Biomedical subjects
Publications and source records attributed to B L Samuels.
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Several mechanisms of drug resistance have been defined using cell lines selected for resistance in vitro. However, the relevance of these to tumor cell resistance in vivo remains unclear. We established tumor cell lines from biopsies of human sarcomas before and after doxorubicin therapy. One pretreatment sarcoma line, STSAR90, was 6-fold less sensitive to doxorubicin than was a normal fibroblast line, AG1522. The sensitivities of six other sarcoma lines were similar to that of AG1522. STSAR90 cells did not overexpress P-glycoprotein mRNA, by Northern analysis with the pCHP1 complementary DNA fragment. Photoaffinity labeling with the vinblastine analogue N-(p-azido-3-125I-salicyl)-N'-beta-aminoethylvindesine did not show increased P-glycoprotein concentrations. Accumulation of [3H]daunomycin was not decreased in STSAR90 compared with a less resistant sarcoma line, STSAR11, nor was the doxorubicin sensitivity of STSAR90 increased by coincubation with verapamil. Glutathione levels were twice as high in STSAR90 as in STSAR11, and glutathione peroxidase activity was 3.5- to 6-fold higher. This was due mostly to an increase in selenium-dependent peroxidase activity. After exposure to doxorubicin, STSAR90 cells formed only half as much measurable hydroxyl radical as STSAR11, as detected by electron spin resonance spectrometry. Doxorubicin sensitivity was increased in STSAR90 cells when intracellular glutathione levels were reduced by buthionine sulfoximine. These results indicate that multidrug resistance due to P-glycoprotein-mediated drug efflux is not the only mechanism of doxorubicin resistance that occurs in sarcomas and that glutathione peroxidase-dependent detoxification of doxorubicin-induced oxygen radicals may contribute to clinical doxorubicin resistance.
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Heat shock proteins (HSPs) are though to represent a ubiquitous cellular response to heat or stress. We tested whether HSPs can be induced in hairy cells, other human leukemic cells, and normal lymphocytes, and whether there are additive or synergistic effects between heat shock and interferon-alpha 2b (IFN-alpha 2b) on these cells. We analyzed lysates of cells from 22 patients (6 with hairy cell leukemia, 12 with other acute and chronic leukemias and lymphocytes of 4 normals) after exposure to a heat shock and/or IFN-alpha 2b by one-dimensional polyacrylamide gel electrophoresis. In all cells a pattern of HSPs was readily induced with prominent bands identified at approximately 115, 90, and 65 kD. None of these major proteins appeared to represent the previously described IFN-alpha 2b induced band at 80 kD. IFN-alpha 2b by itself was not found to induce HSPs. We conclude that a pattern of HSPs can readily be induced in a variety of normal and leukemic human blood cells. IFN-alpha 2b is not a HSP inducer in these cells. The previously described IFN-induced p80 is apparently not a HSP.
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In a significant fraction of patients with NHL or HD, disease develops that is resistant to conventional chemotherapy. Experience using high-dose chemotherapy, with or without TBI, and ABMR is expanding. In HD, remissions can be achieved in approximately half of the patients with relapsed advanced disease. This may also be true in patients with NHL who do not respond to conventional regimens. High-dose chemoradiotherapy regimens are toxic and require extensive supportive care. Relapse frequently occurs in areas of previous disease, suggesting failure of the conditioning regimen rather that an infusion of occult tumor cells in the autologous bone marrow had occurred. Thus, the role of marrow purging in this therapy needs to be further evaluated and compared with findings involving nonpurged marrow reinfusion. It is also important to evaluate the effects of more vigorous attempts at cytoreduction of bulky disease prior to high-dose therapy and ABMR. We recommend that high-dose therapy and ABMR in an investigational setting be used (1) in patients with HD who experience relapse after MOPP/ABVD or equivalent regimens and (2) in patients with intermediate or high-grade NHL whose disease recurs or is resistant to conventional regimens. Potential areas for development include the use of this modality as intensification therapy following conventional therapy in patients with intermediate or high-grade NHL with poor prognostic features. Toxicity can be decreased and efficacy increased only if therapy is administered to patients who have not been heavily pretreated and who have lower tumor burden and a good performance status. The role of high-dose chemotherapy of ABMR in the nodular lymphomas is not known at this point. Finally, high-dose ABMR therapy has a definite role in salvaging patients with malignant lymphomas. Many issues need to be resolved, including (i) the optimal timing of this approach, (ii) the optimal conditioning regimen, and (iii) the need for purging bone marrow prior to reinfusion. The past 10 years have led to significant gains. During the next 10 years, it may be possible to refine this therapy and find solutions to the above issues.
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Specific chromosomal abnormalities are independent predictors of response to therapy in acute nonlymphocytic leukemia (ANLL) de novo. In a series of 149 patients with ANLL, we sought to determine whether the t(8;21), t(15;17), t(9;11) or other abnormalities of the long arm of chromosome 11, inv(16) or t(16;16), inv(3) or t(3;3), trisomy 8, and abnormalities of chromosome 5 (-5/5q-) or of chromosome 7 (-7/7q-) identify differences in susceptibility to chemotherapy drugs in vivo. The immediate outcome of the first cycle of remission induction chemotherapy was analyzed for patients in each cytogenetic subgroup as an index of the drug susceptibility of the leukemia cells in vivo. Patients with t(8;21), inv(16), t(16;16), or 11q abnormalities had high rates of complete remission after initial therapy (60-100%), whereas patients with -7/7q- or -5/5q- had low initial response rates (0-36%), suggestive of drug resistance in vivo. In general, cytogenetic groups with high initial complete remission rates ("drug sensitive") also had long disease-free survivals; those groups with low initial remission rates ("drug resistant") had short remission durations even if these patients eventually achieved complete remission with further therapy. Patients with acute promyelocytic leukemia (APL), all of whom had the t(15;17), were the exception; despite low initial remission rates, they had long disease-free survivals, possibly due to a more rapid cytotoxic effect of chemotherapy on the clonogenic APL cells than on the more numerous malignant promyelocytes. We conclude that the prognostic importance of specific chromosomal abnormalities in ANLL resides in part in differing susceptibilities to chemotherapy.
Vascular toxicity following the use of vinblastine, bleomycin, and cisplatin (VBP) combination chemotherapy has been described. This report gives details of 5 patients who suffered acute life-threatening vascular events following such a chemotherapy regimen for germ cell tumors. In 3 of the cases no evidence of tumor was found at autopsy. Both an acute and a long-term vascular toxicity were seen. Large artery vascular disease may result from synergistic toxicity of the drugs comprising the regimen. These cases, with an additional 16 collected from the literature, suggest that major vascular disease is a significant side-effect of the VBP regimen.
Vascular toxicity following the use of vinblastine, bleomycin, and cisplatin (VBP) combination chemotherapy has been described. This report gives details of five patients who suffered acute life-threatening vascular events following such a chemotherapy regimen for germ cell tumours. In three of the cases no evidence of tumour was found at autopsy. Both acute and long-term vascular toxicity were seen. Large artery vascular disease may result from synergistic toxicity of the drugs comprising the regimen. These cases, with an additional sixteen collected from the literature, suggest that major vascular disease is a significant side-effect of the VBP regimen.
We have investigated the direct effects of interferon (IFN) on hairy cells (HCs) isolated from patients with hairy cell leukemia using one- and two-dimensional gel electrophoresis. We have previously characterized the induction of synthesis of 10-16 specific proteins by IFN-alpha 2b in HCs, as analyzed by one-dimensional electrophoresis. By two-dimensional electrophoresis, we have now confirmed this induction and shown that the synthesis of the same number of specific proteins is down-regulated in HCs exposed to IFN-alpha 2b. When compared to HCs, fewer proteins are induced by IFN-alpha 2b in other normal, or neoplastic, lymphoid cells. We also report that protein induction occurs in HCs exposed in vivo to IFN-alpha 2b. We have demonstrated the presence of tubuloreticular structures in the cytoplasm of HCs exposed to IFN-alpha 2b in vitro, using transmission electron microscopy. We now report that these too are seen in HCs exposed to IFN in vivo during therapy. We investigated the effects of IFN-gamma on HCs and found that it also induces specific proteins. The pattern of induced proteins is distinctly different after IFN-gamma exposure in vitro. The fact that such induction occurs suggests that HCs possess also a receptor for IFN-gamma. These results demonstrate that there are direct effects of IFN-alpha on HCs and that such direct effects might be important in the antitumor activity of IFN-alpha in hairy cell leukemia.
Despite the striking antiproliferative effect of alpha-interferon (alpha-IFN) in hairy cell leukemia, gamma-interferon (gamma-IFN) does not appear to have such an effect. We have previously demonstrated the induction of synthesis of specific proteins by alpha-IFN, both in vitro and in vivo. We have now shown that gamma-IFN induces synthesis of specific proteins, but the pattern differs from that seen after alpha-IFN exposure. The prominent 80,000-dalton protein induced by alpha-IFN was not induced by gamma-IFN, and the prominent 62,000-dalton protein induced by gamma-IFN was only rarely induced by alpha-IFN. Two other proteins were induced by both alpha-IFN and gamma-IFN. The other proteins induced by alpha-IFN were not induced by gamma-IFN. These differences may be related to the different biological response of hairy cells to the two types of IFN. We also showed for both alpha-IFN and gamma-IFN that some IFN-induced proteins are probably transported to the nucleus of the hairy cell, although the majority of proteins induced by both alpha-IFN and gamma-IFN were in the cytosol/membrane fraction of the cell. We have therefore demonstrated that gamma-IFN does have a biochemical effect on hairy cells in terms of induction of specific protein synthesis, leading to the inference that hairy cells must possess another receptor at least functionally analogous to the type II IFN receptors on fibroblasts, with which gamma-IFN interacts.
The mechanism of the antineoplastic effect of interferon (IFN) is not known and may result from direct effects on the neoplastic cells themselves, activation of intermediary effector cells, or a combination of these effects. The synthesis of specific proteins is induced in hairy cells when they are exposed to alpha-IFN in vitro. In particular, the called p80, is markedly induced. We investigated this effect in the hairy cells of seven patients in the leukemic phase of hairy cell leukemia who were being treated with subcutaneous (SC) IFN alpha 2b (r-Hu-IFN-alpha 2). Polyacrylamide gel electrophoresis (PAGE) was carried out on [35S]methionine-labeled whole cell lysates visualized by autoradiography and silver staining. Within 2 days of starting IFN therapy, induction of specific protein synthesis, including p80 was seen by [35S]methionine labeling in freshly isolated circulating hairy cells from 6 of 6 patients tested. Therefore, alpha-IFN has a direct biochemical effect on hairy cells in vivo that is similar to in vitro effects, at least with regard to p80 synthesis, although the kinetics of this effect may vary in the two situations.
Seventeen patients with advanced sarcoma were treated with continuous venous infusion of doxorubicin for a mean of 118 days, achieving total doses up to 1097 mg/m2. Three partial responses and one minor response were obtained. Major toxic effects were stomatitis and hand-foot syndrome. There was a low incidence of leukopenia (18%) and clinical cardiotoxicity (11%). Continuous venous infusion is a safe means of administering doxorubicin, with a response rate similar to that observed with bolus doxorubicin in metastatic sarcoma.
The striking clinical response of hairy cell leukemia to alpha-interferon led us to investigate the effects of interferon on hairy cells in vitro. We examined the nature of protein induction by interferon in the target hairy cells. To do this, we analyzed whole cell lysates of hairy cells from 11 patients by one-dimensional polyacrylamide gel electrophoresis. With this method, we showed the induction of 16 proteins, which ranged from Mr 140,000 to 12,000. Exposure to alpha-interferon caused very rapid induction of specific proteins in hairy cells, and induction continued for at least 9 days. Proteins were induced at extremely low interferon concentrations, and a dose-response effect was seen with increasing concentrations. A larger number of proteins was induced in hairy cells than in other lymphoid cells under the same conditions. Induction of most proteins was inhibited by actinomycin D, showing that new messenger RNA synthesis was required for their induction to occur. The number or pattern of induced proteins, or their prolonged induction, may be relevant to a change in the target hairy cells which is part of the process resulting in the antiproliferative effect of interferon in hairy cell leukemia.
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Clinical features suggesting a diagnosis of Huntington's chorea in several siblings in a Black Rhodesian family are described. A progressive and eventually fatal mental deterioration accompanied by gradually worsening choreiform movements has until the present time occurred in only a single generation of this family, which precludes a definitive diagnosis based on the triad of family history, chorea and dementia. It is suggested that Huntington's chorea is the most likely diagnosis.
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