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Biomedical subjects

S E Salmon

Publications and source records attributed to S E Salmon.

At least 19 recordsLinked to original sources
PubMed1992

Long-term engraftment of fresh human myeloma cells in SCID mice.

Using highly purified myeloma cells from patient bone marrow, we established human-murine myeloma chimeras in severe combined immunodeficiency (SCID) mice and documented secretion of monoclonal human immunoglobulins (Hulgs) in the mice for up to 299 days. Monoclonality of circulating Hulgs was found only when highly purified myeloma cells were injected intraperitoneally. In contrast, injection of unfractionated myeloma marrow led to the development of polyclonal Hulgs in the SCID mice. The criteria for myeloma engraftment included prolonged presence of monoclonal Hulgs in the sera of SCID mice and/or detection of human myeloma cells in their tissues by immunohistochemical examination. Ninety-one percent (10/11) of the fresh purified myeloma specimens engrafted in the SCID mice. Fifty-five percent (6/11) of the patient samples resulted in human B-cell grafts, and 45% (5/11) were identifiable as human myeloma chimeras. Pathologic studies showed that most human plasmacytes were located in the peritoneal cavity but metastatic infiltrates were also found in other organs in 69% of the SCID-human myeloma chimeras. This chimeric model should provide a useful tool for characterization of growth modulation and microenvironmental interactions as well as a means of testing new therapeutic approaches to multiple myeloma.

Adult↗
PubMed1992

Antiproliferative and antitumor activity of the 2-cyanoaziridine compound imexon on tumor cell lines and fresh tumor cells in vitro.

BACKGROUND: Imexon, a 2-cyanoaziridine, is therapeutic and reverses lymphadenopathy and splenomegaly in the LP-BM5 murine retrovirus-induced immunodeficiency disease (murine AIDS). It can restore chemotherapy-induced immunosuppression. Imexon reduced the incidence of lymphoma in severe combined immune deficient mice inoculated with human lymphocytes. PURPOSE: To determine its antitumor activity, we screened imexon against fresh human tumor cells and tumor cell lines. To determine the time-concentration relationships of its cytotoxicity, we studied the effects of imexon on macromolecular synthesis and on the cell cycle. METHODS: Imexon was incubated at 1-200 micrograms/mL with various tumor cell lines, mitogen-stimulated peripheral blood lymphocytes, and fresh tumor cells. Cell survival, macromolecular synthesis, and cell cycle progression were studied. RESULTS: The concentration of imexon that caused 50% inhibition of growth was under 10 micrograms/mL for lymphocytes stimulated with mitogens. It was about 3-10 micrograms/mL for B-cell lymphomas and both multi-drug-resistant and -sensitive myeloma cell lines. Imexon inhibited four of seven fresh lymphoma and 11 of 16 fresh myeloma biopsy specimens to less than 40% of the control. A 1-hour exposure of lymphoma cells to 50-100 microgram/mL followed by removal of drug by washing the cells and continuing culture resulted in greater than 95% inhibition during the next 48-72 hours. Imexon selectively inhibited protein synthesis during the first 24-48 hours of exposure of lymphoma and myeloma cells. Cells exposed to inhibitory concentrations of imexon were blocked in cell cycle progression. CONCLUSION: Imexon may be a potentially useful agent in the treatment of malignant disease, particularly lymphoid malignancies, and should be explored further.

Antineoplastic Agents↗
PubMed1992

Effects of suramin on in vitro growth of fresh human tumors.

BACKGROUND: Suramin is a polysulfonated urea recently tested in clinical trials as an anticancer agent. PURPOSE: To define tumor types for further clinical testing of suramin, we assessed the in vitro activity of suramin against fresh human tumor specimens. METHODS: Inhibition of tumor colony formation (human tumor clonogenic assay [HTCA] method) and inhibition of tritiated thymidine incorporation (TTI method) were used as indicators of drug sensitivity. RESULTS: With the use of the HTCA method, 80% or more of carcinomas of the colon, endometrium, kidney, lung (non-small-cell), and ovary as well as malignant melanoma and mesothelioma were sensitive to 200 micrograms/mL of suramin by continuous exposure. Suramin's antitumor activity was dose dependent, and it was less effective when tested at concentrations of 50 micrograms/mL or less. With the TTI method, the more slowly growing tumors (breast cancer, colon cancer, multiple myeloma, non-Hodgkin's lymphoma, prostate cancer, and sarcoma) appeared to be less sensitive to suramin. However, when the two assay methods were directly compared in melanoma and ovarian cancer specimens, individual tumors were generally more sensitive to suramin (greater inhibition relative to control) using the HTCA method, whereas the TTI method appeared to underestimate suramin's antitumor activity. There was no significant difference in the activity of suramin when tested in the presence of 10% versus 50% serum. CONCLUSION: These results provide an experimental basis for clinical evaluations of suramin therapy in patients with colon, endometrial, kidney, non-small-cell lung, and ovarian cancers as well as malignant melanoma and mesothelioma.

Humans↗
PubMed1992

A phase II evaluation of esorubicin in ovarian cancer. A Southwest Oncology Group study.

Patients with a pathologically confirmed diagnosis of metastatic or advanced epithelial-type ovarian carcinoma were entered into a Phase II trial of esorubicin. Eligibility criteria included measurable disease; performance status (SWOG) 0-2; no more than one prior chemotherapeutic regimen; and no prior doxorubicin therapy. The starting esorubicin dosing schedule was 30 mg/m2 every 3 weeks for good risk patients and 25 mg/m2 every 3 weeks for poor risk patients. Twenty-one patients were eligible for evaluation of response and toxicity to treatment. These patients received a median of 3 courses of esorubicin (range 1-13 courses). None of the 21 patients experienced a response to esorubicin. Median survival was 5.5 months. Leukopenia was the major toxicity. Eleven (79%) of the good risk patients and 2 (29%) of the poor risk patients experienced severe to life-threatening leukopenia. Mild to severe anemia was seen in 10 (71%) of the good risk patients and 7 (100%) of the poor risk patients. We conclude that esorubicin is ineffective in the treatment of ovarian cancer patients who have received primary chemotherapy.

Aged↗
PubMed1992

Drug resistance in myeloma: mechanisms and approaches to circumvention.

Chemotherapy remains the mainstay in the treatment of multiple myeloma today. Despite improvements in survival and quality of life that can be attributed to advances in chemotherapeutic treatment, multiple myeloma remains an incurable disease. The development of drug resistance accounts for most treatment failures. Mechanisms of resistance for chemotherapeutic agents occur at the cellular level. Some of these mechanisms are unique for a given individual drug, whereas other mechanisms may confer resistance to a wide variety of agents. Important steps for improving treatment include investigating the resistance mechanisms, developing methods to identify drug-resistant cells, and preventing or circumventing drug resistance once it occurs.

Drug Resistance↗
PubMed1991

Multidrug-resistant myeloma: laboratory and clinical effects of verapamil as a chemosensitizer.

Verapamil was evaluated as a chemosensitizer for reversing multidrug resistance in multiple myeloma both in vitro and in clinical trials. Bone marrows from 59 myeloma patients in relapse were evaluated for several resistance parameters: expression of p-glycoprotein (MDR1), doxorubicin (Adriamycin) and vincristine sensitivity, and the ability of added verapamil to reduce resistance to the cytotoxic agents. We found that verapamil was capable of sensitizing myeloma cells that exhibited resistance to doxorubicin and vincristine in vitro, but did not enhance sensitivity of cells that were drug sensitive (P less than .001). Myeloma cells expressing MDR1 immunohistochemically tended to be more doxorubicin resistant in vitro than MDR1-negative cells. In the clinical trials, 22 patients with myeloma refractory to vincristine-Adriamycin-dexamethasone (VAD) were treated with VAD plus high-dose intravenous verapamil (Ve). Among the 22 patients treated with VAD/Ve, five achieved a partial remission (23%). The median relapse-free survival for the VAD/Ve responders was 5.4 months and their overall survival from the start of VAD/Ve was better than that of the nonresponders. Among the subset of 10 patients whose myeloma cells were MDR1 positive, four responded clinically (40%), whereas none of five patients with MDR1-negative myeloma cells achieved remission with VAD/Ve. We also observed that myeloma cells from three of four VAD/Ve clinical responders exhibited in vitro chemosensitization with verapamil, whereas in vitro verapamil chemosensitization was seen in only one of six clinical nonresponders. Our observations demonstrate that clinical reversal of multidrug resistance can be achieved in some patients with VAD-refractory myeloma with the use of verapamil. In addition to their value in drug development, in vitro tests of MDR1 expression and of chemosensitizers plus cytotoxic drugs on the patients' bone marrow myeloma cells may identify patients who will respond clinically to chemosensitizer-containing regimens. We anticipate that chemosensitizer regimens capable of inhibiting multidrug resistance will play an increasing role in the treatment of hematologic malignancies, including B-cell neoplasms such as multiple myeloma and the non-Hodgkin's lymphomas.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Synergistic inhibition by verapamil and quinine of P-glycoprotein-mediated multidrug resistance in a human myeloma cell line model.

In an effort to develop a clinically useful approach to overcoming P-glycoprotein-mediated multidrug resistance (MDR1), we evaluated combined chemosensitization with verapamil and quinine in a multidrug-resistant (MDR) human myeloma cell line model. In clonogenic assay, verapamil was used at concentrations from 0.1 to 1.0 micrograms/mL, bracketing the plasma levels achieved by oral administration and high-dose intravenous (IV) infusion, respectively. The dose of quinine was held constant at 1.0 micrograms/mL, a plasma concentration readily achieved by oral administration. At each dose level of verapamil tested, the combination with quinine proved more effective than either drug individually in reversing resistance to doxorubicin and vinblastine and synergistic chemosensitizing interaction was observed. Verapamil at 0.1 microgram/mL combined with quinine was capable of restoring sensitivity to doxorubicin fully and reduced resistance to vinblastine as effectively as verapamil alone at 1.0 micrograms/mL. Furthermore, the combination of 1.0 mumol verapamil with 10 mumols quinine increased accumulation and retention of anthracycline in the resistant cells to a greater extent than did either drug individually (P less than .001) and inhibited drug efflux as effectively as verapamil alone at 10 mumols. Our findings suggest that combined chemosensitization with verapamil and quinine may prove useful for overcoming MDR1 in patients with drug-refractory B-cell neoplasms such as multiple myeloma or non-Hodgkin's lymphomas.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil.

P-glycoprotein is a transmembrane protein thought to function as an efflux pump to detoxify cells. It is associated with multidrug resistance in laboratory systems and has recently been found in human tumors associated with in vitro and clinical drug resistance. We used an immunohistochemical method employing two monoclonal antibodies, JSB-1 and C-219, to detect expression of P-glycoprotein in lymphoma patients. One of 42 newly diagnosed and untreated lymphoma patients (2%) and seven of 11 previously treated and drug-resistant patients (64%) had detectable levels of P-glycoprotein (P less than .001). Based on prior reports suggesting that verapamil sensitizes drug-resistant cancer cells to chemotherapy by competitive inhibition of the P-glycoprotein, we tested the efficacy of verapamil as a chemosensitizer in 18 patients with drug-refractory disease. All patients had previously failed or relapsed within 3 months of a doxorubicin-vincristine-containing drug regimen. Patients received day-1 cyclophosphamide, and 4-day continuous infusion doxorubicin and vincristine and oral dexamethasone (CVAD). CVAD was combined with 5-day continuous infusion verapamil given at maximally tolerated dose. Overall, 13 of 18 patients (72%) responded to treatment including five complete remissions (CRs; 28%). The median duration of response was 200 days and median survival was 242 days. The dose-limiting toxicity of the verapamil infusion was temporary cardiac dysfunction including hypotension, congestive heart failure, and cardiac arrhythmia. We conclude that the P-glycoprotein is uncommonly expressed in untreated lymphomas and frequently expressed in clinically drug-resistant disease, and that chemotherapy using CVAD plus maximally tolerated doses of verapamil results in a high response rate in patients carefully selected for clinical drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Phase II study of fludarabine phosphate in multiple myeloma. A Southwest Oncology Group study.

Thirty-one patients with multiple myeloma refractory to therapy or relapsing after response to initial therapy were treated with Fludarabine Phosphate utilizing a daily intravenous schedule for five consecutive days. There were no objective responses seen and only one patient showed clinical improvement. Myelosuppression manifest as leucopenia and granulocytopenia was the primary toxicity seen. Fludarabine Phosphate is inactive in previously treated myeloma patients when given by the daily intravenous route.

Adult↗
PubMed1979

Comparative trial of low-dose adriamycin plus cyclophosphamide with or without additive hormonal therapy in advanced breast cancer.

We treated 56 women with advanced metastatic breast cancer who had not received prior chemotherapy in a comparative trial of cytotoxic chemotherapy with low-dose adriamycin plus cyclophosphamide alone or in combination with the androgenic steroid calusterone. The response rate to chemohormonal therapy (65%) could not be shown to be statistically better than that for chemotherapy alone (53%) for this size patient population. However, the median remission duration (21.5 months) was significantly prolonged over the 11.5-month remission duration for chemotherapy alone (p = 0.03). The median survival of the chemohormonal therapy group was 23.5 months, whereas that for chemotherapy alone was 13.5 months (p = 0.05). These results indicate that the addition of a potent hormonal agent to effective cytotoxic chemotherapy improves the results of treatment of women with metastatic breast cancer.

Breast Neoplasms↗
PubMed1979

Combination chemotherapy for advanced breast cancer utilizing vincristine, adriamycin, and cyclophosphamide (VAC).

Thirty-two patients with advanced breast cancer were treated with a combination of vincristine (1 mg/m2, not exceeding 2 mg, administered intravenously on day 1), adriamycin (40 mg/m2 administered intravenously on day 1), and cyclophosphamide (200 mg/m2 administered orally for 4 days on days 3-6). Courses were repeated at 21-28-day intervals. The mean age of the patients was 57 years (range, 30-79 years) and 18 patients were postmenopausal. None of the patients had received prior chemotherapy although 15 had prior endocrine treatment. Objective response was observed in 23 (72%) of the 32 patients and 9 responses (28%) were complete. The median remission duration was estimated to be 22 months. Median survival has not been reached but exceeds 24 months with a median time of follow-up of 17 months. Toxicity was acceptable and included mild nausea, vomiting, alopecia, and paresthesias. Only one instance of serious infection and no instances of bleeding were observed. The addition of vincristine to combination chemotherapy with adriamycin and cyclophosphamide appears to prolong the remission duration and survival in patients with advanced breast cancer to a greater extent than is achieved with adriamycin and cyclophosphamide alone.

Adult↗
PubMed1979

The nature of cells generating human myeloma colonies in vitro.

Freshly explanted human myeloma cells formed colonies of monoclonal plasma cells in soft agar in the presence of medium conditioned by the adherent spleen cells of mineral oil-primed BALB/c mice. The medium showed peak activity at a dilution of 1:4. 2-mercaptoethanol or monothioglycerol was necessary for colony formation. Other thiols tested were ineffective in promoting colony growth. Colony-forming cells adhered to nylon wool, but not glass beads or plastic dishes. The presence of E-rosetting cells was not required for myeloma colony formation. Antibody prepared against a human myeloma cell line, RPMI 8226, reduced colony formation. These studies demonstrate the usefulness of this bioassay for determining functional properties of the myeloma colony-forming cell.

Antibodies↗
PubMed1979

[Combination of adriamycin and cyclophosphamide (alone or with other substances) in the treatment of breast cancer].

This paper reviews clinical trials at the University of Arizona Cancer Center which were designed to improve the outcome in breast cancer by utilizing the combination of adriamycin and cyclophosphamide (A--C) alone or with the addition of other agents or modalities. Our initial trial in advanced breast cancer with A--C produced an overall objective response rate of 78% in 51 patients with advanced breast cancer without prior chemotherapy. The median duration of disease control was 12 months. Subsequent studies showed that the addition of either vincristine or the androgen, calusterone, effectively doubled the remission duration and prolonged survival. In our surgical adjuvant trial with 6 months of treatment with A--C there has been only a 9% relapse rate in stage II patients thus far, with a median follow-up of close to 2 years. A subset of stage II patients who received regional radiotherapy along with A--C have not yet shown added benefit compared to the use of A--C alone. Since 1975, stage I patients have been treated with an abbreviated treatment schedule (3 courses of A--C over 9 weeks). While there have not yet been relapses in this category, much longer periods of follow-up will be required. The use of A--C (plus other drugs) has clearly provided excellent palliation and improved survival in patients with advanced or recurrent breast cancer; in our opinion it should be used as initial cytotoxic chemotherapy. The brief intensive program of A--C as a surgical adjuvant also shows considerable promise for erradicating occult micrometastases in both pre- and postmenopausal women.

Aged↗
PubMed1979

Radioiodine in the treatment of medullary carcinoma of the thyroid.

Medullary carcinoma (MC) of the thyroid, in contrast to papillary-follicular carcinoma, fails to concentrate iodine and thus has not been treated with radioactive iodine. We have successfully treated a 16-yr-old Mexican-American girl with residual MC after maximal thyroidectomy (Tx), utilizing radioiodine (131I) to deliver radiation to residual follicular cells in the tumor bed. Immediately after Tx, plasma thyrocalcitonin levels before and during calcium infusion were all elevated (640--1200 pg/ml). 131I (150 mCi) was administered 12 days after Tx after four daily im injections of bovine TSH. Three months after 131I therapy, thyrocalcitonin levels before and during calcium infusion were all normal (less than 50 pg/ml). Ten months after 131I therapy, thyrocalcitonin levels before and after iv pentagastrin were all normal (less than 60 pg/ml). These results suggest that parafollicular cells are radiosensitive, and that therapeutic levels of radiation can be delivered to these cells after Tx if iodine trapping by the remaining follicular cells is enhanced by high levels of circulating TSH. 131I may be the therapy of choice for MC after Tx, if disease has not spread beyond the area proximate to the thyroid gland.

Adolescent↗