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Biomedical subjects

C E Welander

Publications and source records attributed to C E Welander.

At least 37 records · Page 2Linked to original sources
PubMed1988

Effects of scheduling and ascites-associated macrophages on combined antiproliferative activity of alpha-2b interferon and gamma-interferon in a clonogenic assay.

Effects of combination treatment with human recombinant alpha-2b interferon (IFN-alpha 2b) and gamma interferon (IFN-gamma) and sequencing of the combination on colony formation of human tumor cells were studied in a human tumor clonogenic assay (HTCA) with or without ascites-associated macrophages (AAM). Five different human tumor cell lines were studied. Three of the five cell lines (ovarian cancer cell line BG-1, cervical cancer cell line ME-180, and melanoma cell line SK-MEL 28) were sensitive to both IFNs. Cervical cancer cell line CaSki was sensitive to IFN-alpha 2b but resistant to IFN-gamma. Endometrial cancer cell line HEC-1A was resistant to both IFNs. Synergistic interaction was observed in BG-1 and SK-MEL 28 with a combination of the IFNs. ME-180 did not exhibit a positive interaction, in spite of its sensitivity to each IFN. CaSki and HEC-1A also did not exhibit a positive combined interaction at clinically achievable concentrations. One sequential combination method (method 1: IFN-alpha 2b----IFN gamma with a 24-h interval) resulted in a similar antitumor effect as the simultaneous combination. A reversed sequential method (method 2: IFN-gamma----IFN-alpha 2b with a 24-h interval) was less effective in three of the five cell lines. In BG-1, AAM enclosed in the lower layer markedly enhanced the antitumor effect of combined IFNs as well as each IFN alone. The antitumor effect with method 1 was significantly greater than that achieved with simultaneous combination or combination according to method 2 in the presence of AAM (P less than 0.01). These results suggest that (1) a synergistic antitumor effect of IFN-alpha 2b and IFN gamma is demonstrable in selected types of tumors, depending upon the sensitivity of each tumor cell line to both IFNs; (2) optimal scheduling for the direct antitumor effect of combined IFNs seems to be long-term exposure of cells to the IFN, the cells being treated with both IFNs either simultaneously or sequentially (IFN-alpha 2b preceding IFN-gamma); and (3) AAM potentiate the antitumor effect of IFNs either alone or in combination. Finally, IFN-alpha 2b may have some priming effects for the indirect effect of IFN gamma mediated through AAM in certain tumor cells.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

A phase II study of the efficacy of recombinant interferon gamma in relapsing ovarian adenocarcinoma.

Fourteen patients with relapsing ovarian cancer were treated with a regimen of intravenous interferon gamma (IFN gamma). During an initial induction phase, patients received 2 mg/m2 IFN gamma intravenously over 2 h daily for 5 days, repeated every 2 weeks for six courses. Patients who responded were continued on a maintenance phase, receiving 3 mg/m2 intravenously over 2 h, twice weekly every 2 weeks for 2 to 6 months. All patients had received prior cisplatin containing chemotherapy regimens. Of the 14 patients entered, 7 completed the six courses of the induction treatment. Four patients were clinical responders and continued on maintenance therapy. The most commonly reported toxicities included malaise, fever, and deteriorating performance status. There appears to be some clinically apparent antitumor activity demonstrated by this dosing schedule of interferon gamma in ovarian cancers.

Adenocarcinoma↗
PubMed1987

Interferons in the treatment of multiple myeloma.

Recently, recombinant DNA methods have been successfully applied to interferon production, making adequate quantities available for both in vitro and in vivo testing. Although interferons are in the class of biologic response modifiers, they do have some direct cytotoxic effects on human tumor cells that can be quantitated in vitro with the colony-forming assay. In the clonogenic assay, RPMI-8226 myeloma cells were tested with interferon alfa-2b (Intron A, Schering Corp., Kenilworth, NJ), melphalan, cyclophosphamide, and prednisone. With concentrations of interferon alfa-2b as low as 1 U/ml (international antiviral activity), colony number was reduced to less than 30% of the untreated control cultures. Both melphalan and cyclophosphamide showed measurable cytotoxic activity, with the ID50 of melphalan at 0.15 microgram/ml and that of cyclophosphamide at 0.4 microgram/ml. Prednisone had the least cytotoxic effect when tested with these myeloma cells as a single agent. Additive antiproliferative effects were noted with combinations of interferon alfa-2b plus cyclophosphamide and interferon alfa-2b plus prednisone. However, the interferon-melphalan combination showed synergistic effects on tumor colony cell reduction. Even greater cytotoxic activity was seen with the three-drug combination of interferon alfa-2b, melphalan, and prednisone. Clinical trials have shown that interferon alfa-2b may be effective in relapsing and refractory patients with multiple myeloma. Of 38 evaluable patients, a total of seven responded to treatment; one patient had a complete response, and six had a partial response. Three of the seven responders have continued to respond for over 33 months, with monoclonal proteins approaching undetectable levels. A pilot study of the feasibility of combining interferon alfa-2b with melphalan and prednisone in previously untreated patients with multiple myeloma has been completed. It is concluded that interferon alfa-2b, in dosages not exceeding 2.0 X 10(6) IU/m2, can be safely given in combination with melphalan and prednisone, without compromising melphalan dosage. Although response was not the primary objective of the study, an overall response of 75% was achieved using the criteria established by the Chronic Leukemia-Myeloma Task Force.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Use of interferon in the treatment of ovarian cancer as a single agent and in combination with cytotoxic drugs.

In vitro studies have shown that human ovarian cancers are sensitive to the antiproliferative effects of recombinant human alpha interferon. The degree of anticellular effect is related to the concentration of interferon achieved and to the duration of tumor cell exposure. In a clinical setting, the highest levels of interferon that can be achieved are seen when interferon is given by the intraperitoneal route. One Phase I clinical trial of intraperitoneally administered alpha interferon has shown complete (CR) and partial responses (PR) in 5 (45%) of 11 patients, each response determined by surgical re-exploration. The most favorable patient group for the tumor responses was the one having residual tumor bulk less than 5 mm in size. Combinations of interferon and standard cytotoxic drugs have been studied both in preclinical and clinical trials. One of the most active combinations is that of alpha interferon plus doxorubicin, which often shows an additive and occasionally synergistic combined effect. In a Phase II clinical trial of combined parenterally administered alpha interferon and doxorubicin, clinically determined CR and PR were seen in 7 (29%) of 24 patients with relapsing ovarian cancers. In this preliminary clinical trial, toxicity of the combination regimen was acceptable.

Antineoplastic Agents↗
PubMed1987

Overview of preclinical and clinical studies of interferon alfa-2b in combination with cytotoxic drugs.

Both in vitro and in vivo studies have demonstrated antiproliferative effects of interferon alfa-2b (Intron A; Schering-Plough) when tested with human tumor cells. A clonogenic assay has been widely used to determine its direct antiproliferative effects on human tumor cells in vitro using colony reduction as a reproducible endpoint. As a single agent, interferon alfa-2b shows maximum tumor cell colony reduction when used in high concentrations with continuous cell exposure. Short-term exposure to interferon alfa-2b does not produce significant tumor cell colony reduction. Clonogenic assays have also been used to test combinations of interferon alfa-2b with cytotoxic drugs. Variations in drug scheduling, sequencing and concentrations have indicated the best combinations which maximize tumor cell colony reduction. Combinations of interferon alfa-2b with doxorubicin, cisplatin, vinblastine, melphalan and cyclophosphamide have been shown to have at least additive and occasionally synergistic antiproliferative effects. In clinical trials, optimal pairs of agents have been identified frequently combining either doxorubicin, cisplatin or vinblastine with interferon alfa-2b. Pretreatment with interferon alfa-2b has been adopted from in vitro studies and applied to most clinical trials. One study has enrolled 135 patients having a variety of advanced or recurrent solid tumor types, using a schema which combines interferon alfa-2b and doxorubicin administration, both given on a weekly basis for three weeks, followed by treatments every two weeks in responding patients. Clinical responses have been seen using this regimen in patients with ovarian, cervical, colorectal and pancreatic carcinomas and in one lymphoma patient. Another study has been designed combining melphalan, prednisone and interferon alfa-2b for the treatment of patients with relapsing multiple myeloma. This is also based upon preclinical data. New methods of administration are being studied giving interferon alfa-2b as a single agent or in combination with cisplatin by the intraperitoneal route to patients with relapsing ovarian carcinomas limited to the peritoneal cavity. This method can maximize both the levels of interferon alfa-2b as well as the tumor cell exposure time.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Interferon-gamma and cytotoxic agents studied in combination using a soft agarose human tumor clonogenic assay.

The in vitro antiproliferative activity of human recombinant interferon-gamma (IFN-gamma) was tested against human tumor cells in vitro in combination with doxorubicin, cisplatin, or vinblastine. Using a human tumor clonogenic assay (HTCA), IFN-gamma alone showed dose-dependent inhibition of colony growth in six or seven human tumor cell lines as well as in each of nine fresh ovarian tumor specimens. The combination of IFN-gamma and either doxorubicin or cisplatin showed additive antiproliferative effects against all the cell lines with the exception of an IFN-gamma-resistant endometrial cancer cell line (HEC-1A). In combination with vinblastine, IFN-gamma rarely had an additive effect. Inclusion of macrophages from malignant effusions in the HTCA potentiated the antiproliferative effect of IFN-gamma alone as well as the combination of IFN-gamma and doxorubicin; however, the efficacy of the two agents was never more than additive. The results show that combinations of IFN-gamma with doxorubicin or cisplatin are additive and warrant further investigation. The antitumor effect of IFN-gamma alone or in combination with cytotoxic drugs may be significantly enhanced by tumor-associated macrophages.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Antitumor activity of new anthracycline analogues in combination with interferon alfa.

Combinations of recombinant interferon alfa2 (IFN-alpha 2) with doxorubicin, 4'-epidoxorubicin, 4'-deoxydoxorubicin, or 4-demethoxydaunorubicin were tested for antiproliferative activity against a panel of human tumor cell lines in a human tumor clonogenic assay. The histologies of the cell lines were ovary, cervix, breast, and melanoma. Each of the cytotoxic compounds showed dose-dependent antiproliferative effects against each of the cell lines, and the results indicated that doxorubicin derivatives were consistently more potent than the parent drug. In all instances, 4-demethoxydaunorubicin was the most potent derivative, requiring 2-20 times less drug to inhibit 70% of tumor colony formation. Combinations of IFN-alpha 2, with doxorubicin or its derivatives may show additive or synergistic antiproliferative activity against certain tumor cell lines. The ovarian carcinoma cell line, BG-1, responded synergistically to each of the four compounds in combination with IFN-alpha 2. The cervical carcinoma cell line, CaSki, and the breast carcinoma line, MCF-7, responded to the combinations in a manner best described as additive. In the melanoma line, SK-Mel-28, the drugs were found to be subadditive or even antagonistic. While the potency of the anthracycline derivatives ranked consistently across the different cell lines, the synergistic interaction with IFN-alpha 2 is a cell line-specific phenomenon unrelated to sensitivity to either anthracyclines or interferon.

Cell Line↗
PubMed1987

In vitro growth characteristics and chemosensitivities of endometrial cancer using a soft agar clonogenic assay.

A soft agar clonogenic assay was used to analyze 91 fresh human endometrial tumor samples for in vitro growth and chemosensitivities. Overall cloning success was 81%. Of the 75 samples adequate for drug testing (30 or more colonies per plate), histologic analysis demonstrated 36 adenocarcinomas, seven adenoacanthomas, ten adenosquamous carcinomas, nine mixed mesodermal sarcomas, seven carcinosarcomas, three papillary adenocarcinomas, and three clear-cell carcinomas. Mixed mesodermal sarcoma specimens demonstrated the most efficient growth, followed by the adenosquamous adenocarcinoma and adenoacanthoma samples. In vitro chemosensitivities were determined by colony inhibition resulting from continuous exposure of tumor cells to known achievable peak plasma and one-tenth peak plasma concentrations of a particular agent. The plating efficiency reflected the clinical virulence by cell type. Thus, we found that malignant endometrial tumors can be cloned in vitro, and the observed chemosensitivities reflect the relative clinical resistance of the tumors to these agents. Based on the high cloning success, this tumor type may be well suited as a model using in vitro soft agar cloning for new drug screening, evaluation of novel drug combinations, and studies of human tumor biology.

Antineoplastic Agents↗
PubMed1986

Dosage range study of morphine sulfate controlled-release.

The purpose of this study was to assess the efficacy and side effects of morphine sulfate controlled-release (MSCR) in patients with cancer pain who had previously required narcotic analgesia. The study design included an attempt at conversion of 30 patients from the previously required narcotic analgesic to around the clock (ATC) 4-h dosing of morphine sulfate immediate-release (MSIR) that would provide satisfactory analgesia. All patients controlled on MSIR at 4-h ATC were then successfully converted to MSCR and had an appropriate dosage regimen established. The patients were subsequently maintained for 4 weeks on MSCR, with the majority of patients adhering to a 12-h schedule at two-thirds the total daily morphine dose of the q 4 h regimen. Twenty-four patients completed this dosage range study. Five dropouts were not related to use of MSCR, while one patient was discontinued because of nausea following administration of both MSIR and MSCR. Patients preferred the analgesic relief of MSCR over their previous narcotic regimen. Half the patients manifested fewer side-effects compared with their prestudy narcotics. No patients had greater side-effects with MSCR. These findings support the efficacy and safety of MSCR at appropriate dosage for the prolonged relief of cancer pain.

Delayed-Action Preparations↗
PubMed1986

Direct and indirect effects of human recombinant gamma-interferon on tumor cells in a clonogenic assay.

Purified, recombinant human gamma-interferon (rIFN-gamma) was tested at clinically achievable doses for direct and indirect antiproliferative activity against human tumor cell lines using a clonogenic assay. One-h treatment with rIFN-gamma showed direct dose dependent inhibition of tumor colony growth in cell lines established from human melanoma, myeloma, renal cell, and cervical cancers. Longer treatments resulted in suppression of ovarian and breast carcinoma clonogenicity. In order to test for indirect antiproliferative effects of rIFN-gamma, feeder cells were included in a separate agarose underlayer in the cloning assay. These feeder cells included mouse peritoneal macrophages, U-937 (human histiocytic lymphoma cell line), and adherent cells from human malignant ascites specimens. Colony growth of ovarian carcinoma and melanoma cell lines was stimulated by each of these feeder cell types. Cultures containing mouse peritoneal macrophages or U-937 cells showed the same antiproliferative responses to rIFN-gamma as did control cultures without feeder cells. In contrast, human adherent ascites cells (greater than 80% macrophages) became strongly inhibitory to tumor colony growth when treated with rIFN-gamma. These results suggest that human tumor associated macrophages may become tumoricidal under the influence of rIFN-gamma, producing a diffusable substance in agarose culture which causes the observed antiproliferative effects on tumor cells.

Cell Cycle↗
PubMed1985

Autologous antibodies eluted from membrane fragments isolated from the effusions of human ovarian epithelial neoplasms. I. Quantitation of antibodies.

Cyst and ascites fluids from patients with ovarian epithelial neoplasms contain large amounts of soluble immunoglobulins without detectable antibody activity against human ovarian tumor cell lines by indirect immunofluorescence. Membrane fragments were prepared from 56 human ovarian effusions, and the presence of membrane-bound IgG, IgA, and IgM was demonstrated. The predominant membrane-bound immunoglobulin class was IgG, which ranged from 18 to 4275 ng/ml on samples tested, whereas IgA was present in the range of 5 to 52 ng/ml. The autologous membrane-bound antibodies strongly recognized cell-surface antigens on four human ovarian cell lines and four surgical specimens of human ovarian adenocarcinoma but did not react with normal human ovaries, non-ovarian normal and neoplastic tissues, or non-ovarian human cell lines by indirect immunofluorescence assay. These studies indicate that patients with ovarian cancer have the capability of recognizing and forming antibodies against autologous ovarian tumor-associated antigens.

Adenocarcinoma↗
PubMed1985

Combined recombinant human interferon alpha 2 and cytotoxic agents studied in a clonogenic assay.

A human tumor clonogenic assay has been used to test the antiproliferative effect of recombinant human leukocyte interferon alpha 2 alone and in combination with each of 8 cytotoxic agents. Cell lines derived from 6 human tumors and primary tumor cells from 13 patients have been used in these clonogenic assay studies. Results show that interferon as a single agent causes insignificant reduction in tumor cell colony survival if the short-term 1-hr cell exposure method is used; only high concentrations of interferon used in continuous cell exposure in the clonogenic assay can demonstrate a reduction in colony survival to below 50% of control values. Combinations of interferon with either doxorubicin or cisplatin frequently show additive and occasionally synergistic antiproliferative effects on tumor cell colony formation. Variations in drug concentrations and sequencing of drugs have been tested, showing that optimal antiproliferative effects of combined interferon and doxorubicin are realized when maximal concentrations of interferon and prolonged cell exposure time of both interferon and doxorubicin are employed. Combinations of interferon and doxorubicin tested in the clonogenic assay demonstrate cytotoxicity superior to that of either agent tested alone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Use of the human tumor stem cell assay to study chemotherapy sensitivity in cancer of the cervix.

Two questions concerning chemotherapy of cervical cancers are addressed in this study. 1) Can the human tumor stem cell assay identify active chemotherapeutic agents?; and 2) Can the human tumor stem cell assay predict which patient's tumors will demonstrate clinical responsiveness to chemotherapy? Sixty-seven of 76 cervical cancer specimens (88.2%) were grown in the human tumor stem cell assay, resulting in 159 separate drug assays. Based on the known activity of standard chemotherapeutic agents demonstrated in clinical trials, cisplatin, bleomycin, vincristine, and mitomycin C were chosen for testing. In vitro sensitivity patterns, seen at one-tenth of the peak plasma drug concentration, were similar to those seen in historic clinical trials. Retrospective correlations between in vitro drug sensitivity data and patient responses to chemotherapy are available from 13 patients, demonstrating clinically helpful predictive capabilities of the assay. Two conclusions were made: 1) The human tumor stem cell assay can determine single agent activity, which is often dose related; and 2) Useful correlations with clinical responses were observed.

Adenocarcinoma↗
PubMed1983

In vitro chemotherapy testing of gynecologic tumors: basis for planning therapy?

The human tumor stem cell assay (HTSCA) has broad research applications in the field of cell biology as well as in clinical chemotherapy. This report examines the applicability of the HTSCA to patient treatment planning, asking: (1) How often will gynecologic tumors grow in the assay? (2) What kinds of therapeutically useful information can be gained from the assay? (3) What are the correlations between in vitro results and patient treatment responses? Tumor specimens from 207 patients having ovarian, cervical, or endometrial carcinomas have been studied with the HTSCA, 183 of which have grown in vitro. Of 103 ovarian cancer specimens which grew in culture, 564 separate drug assays have been done, looking for patterns of sensitivity among "first line" drugs as well as drugs used for relapsing patients. More than half of the patients studied had one or more drugs which showed in vitro activity. Nineteen patients have had single-agent chemotherapy prospectively selected on the basis of the HTSCA results with a "sensitive" predictive accuracy of 90% and a "resistant" predictive accuracy of 100%.

Antineoplastic Agents↗
PubMed1982

In vitro growth stimulation of human ovarian cancer cells by xenogeneic peritoneal macrophages.

For improvement of the in vitro growth rate of human ovarian tumors, an irradiated xenogeneic feeder layer of adherent peritoneal cells was added to such cultures. This adherent peritoneal cell population was obtained from oil-primed adult (C57BL/6J x DBA/2J)F1 mice and contained predominantly macrophages. After irradiation of the feeder layer with 3,000 rad 137Cs, cell suspensions prepared from fresh, solid human ovarian cancers were cocultivated with the feeder cells. Two end points were used to evaluate the growth enhancement added by such a feeder layer: 1) Primary monolayer cultures of ovarian tumors were successfully grown in continuous culture through five or more serial subcultures in 25 of 64 different patient specimens studied. Control cultures without the feeder layers did not continue growing through serial subcultures. 2) With the use of the soft agar clonogenic assay, addition of the feeder layer to the petri dishes increased the number of tumor cell colonies in each of six separate experiments, compared to the number seen in control plates without the feeder layer.

Adenocarcinoma↗