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C B Powell

Publications and source records attributed to C B Powell.

29 records · Page 2Linked to original sources
PubMed1993

Interferon-alpha (IFN alpha) induces a cytolytic mechanism in ovarian carcinoma cells through a protein kinase C-dependent pathway.

We have recently shown that IFN alpha induces a cytolytic mechanism in human ovarian carcinoma cell lines which is revealed when protein synthesis is subsequently inhibited. In order to determine whether the cytolytic activity induced by IFN alpha was activated through a pathway involving the activation of PKC, the human ovarian carcinoma cell line Caov-3 was exposed to phorbol 12-myristate 13-acetate (PMA). Under conditions where PMA activates PKC, PMA mimicked IFN alpha in its ability to induce a cytolytic mechanism. In contrast, under conditions where PMA depletes PKC, PMA not only did not induce cytolytic activity, but it prevented IFN alpha from inducing cytolytic activity. To further investigate the involvement of PKC in the signaling of cytolytic activity by IFN alpha, the ability of the protein kinase inhibitors, staurosporine, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride (H7), N-[2-(methylamino) ethyl]-5-isoquinolinesulfonamide dihydrochloride (H8), and N-(2-guanidinoethyl)-5-isoquinolinesulfonamide dihydrochloride (HA1004) to block the induction of cytolytic activity by IFN alpha was determined. The fact that H7, H8, and staurosporine, but not HA1004, blocked the induction of cytolytic activity by IFN alpha provides additional evidence of the involvement of PKC in this activity. Taken together these results indicate that the cytolytic activity induced by IFN alpha is induced through apathway that involves the activation of PKC.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Interferon alfa activates a lytic mechanism in ovarian and cervical carcinoma cells.

OBJECTIVE: Our purpose was to examine the in vitro cytolytic potential of interferon alfa for human cervical and ovarian carcinoma cell lines. STUDY DESIGN: The lytic potential of interferon alfa alone and in the presence the protein synthesis inhibitors actinomycin D and emetine was determined in the human cervical carcinoma cell lines ME-180, MS751, SiHa, HT-3, and C-33A and the ovarian carcinoma cell lines Caov-3, NIH:OVCAR-3, SK-OV-3 carcinoma cell lines by means of an 18-hour chromium 51 release assay. RESULTS: Exposure of these cell lines to interferon alfa alone did not result in lysis. Similarly, when cells were simultaneously exposed to interferon alfa and either actinomycin D or emetine there was no additional increase in lysis above that seen with actinomycin D or emetine alone. Pretreatment of cells with interferon alfa (10(3), 10(4), or 10(5) U/ml) followed by protein synthesis inhibition by actinomycin D or emetine resulted in a synergistic increase in lysis. CONCLUSION: The ability to reveal the lytic potential of interferon alfa when protein synthesis is subsequently inhibited could have practical applications for the treatment of gynecologic malignancies.

Dactinomycin↗
PubMed1992

Resistance to cytolysis by tumor necrosis factor alpha in malignant gynecological cell lines is associated with the expression of protein(s) that prevent the activation of phospholipase A2 by tumor necrosis factor alpha.

Although there are a limited number of cell lines that are sensitive to cytolysis by tumor necrosis factor alpha (TNF alpha), the vast majority are resistant. The analysis of TNF alpha-sensitive cells has shown that phospholipase A2 is activated by TNF alpha in these cells and that the activity of phospholipase A2 is required for their cytolysis. Many cell lines that are resistant to TNF alpha-mediated cytolysis are dependent on the maintenance of protein synthesis for their resistance. We have recently shown that this is also true for TNF alpha-resistant cell lines derived from cervical (ME-180 and SiHa) and ovarian (SK-OV-3 and OVCAR-3) carcinomas, in that they are sensitive to cytolysis by TNF alpha only in the presence of protein synthesis inhibitors. Here we show that the TNF alpha-mediated cytolysis of these resistant cell lines in the presence of the protein synthesis inhibitor emetine is similar to that of sensitive cells, in that cytolysis is inhibited by the inhibitors of phospholipase A2. The measurement of the release of radiolabeled material from cervical and ovarian carcinoma cell lines prelabeled with [3H]arachidonic acid showed that not only was phospholipase A2 required for the cytolysis of these cells by TNF alpha in the presence of protein synthesis inhibitors, but more importantly, phospholipase A2 was not activated by TNF alpha unless protein synthesis was inhibited. These results indicate that a protein synthesis-dependent resistance mechanism expressed by these cell lines blocks TNF alpha-mediated cytolysis by preventing the activation of phospholipase A2 by TNF alpha.

Animals↗
PubMed1991

Inhibition of protein synthesis enhances the lytic effects of tumor necrosis factor alpha and interferon gamma in cell lines derived from gynecological malignancies.

Few clinical responses have occurred in preliminary studies using the cytokines tumor necrosis factor alpha (TNF alpha) or interferon gamma (IFN gamma) in cancer patients. This may be related to the observation that many malignant cell lines are resistant to lysis by these cytokines in vitro. Resistance to lysis by TNF alpha or IFN gamma in many cells is controlled by a protein-synthesis-dependent mechanism, such that when protein synthesis is inhibited cells become sensitive to lysis by these cytokines. Because there is some evidence that TNF alpha and IFN gamma act through different lytic mechanisms and are opposed by different resistance mechanisms, we treated a panel of eight cell lines, five derived from human cervical carcinomas (ME-180, MS751, SiHa, HT-3, and C-33A) and three derived from ovarian carcinomas (Caov-3, SK-OV-3, and NIH: OVCAR-3) with both TNF alpha and IFN gamma to determine whether such combination treatment might maximize in vitro cell lysis. Our results showed that pretreatment with IFN gamma followed by exposure to TNF alpha in the presence of protein synthesis inhibitors increased lysis of seven of the eight cell lines above that seen with either TNF alpha or IFN gamma and inhibitors of protein synthesis. Only the cell line C-33A was resistant to lysis by TNF alpha and IFN gamma, when exposed to these agents both alone and in combination with protein synthesis inhibitors. Clinically, combining the cytokines TNF alpha and IFN gamma with protein synthesis inhibitors may maximize the in vivo lytic effects of these cytokines.

Cell Line↗
PubMed1990

Expression of a resistance mechanism in ovarian and cervical carcinoma cells prevents their lysis by gamma-interferon.

Despite extensive evidence that recombinant human gamma-interferon (IFN-gamma) exerts antiproliferative effects on a variety of cancer cell lines, IFN-gamma has not been shown to lyse cells in vitro. In order to determine whether some cancer cells might actively resist lysis by IFN-gamma, we examined eight arbitrarily selected cell lines derived from gynecological malignancies (ME-180, MS751, HT-3, SiHa, and C-33A human cervical carcinoma lines; Caov-3, SK-OV-3, and NIH:OVCAR-3 human ovarian carcinoma cell lines) for lysis by IFN-gamma. In a 24-h assay involving release of 51Cr from cells, none of these cell lines was lysed by IFN-gamma, either alone or in combination with actinomycin-D or emetine, two inhibitors of protein synthesis. However, pretreatment of cells with 100 units/ml of IFN-gamma for 24 h, followed by inhibition of protein synthesis, led to significantly increased lysis of the cell lines ME-180, MS751, and Caov-3. These results indicate that IFN-gamma induces a lytic mechanism in some cancer cells that is opposed by a protein synthesis-dependent resistance mechanism. This suggests that a combination therapy involving IFN-gamma and inhibitors of protein synthesis may be useful in the treatment of some cancers.

Cell Line↗
PubMed1990

Dexamethasone used as an antiemetic in chemotherapy protocols inhibits natural cytotoxic (NC) cell activity.

Because dexamethasone is often included as an antiemetic in chemotherapy protocols that involve cisplatin and because cisplatin has been shown to increase the in vitro lysis of tumor cells by natural cytotoxic (NC) effector cells, we determined the NC activity of 27 patients who received dexamethasone in conjunction with seven different cisplatin-based chemotherapy protocols. The results of this analysis showed that the NC activity of patients who received cisplatin-based chemotherapy protocols that included dexamethasone was reduced significantly 24 hours after treatment compared with before treatment (P less than 0.001). The addition of dexamethasone (at a concentration equivalent to the plasma level of patients treated with dexamethasone) to the in vitro assay of NC activity caused a significant decrease in NC activity compared with when dexamethasone was not added (P less than 0.001). There was no cumulative effect of dexamethasone in that the reduction of NC activity by dexamethasone was not significantly different in patients who had been treated previously at least four times and in patients who were treated for the first time. When dexamethasone was not included in the chemotherapy protocol the NC activity of 19 patients was not reduced 24 hours after treatment. These results indicate that dexamethasone causes a significant reduction in NC activity. Although the tumor surveillance role of human NC cells in vivo has not been established, the effect of dexamethasone on NC cells suggests that additional research of the effect of dexamethasone in cisplatin-based chemotherapy protocols is warranted.

Adult↗
PubMed1990

Common expression of a tumor necrosis factor resistance mechanism among gynecological malignancies.

The efficacy of tumor necrosis factor alpha (TNF alpha) as an anticancer agent is limited. This limitation might be related to the expression of a protein-synthesis-dependent resistance mechanism that prevents the lysis of tumor cells by TNF alpha. To test this possibility eight randomly selected human cell lines, three derived from ovarian carcinomas and five derived from cervical carcinomas, were tested for their in vitro sensitivity to TNF alpha-mediated lysis. The results of this analysis showed that all eight cell lines are normally resistant to lysis by TNF alpha. However, in the presence of inhibitors of protein synthesis, seven of them showed a significant increase in TNF alpha-mediated lysis. Measurement of protein synthesis showed that there is a linear correlation between the level of inhibition of protein synthesis and the level of TNF alpha-mediated lysis. The fact that seven of eight randomly selected cell lines are resistant to TNF alpha because they express a protein-synthesis-dependent resistance mechanism suggests that this mechanism of resistance may be common among gynecological cancers. The results also suggest that a therapy involving TNF alpha and inhibitors of protein synthesis might be useful for the treatment of gynecological malignancies.

Antibodies, Neoplasm↗
PubMed1990

Reduced natural cytotoxic cell activity in patients receiving cisplatin-based chemotherapy and in mice treated with cisplatin.

In mice natural cytotoxic (NC) cells are known to play a role in the rejection of tumours that are sensitive to NC-mediated lysis. We have recently shown that in vitro human and murine tumour cells become more sensitive to lysis mediated by NC cells in the presence of the anti-cancer drug cisplatin. If NC activity plays a role in tumour surveillance in humans, then the ability of NC cells to eliminate tumours in patients treated with cisplatin would not only be dependent on cisplatin increasing the sensitivity of tumours to NC mediated lysis, but would also depend on the maintenance of high levels of NC activity during chemotherapy. Here we report that patients receiving chemotherapy that included cisplatin showed a time-dependent reduction in NC activity. NC activity was normal 1 day after treatment; however, 15 days after treatment patients had an eight- to 16-fold reduction in NC activity that returned to normal levels by day 21. The reduction in NC activity of patients was coincident with a reduction in circulating monocytes. Mice treated with only cisplatin showed a similar reduction in NC activity. Mice treated with cisplatin had a reduced level of NC activity that was first apparent 8 days after treatment, reached a nadir on day 15, and returned to normal levels on day 22.

Adult↗
PubMed1989

In vitro analysis of the anticancer potential of tumor necrosis factor in combination with cisplatin.

We have recently shown that cisplatin increases the natural cytotoxic (NC) cell-mediated lysis of a variety of human adenocarcinoma cell lines that are resistant to cisplatin or NC activity alone. Because NC lysis is mediated by tumor necrosis factor alpha (TNF) bound to the surface of NC effector cells, we analyzed the ability of TNF in combination with cisplatin to increase the lysis of tumor cells. The in vitro anticancer potential of the combination of TNF and cisplatin was determined for both dividing and nondividing populations of two human ovarian carcinoma cell lines, SK-OV-3 and OVCAR-3. Nondividing SK-OV-3 and OVCAR-3 cells are resistant to cisplatin and TNF when used as single agents. Dividing OVCAR-3 cells are approximately two times more sensitive to TNF than dividing SK-OV-3 cells, whereas dividing SK-OV-3 cells are approximately ten times more sensitive to cisplatin than dividing OVCAR-3 cells. TNF at 1000 units/ml in the presence of clinically low concentrations of cisplatin (0.6-0.25 micrograms/ml) increased the lysis of dividing OVCAR-3 cells above the value expected for the sum lysis mediated by cisplatin alone and lysis mediated by TNF alone. Similar results were obtained with dividing populations of the SK-OV-3 cell line. The combination of cisplatin and TNF did not increase the lysis of the nondividing populations of either cell line. The increased lysis of tumor cells combined with the maintenance of specificity for only dividing cells indicates that the combination of cisplatin and TNF may be useful for the treatment of tumors that are resistant to either cisplatin or TNF.

Adenocarcinoma↗
PubMedDate not supplied

Discordance between beliefs and recommendations of gynecologic oncologists in ovarian cancer management.

PURPOSE: The purpose of this study was to determine how physician experts make decisions for clinical scenarios in ovarian cancer and describe a profile of factors reported to influence treatment decisions. METHODS: A questionnaire was sent to Full Members of the Society of Gynecologic Oncologists regarding surgery and chemotherapy for scenarios of primary and recurrent ovarian cancer. RESULTS: In a scenario of primary presentation, 94% of respondents chose a treatment of tumor resection over chemotherapy. Despite the preference for surgery in a clinical scenario, 50% agreed with a statement that neoadjuvant chemotherapy is equivalent to primary surgery. In a scenario of recurrent disease, a comparable number of respondents chose a treatment of secondary cytoreductive surgery (45%) versus direct retreatment with chemotherapy (49%). Those choosing surgery responded that they believed in extensive surgery to achieve optimal cytoreduction. Most (62%) respondents described themselves as collaborative in treatment planning, yet only 24% reported that patient preference strongly influences their decision making. CONCLUSIONS: Although a plan for primary cytoreduction is favored, in specific scenarios, views were divided for the role of neoadjuvant chemotherapy. For a recurrent disease scenario, support was divided between secondary cytoreductive surgery and direct retreatment with chemotherapy. Further clinical research is necessary to minimize the discordance between physician beliefs and recommendations.

Combined Modality Therapy↗