that additional resources are needed to improve the care of patients with ovarian cancer.

Research paper thumbnail of Enhancement of progesterone receptor levels by interferons in AE-7 endometrial cancer cells

Cancer

Interferon (IFN) has been reported to increase hormone receptor expression in breast cancer cells... more Interferon (IFN) has been reported to increase hormone receptor expression in breast cancer cells and to sensitize them to antiproliferative hormones. Endometrial cancer cells with high progesterone receptor (PR) level respond better to progesterone therapy than cells with either low or absent PR level. The effect of four different interferons (alpha and beta, both natural [n] and recombinant [r]) on cell proliferation and steroid receptor levels was investigated in the PR positive AE-7 human endometrial cancer cell line over a period of 12 days. Cells were exposed to 10,100 and 1000 IU/ml of each IFN either for 3 days or continuously for 12 days. Hormone receptors were determined by the monoclonal enzyme immunoassay. Chemosensitivity was evaluated with the adenosine triphosphate-cell viability assay. AE-7 has a low level of estrogen receptors, which was not significantly affected by IFN exposure. The four IFN showed significantly enhanced PR levels over 12 days in both the 3-day and continuous-exposure experiments. No significant difference of PR enhancement was observed between 3 days and continuous exposure to IFN. This increase of receptors did not appear to be dose related. IFN enhanced PR level to a maximum level of about two times control cells. IFN did not produce significant cytotoxicity. Antiproliferative activity was observed with nIFN beta and rIFN beta at 1000 IU/ml dose in continuous-exposure experiments, which showed survival values of 79% and 69% respectively, compared with control at day 12. These preliminary data on PR expression modulation support other studies, which have shown that IFN modulate hormone receptor expression and, therefore, may play a role in the treatment of endometrial cancer.

Research paper thumbnail of Screening in gynecologic cancers

Cancer

Gynecologic malignancies account for approximately 13% of cancers in women. Ovarian and uterine c... more Gynecologic malignancies account for approximately 13% of cancers in women. Ovarian and uterine cancer are among the five most common causes of cancer deaths in women, exceeded in incidence only by cancers of the breast, colon, and lung. Improved survival in patients with genital cancers predominantly reflects early diagnosis and not improved treatments. Even cancers for which there are effective screening and satisfactory treatments are seen more often than is acceptable. It is paramount that those entrusted with the health of women be knowledgeable about all cancer screening techniques and be able to identify the patient at risk for gynecologic malignancy. The provider's obligation to be vigilant about the signs and symptoms of cancer must be matched by the patients' responsibility to her own health. Regular gynecologic examinations, Papanicolaou (Pap) tests, and immediate reporting of unusual signs and symptoms are requirements that cannot be dismissed by patients. Education directed toward patients and health care providers can optimize survival. The Pap test for cervical cancer remains a universally accepted screening procedure. Human papillomavirus (HPV) DNA typing, cervicography, loop electrosurgical excision procedure (LEEP), transvaginal ultrasonography, color flow doppler, endometrial sampling, and serum CA 125 measurements are some of the newer techniques being investigation as potential screening tools. Although additional prospective studies are needed to establish the value of these modalities, there is little doubt that prognostic information obtained from these modalities will influence the clinical care of patients in the near future.

Research paper thumbnail of Adenosquamous carcinoma of the cervix: prognosis in early stage disease treated by radical hysterectomy

Research paper thumbnail of Paclitaxel: a radiation sensitizer of human cervical cancer cells

Gynecologic Oncology

Paclitaxel is an exciting chemotherapeutic agent active in a variety of malignant tumors. This st... more Paclitaxel is an exciting chemotherapeutic agent active in a variety of malignant tumors. This study was designed to explore the radiosensitizing potential of paclitaxel in human cervical cancer cell lines. The cell lines ME180, SiHa, and MS751 were evaluated. Experiments were performed in the proliferative phase of growth. Paclitaxel doses were treated at 0.01x, 0.02x, 0.03x, 0.04x, and 0.05x peak plasma concentration (PPC) in ME180 and 0.001x, 0.002x, 0.003x, 0.004x, and 0.005x PPC in SiHa and MS751. Radiation (RT) doses of cobalt-60 were 0, 2, 4, 6, 8, and 10 Gy. In the combination group RT was given 48 hr after paclitaxel treatment. To allow for median effect analyses, combination doses were kept at a fixed ratio: 0.01x/2 Gy, 0.02x/4 Gy, 0.03x/6 Gy, 0.04x/8 Gy, and 0.05x/10 Gy for ME180 and 0.001x/2 Gy, 0.002x/4 Gy, 0.003x/6 Gy, 0.004x/8 Gy, and 0.005x/10 Gy in MS-751 and SiHa. Adenosine triphosphate bioluminescence was performed on Day 7 after treatment and compared to untreated controls. Dose-response data were fit to the linear quadratic model and mean inactivation dose D was calculated. Data analysis with t test was performed. The median effect principle was used to evaluate the nature of the interaction between the two therapeutic modalities. Paclitaxel increased radiation cytotoxicity in all three cell lines. Mean inactivation D values for RT versus combination were 6.70 (+/- 0.15) and 4.33 (+/- 0.43) (P = 0.004) in ME180, 6.08 (+/- 0.70) and 4.54 (+/- 0.093) (P = 0.033) in MS751, and 7.03 (+/- 0.46) and 5.97 (+/- 0.51) (P = 0.034) in SiHa. The interaction of paclitaxel and RT was found to be supraadditive in ME180 and SiHa and subadditive in MS751. We conclude that paclitaxel has modest radiation-sensitizing effects in cervical cancer cell lines and that further clinical trials should be considered.

Research paper thumbnail of Cell Cycle Perturbations of Platinum Derivatives on Two Ovarian Cancer Cell Lines

Cancer Investigation, 1993

Cisplatin continues to be one of the most commonly used cytotoxic agent. Problems of drug resista... more 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.

Research paper thumbnail of Comparative evaluation of single and combination chemotherapy in uterine cancer cell lines

Gynecologic Oncology

Controversy over the chemotherapy of uterine cancers still exists. This study was designed to dir... more 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.

Research paper thumbnail of Notice of retraction. The impact of National Health Service Corps physicians in the lowering perinatal mortality rate in Dade County, Florida

Obstetrics and Gynecology

Research paper thumbnail of The impact of National Health Service Corps physicians in the lowering perinatal mortality rate in Dade County, Florida

Obstetrics and Gynecology

In some parts of Dade County, Florida, perinatal mortality rates have revealed serious problems i... more In some parts of Dade County, Florida, perinatal mortality rates have revealed serious problems in the delivery of health care to poor pregnant women. From 1982-1985, the reported perinatal mortality rates varied from 32-36 per 1000 live births, more than double the national average. Under the leadership of the Primary Health Care Consortium of Dade County (a federation of community health centers and other primary care providers), National Health Service Corps obstetricians and pediatricians served inner-city, medically needy patients as part of a coordinated perinatal plan from 1987-1989. Data on fetal and neonatal deaths, collected from census tracts adjacent to the community health centers, were used to study the impact of Corps obstetrician and pediatrician placement. The respective perinatal mortality rates were compared with those of 1986 as historic controls. Within a year, the overall perinatal mortality rate was reduced by 45%. As a result, an estimated 320 lives were saved between 1987-1989. This public health achievement represents a measurable impact due to assignment of National Health Service Corps physicians and can be used as a working model to reduce perinatal mortality in medically underserved communities in the United States.

Research paper thumbnail of Radical hysterectomy for invasive cervical cancer: A 25‐year prospective experience with the Miami technique

Cancer

Background. The Miami modification of the traditional Wertheim-Meigs radical hysterectomy was use... more Background. The Miami modification of the traditional Wertheim-Meigs radical hysterectomy was used to treat Stage IB-IIA cervical cancer in a 25-year prospective study involving 978 patients.

Research paper thumbnail of Radical hysterectomy for stage IB adenocarcinoma of the cervix: the University of Miami experience

Research paper thumbnail of Cell cycle perturbations of platinum derivatives on two ovarian cancer cell lines

Cancer Investigation

Cisplatin continues to be one of the most commonly used cytotoxic agent. Problems of drug resista... more 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.

Research paper thumbnail of Preliminary experience with a modified Tenckhoff catheter for intraperitoneal chemotherapy

Journal of Surgical Oncology

This study reports our preliminary experience with a modified Tenckhoff catheter for intraperiton... more This study reports our preliminary experience with a modified Tenckhoff catheter for intraperitoneal chemotherapy, primarily designed to be larger, longer, and have more perfusion holes. There were 137 catheters implanted in 125 ovarian cancer patients from June 1988 to December 1990, among which 116 were actually used for intraperitoneal chemotherapy. A total of 559 cycles of intraperitoneal chemotherapy was given with a range of 1 to 16 uses per catheter. There were seven infections (6.0%), four inflow obstructions (3.4%), three bowel perforations (2.6%), and one leakage (0.8%). Among patients with catheter infection, three had delayed bowel perforation. Although the incidence of inflow obstruction was reduced from 5.5 to 3.4%, the improvement did not reach statistical significance. The frequency of delayed bowel perforation and infection were similar to the literature experience of other catheters. An unused catheter should be removed to avoid this serious complication. Further study is needed to evaluate fully the performance of this catheter system.

Research paper thumbnail of Chemosensitivity to the new anthracycline pirarubicin and other chemotherapeutic agents in primary and recurrent ovarian tumors in vitro

Gynecologic Oncology

... MD, PH.D.,2 JAMES P. PERRAS, PH.D., ROBERTO ANGIOLI, MD,+ ANDREA BAIBL, HOA ... in drug refra... more ... MD, PH.D.,2 JAMES P. PERRAS, PH.D., ROBERTO ANGIOLI, MD,+ ANDREA BAIBL, HOA ... in drug refractory cancer, in Important advances in oncology (VT DeVita, S. Hellman, and S ... Salmon, SE, Alberts, DS, Durie, BGM, Meyskens, FL, Jones, SE, Soehnlen, B., Chen, HSG, and ...

Research paper thumbnail of In vitro potentiation of radiation cytotoxicity by recombinant interferons in cervical cancer cell lines

Cancer

This investigation, which evaluates the combination of radiation and interferon, bridges two clin... more This investigation, which evaluates the combination of radiation and interferon, bridges two clinical treatments of cancer. Radiation therapy (RT) is an integral part of cervical cancer treatment; interferons (IFN), however, are classified as modifiers of biologic response. The authors evaluated the radiation-modulation effects of recombinant alpha-IFN and beta-IFN on two different human cervical cancer cell lines: ME-180 and SiHa. The radiation sensitivity based on the cell growth rate (logarithmic growth phase versus confluence) was also evaluated. Control cells and cells pretreated with either alpha-IFN or beta-IFN were exposed to RT at doses of 0, 2, 5, 10, and 15 Gy. The pretreated cells received IFN at doses of 100, 500, 1000 and 5000 IU/ml for 24 hours. The adenosine triphosphate bioluminescence assay was used to measure the surviving fractions after 7 days of incubation. The data were analyzed using the linear-quadratic model and the radiosensitivity index D. The combined effects of IFN and RT on cytotoxicity were evaluated using the synergistic interaction formula for anticancer agents. The ME-180 and SiHa cell lines had the same mean inactivation D values of 13.2 when radiated at confluence. Irradiation of ME-180 and SiHa cells in the logarithmic growth phase resulted in mean inactivation D values of 7.5 and 10.2, respectively. Enhanced radiosensitivity was observed in all IFN-RT combinations. Synergism was observed in the majority of experiments. Recombinant alpha-IFN and beta-IFN potentiate the radiotoxicity of two cervical cancer cell lines. ME-180 cells were less sensitive to IFN alone than were SiHa cells, but they showed higher a radiosensitizing effect from both IFN. Proliferating cells were more sensitive than confluent cells to RT by itself and to RT-IFN combinations.

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

Journal of Cancer Research and Clinical Oncology

Adolezesin is an analog of CC-1065. These compounds are among the most potent alkylating agents k... more 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.

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

Gynecologic Oncology

The ATP bioluminescence assay has demonstrated a strong potential to become a clinical assay for ... more 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.

Research paper thumbnail of Radiosensitization of uterine cancer cell lines by cytotoxic agents

Research paper thumbnail of Rationale of combining radiation and interferon for the treatment of cervical cancer

Oncology

The recent surge of interest in the mechanisms of action of biomodulators, also known as biologic... more 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.

Research paper thumbnail of The role of DNA index as a prognostic factor in early cervical carcinoma

Research paper thumbnail of National survey of ovarian carcinoma. I. A patient care evaluation study of the American College of Surgeons

Cancer

The Commission on Cancer of the American College of Surgeons recently finished a national survey ... more The Commission on Cancer of the American College of Surgeons recently finished a national survey of patients with ovarian cancer patients. The goal was to compare the patterns of care over a 5-year period. Data were collected from 25 consecutive patients whose disease was diagnosed first at 904 hospitals with cancer programs in 1983 and 1988. There was a total of 12,316 patients, of whom 80% were 45-85 years old. Contrary to popular belief, only 8.2% of patients were nulliparous; 85% of patients had one to five children. Of significance, 18.2% of patients with ovarian cancer had undergone a previous hysterectomy with ovarian preservation. Primary surgical treatment was used in 94.9% of patients and consisted of: oophorectomy, 81.9%; hysterectomy, 55.1%; and omentectomy, 59.0%. However, only 12-25% of patients had biopsies of the diaphragm, paracolic gutters, colon, small bowel, pelvic and paraaortic lymph nodes, and cul-de-sac to permit adequate surgical staging. The primary surgeons were: gynecologic oncologists, 21%; obstetrician-gynecologists, 45%; general surgeons, 21%; and others, 13%. These data indicate that additional resources are needed to improve the care of patients with ovarian cancer.

Research paper thumbnail of Enhancement of progesterone receptor levels by interferons in AE-7 endometrial cancer cells

Cancer

Interferon (IFN) has been reported to increase hormone receptor expression in breast cancer cells... more Interferon (IFN) has been reported to increase hormone receptor expression in breast cancer cells and to sensitize them to antiproliferative hormones. Endometrial cancer cells with high progesterone receptor (PR) level respond better to progesterone therapy than cells with either low or absent PR level. The effect of four different interferons (alpha and beta, both natural [n] and recombinant [r]) on cell proliferation and steroid receptor levels was investigated in the PR positive AE-7 human endometrial cancer cell line over a period of 12 days. Cells were exposed to 10,100 and 1000 IU/ml of each IFN either for 3 days or continuously for 12 days. Hormone receptors were determined by the monoclonal enzyme immunoassay. Chemosensitivity was evaluated with the adenosine triphosphate-cell viability assay. AE-7 has a low level of estrogen receptors, which was not significantly affected by IFN exposure. The four IFN showed significantly enhanced PR levels over 12 days in both the 3-day and continuous-exposure experiments. No significant difference of PR enhancement was observed between 3 days and continuous exposure to IFN. This increase of receptors did not appear to be dose related. IFN enhanced PR level to a maximum level of about two times control cells. IFN did not produce significant cytotoxicity. Antiproliferative activity was observed with nIFN beta and rIFN beta at 1000 IU/ml dose in continuous-exposure experiments, which showed survival values of 79% and 69% respectively, compared with control at day 12. These preliminary data on PR expression modulation support other studies, which have shown that IFN modulate hormone receptor expression and, therefore, may play a role in the treatment of endometrial cancer.

Research paper thumbnail of Screening in gynecologic cancers

Cancer

Gynecologic malignancies account for approximately 13% of cancers in women. Ovarian and uterine c... more Gynecologic malignancies account for approximately 13% of cancers in women. Ovarian and uterine cancer are among the five most common causes of cancer deaths in women, exceeded in incidence only by cancers of the breast, colon, and lung. Improved survival in patients with genital cancers predominantly reflects early diagnosis and not improved treatments. Even cancers for which there are effective screening and satisfactory treatments are seen more often than is acceptable. It is paramount that those entrusted with the health of women be knowledgeable about all cancer screening techniques and be able to identify the patient at risk for gynecologic malignancy. The provider's obligation to be vigilant about the signs and symptoms of cancer must be matched by the patients' responsibility to her own health. Regular gynecologic examinations, Papanicolaou (Pap) tests, and immediate reporting of unusual signs and symptoms are requirements that cannot be dismissed by patients. Education directed toward patients and health care providers can optimize survival. The Pap test for cervical cancer remains a universally accepted screening procedure. Human papillomavirus (HPV) DNA typing, cervicography, loop electrosurgical excision procedure (LEEP), transvaginal ultrasonography, color flow doppler, endometrial sampling, and serum CA 125 measurements are some of the newer techniques being investigation as potential screening tools. Although additional prospective studies are needed to establish the value of these modalities, there is little doubt that prognostic information obtained from these modalities will influence the clinical care of patients in the near future.

Research paper thumbnail of Adenosquamous carcinoma of the cervix: prognosis in early stage disease treated by radical hysterectomy

Research paper thumbnail of Paclitaxel: a radiation sensitizer of human cervical cancer cells

Gynecologic Oncology

Paclitaxel is an exciting chemotherapeutic agent active in a variety of malignant tumors. This st... more Paclitaxel is an exciting chemotherapeutic agent active in a variety of malignant tumors. This study was designed to explore the radiosensitizing potential of paclitaxel in human cervical cancer cell lines. The cell lines ME180, SiHa, and MS751 were evaluated. Experiments were performed in the proliferative phase of growth. Paclitaxel doses were treated at 0.01x, 0.02x, 0.03x, 0.04x, and 0.05x peak plasma concentration (PPC) in ME180 and 0.001x, 0.002x, 0.003x, 0.004x, and 0.005x PPC in SiHa and MS751. Radiation (RT) doses of cobalt-60 were 0, 2, 4, 6, 8, and 10 Gy. In the combination group RT was given 48 hr after paclitaxel treatment. To allow for median effect analyses, combination doses were kept at a fixed ratio: 0.01x/2 Gy, 0.02x/4 Gy, 0.03x/6 Gy, 0.04x/8 Gy, and 0.05x/10 Gy for ME180 and 0.001x/2 Gy, 0.002x/4 Gy, 0.003x/6 Gy, 0.004x/8 Gy, and 0.005x/10 Gy in MS-751 and SiHa. Adenosine triphosphate bioluminescence was performed on Day 7 after treatment and compared to untreated controls. Dose-response data were fit to the linear quadratic model and mean inactivation dose D was calculated. Data analysis with t test was performed. The median effect principle was used to evaluate the nature of the interaction between the two therapeutic modalities. Paclitaxel increased radiation cytotoxicity in all three cell lines. Mean inactivation D values for RT versus combination were 6.70 (+/- 0.15) and 4.33 (+/- 0.43) (P = 0.004) in ME180, 6.08 (+/- 0.70) and 4.54 (+/- 0.093) (P = 0.033) in MS751, and 7.03 (+/- 0.46) and 5.97 (+/- 0.51) (P = 0.034) in SiHa. The interaction of paclitaxel and RT was found to be supraadditive in ME180 and SiHa and subadditive in MS751. We conclude that paclitaxel has modest radiation-sensitizing effects in cervical cancer cell lines and that further clinical trials should be considered.