ABSTRACT
This study evaluates the in vitro sensitivities of 42 ovarian cancer specimens to the new anticancer agent Paclitaxel (taxol, Tx), cisplatin (DDP), and the combination Tx-DDP with the adenosine triphosphate cell viability assay (ATP-CVA). In vitro response is defined by > or = 50% ATP decrease compared to untreated controls 6-7 days after drug treatment with 20% of the peak plasma concentration (PPC). Response rates were 12% to Tx, 19% to DDP, and 27% to Tx + DDP. The mean IC50's of Tx, DDP, and the combination Tx-DDP were (2.6x, 1.0x, and 0.38x PPC, respectively). The mean inhibition of cell viability was significantly greater with drug combinations compared to single drugs. In 7/11 tumors synergistic effects and in 2/11 additive effects were found between Tx and DDP. We conclude that based on ATP-CVA in vitro results, Tx-DDP shows significantly better activity compared to each of the single drugs in ovarian cancer.
Subject(s)
Adenosine Triphosphate/analysis , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cisplatin/pharmacology , Ovarian Neoplasms/drug therapy , Paclitaxel/pharmacology , Adenosine Triphosphate/antagonists & inhibitors , Cell Survival/drug effects , Cisplatin/administration & dosage , Drug Screening Assays, Antitumor , Female , Humans , Ovarian Neoplasms/metabolism , Paclitaxel/administration & dosageABSTRACT
BACKGROUND: An analysis was conducted by the American College of Surgeons Cancer Commission evaluating the patterns of care of ovarian cancer patients diagnosed in 1983 and 1988. The purpose of this study was to investigate whether there was a difference in the care patterns of elderly ovarian cancer patients and its impact on survival. METHODS: Data were collected from 25 consecutive patients whose disease was diagnosed initially at 904 participating hospitals with cancer programs in 1983 and 1988. The survival and care of patients greater than or equal to 80 years of age were compared to those less than 80 years of age. RESULTS: Of the 12,316 patients evaluated, 1,115 were 80 years or older. A significant reduction in survival was noted among patients 80 years and older as compared to their younger counterparts (P = 0.03-0.00001). The 5-year survivals were: stage I, 89% versus 79%; stage II, 58% versus 40%; stage III, 25% versus 11%; and stage IV, 13% versus 3%, respectively, for those less than 80 years old as compared to those greater than or equal to 80 years old. Most elderly ovarian cancer patients were cared for by nononcologists such as general surgeons (31%) and obstetricians/gynecologists (29%). As a group, older patients had fewer total abdominal hysterectomies, bilateral salpingo-oophorectomies, and omentectomies than their younger counterpart (P < 0.00001). As further evidence for a less aggressive surgical approach, the optimal tumor debulking rates of women greater than or equal to 80 years were significantly less than those of younger patients (P < 0.001). There was no significant increase in anesthesia complications between age groups. Generally, older patients are less likely to receive adjuvant chemotherapy than younger patients (42% versus 69%, P < 0.0001). CONCLUSION: It appears that conservative treatments contributed to the decreased survival of older ovarian cancer patients.
Subject(s)
Ovarian Neoplasms/mortality , Ovarian Neoplasms/therapy , Age Factors , Aged , Aged, 80 and over , Chemotherapy, Adjuvant/statistics & numerical data , Female , Humans , Hysterectomy/statistics & numerical data , Middle Aged , Omentum/surgery , Ovariectomy/statistics & numerical data , Surveys and Questionnaires , Survival Rate , United States/epidemiologyABSTRACT
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Subject(s)
Endometrial Neoplasms/metabolism , Interferon-alpha/pharmacology , Interferon-beta/pharmacology , Receptors, Progesterone/metabolism , Adenosine Triphosphate/metabolism , Cell Division/drug effects , Endometrial Neoplasms/pathology , Female , Humans , Receptors, Estrogen/drug effects , Receptors, Estrogen/metabolism , Receptors, Progesterone/drug effects , Recombinant Proteins/pharmacology , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Benzofurans , Cyclohexanecarboxylic Acids/pharmacology , Endometrial Neoplasms/drug therapy , Indoles/pharmacology , Ovarian Neoplasms/drug therapy , Urea/analogs & derivatives , Uterine Cervical Neoplasms/drug therapy , Adenosine Triphosphate/metabolism , Cisplatin/pharmacology , Cyclohexenes , Dose-Response Relationship, Drug , Doxorubicin/pharmacology , Drug Screening Assays, Antitumor , Duocarmycins , Endometrial Neoplasms/enzymology , Female , Humans , In Vitro Techniques , Ovarian Neoplasms/enzymology , Tumor Cells, Cultured , Urea/pharmacology , Uterine Cervical Neoplasms/enzymologyABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Doxorubicin/analogs & derivatives , Ovarian Neoplasms/drug therapy , Adenosine Triphosphate/analysis , Cisplatin/pharmacology , Cyclophosphamide/analogs & derivatives , Cyclophosphamide/pharmacology , Doxorubicin/pharmacology , Drug Screening Assays, Antitumor/methods , Female , Humans , In Vitro Techniques , Ovarian Neoplasms/chemistry , RecurrenceABSTRACT
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.
Subject(s)
Adenosine Triphosphate/analysis , Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Cyclohexanecarboxylic Acids/pharmacology , Indoles , Ovarian Neoplasms/drug therapy , Uterine Cervical Neoplasms/drug therapy , Benzofurans , Cyclohexenes , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor/methods , Duocarmycins , Female , Humans , In Vitro Techniques , Ovarian Neoplasms/chemistry , Regression Analysis , Uterine Cervical Neoplasms/chemistryABSTRACT
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.