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Biomedical subjects

R D Issels

Publications and source records attributed to R D Issels.

At least 19 recordsLinked to original sources
PubMed2006

[Clinical impact of locoregional hyperthermia in gynecological oncology].

In the last decade progress in gynecological oncology has been achieved mainly by new cytotoxic drugs and advances in radiation technology. For example, the use of taxanes in the primary therapy of ovarian cancers and of combined radio-chemotherapy in cervical cancer has led to significant prolongations of survival. However, in case of relapse most gynaecological malignancies are associated with very poor prognosis. Efficacy of local and systemic therapy can be increased by combining radiotherapy and/or chemotherapy with locoregional hyperthermia (LRH). Increasing the temperature of the target tissue up to 41-43 degrees C leads to local hyperaemia and the tumor tissue becomes more responsive to cytotoxic interventions. In several prospective randomized studies the combination between LRH and radiotherapy was superior to radiotherapy alone in terms of local control (e. g. chest wall recurrence in breast cancer) and has led to longer overall survival in advanced cervical cancer. Platinum derivatives and other cytotoxic drugs have shown synergistic effects with LRH and the combination of both has elicited high response rates in recurrent cervical cancer. In phase-II-clinical trials the newly developed liposomal anthracyclines demonstrated synergistic effects with LRH in patients with refractory ovarian cancer. Our own experience has shown that adding LRH to radio- and/or chemotherapy is well tolerated by the patients. Despite of the fact, that the available data are still preliminary, the inclusion of LRH into multimodal cancer therapy concepts appears to be very promising. Well-designed comparative studies are still needed to evaluate the role of hyperthermia as an adjunct to conventional cancer therapy.

Combined Modality Therapy↗
PubMed2004

[Principles, technology and indication of hyperthermia and part body hyperthermia].

Clinical hyperthermia with controlled alteration of temperature (40 to 44 degrees C) in the target area is used in interdisciplinary treatment concepts for tumor treatment in combination with radiation and/or radiotherapy. Besides the direct cytotoxic power of hyperthermia there is an immunomodulatory effect and a radiation and chemotherapy sensitizing effect in the heated tissue. Clinical hyperthermia is an invasive or non-invasive supply of energy to the body of the patient, which leads to an artificial heating of the tumor and the surrounded tissue. The clinical hyperthermic procedures should take into account the oncologic disease and its pattern of organ involvement. There are three different types of hyperthermia: local hyperthermia (LHT), regional hyperthermia (RHT) and part body hyperthermia (PBH). PBH is used to heat regions of the body in case of metastatic disease, e. g. to the abdomen. I and phase II trials could show that the effects of radiation and chemotherapy can be altered by the simultaneous addition of hyperthermia. Data of trials involving skin metastasis in malignant melanoma, local relapse in breast cancer, tumors of the head and neck with regional lymph node metastasis, as well as trials in colorectal tumors, bladder cancer, pancreatic cancer, cervical cancer and sarcoma are presented. The results shows, that response to treatment can be improved by hyperthermia.

Combined Modality Therapy↗
PubMed2004

Ifosfamide, carboplatin and etoposide (ICE) as second-line regimen alone and in combination with regional hyperthermia is active in chemo-pre-treated advanced soft tissue sarcoma of adults.

PURPOSE: To evaluate the efficacy and safety of the combination of ICE (ifosfamide 1.5 g m(-2), carboplatin 100 mg m(-2) and etoposide 150 mg m(-2), days 1-4, q 28 days, G-CSF 5 microg kg(-1) starting from day 6) alone and in combination with regional hyperthermia (RHT) in soft tissue sarcoma (STS) refractory to previous standard doxorubicin-ifosfamide-based chemotherapy. PATIENTS AND METHODS: Twenty patients with advanced STS of different histological sub-types were treated with the ICE regimen with 13 patients receiving additional RHT. A median of four courses of ICE were administered with RHT on days 1 and 3 (60 min, T(max) 42 degrees C). RESULTS: The objective response rate was 20%, with four partial responses (all treated with hyperthermia). In addition, two patients showed mixed responses and five patients stable disease. After a median follow-up time of 15 months, median time to progression was 6 months. Progression free rate estimates were 60% and 45% at 3 and 6 months, respectively. Median overall survival for all patients was 14.6 months. CONCLUSION: These results suggest that ICE alone or combined with RHT shows activity as second-line therapy in doxorubicin-ifosfamide-refractory STS.

Adolescent↗
PubMed2003

Feasibility and morbidity of combined hyperthermia and radiochemotherapy in recurrent rectal cancer--preliminary results.

BACKGROUND: The local recurrence rate of colorectal cancer has been significantly reduced due to the use of combined radiochemotherapy. Despite this improvement regarding locally advanced tumour recurrences, the treatment strategy for pre-treated patients remains difficult and unresolved. PATIENTS AND METHODS: We analysed treatment and follow-up data of 14 patients with local recurrence of rectal cancer who were treated with radiation therapy (RT), chemotherapy (CT) and regional hyperthermia (RHT) from November 1997 to December 2001. Nine of these patients had received irradiation and CT (= pre-treated patients) in the past. For this group, 30.6-39.6 Gy RT, 5-fluorouracil (5-FU) as a continuous infusion over 5 days per week (350 mg/m(2)/24 h) combined with RHT twice a week was given. The 5 remaining patients (= not pre-treated) received conformal irradiation of 45 Gy with a boost between 9 and 14.4 Gy, combined with continuous infusion of 5-FU on days 1-4, and 29-33 (500 mg/m(2)/ 24 h), and RHT twice a week. Response to therapy was evaluated by means of computed tomography (CT) or magnetic resonance imaging (MRI) and by clinical follow-up. RESULTS: Among 13 evaluated cases, the overall objective response rate was 54% (5 complete responses, 2 partial responses). At mean follow-up of 13.9 months (range 5-32 months) 7 patients were alive. CONCLUSION: The therapeutic regimen appears to be active in the treatment of local recurrences of rectal cancer. Larger-scaled studies are needed to evaluate the potency of hyperthermia in this therapeutic strategy.

Antimetabolites, Antineoplastic↗
PubMed2003

Ifosfamide with regional hyperthermia in soft-tissue sarcomas.

For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Therefore, systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. The combination with regional hyperthermia as a new treatment strategy seems to open a new therapeutic window.

Antineoplastic Agents, Alkylating↗
PubMed2002

Current trials and new aspects in soft tissue sarcoma of adults.

PURPOSE: For high-risk soft tissue sarcoma (HR-STS) of adults new treatment strategies are needed to improve outcome with regard to local control and overall survival. Therefore, systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. METHODS AND RESULTS: The Soft Tissue and Bone Sarcoma Group (STBSG) of the European Organization for Research and Treatment of Cancer (EORTC) is conducting an open randomized trial of adjuvant chemotherapy in high-grade primary or recurrent STS at any site (EORTC 62931). In all cases primary surgery should be curative in intent. All eligible patients are randomized after completion of definitive surgery to receive either radiotherapy alone with no further treatment (observation arm) or five cycles of doxorubicin (70 mg/m(2)) plus ifosfamide (5 g/m(2)) using G-CSF to support dose intensity followed by radiotherapy (chemotherapy arm). This more aggressive chemotherapy regimen within an adjuvant setting might retain sufficient antitumor activity to convert response rates into survival benefit. At present more than 220 patients have been recruited for this trial. To explain the rationale for the EORTC 62931 protocol, reported results of other clinical adjuvant protocols including a meta-analysis are given. In close collaboration with the European Society of Hyperthermic Oncology (ESHO) the STBSG has also initiated a randomized trial of neoadjuvant chemotherapy in primary or recurrent HR-STS as an EORTC Intergroup study. According to the inclusion criteria as defined (tumor size >or=5 cm + grade II or III + deep location + extracompartmental extension) for the EORTC 62961/ESHO RHT-95 Intergroup study, the majority of patients with HR-STS recruited for this pre- and postoperative multimodality treatment protocol cannot be cured by standard procedures. All eligible patients are randomized to receive either four cycles of EIA (etoposide 250 mg/m(2) + ifosfamide 6 g/m(2) + doxorubicin 50 mg/m(2)) within 12 weeks (chemotherapy arm) or the same EIA regimen combined with regional hyperthermia (RHT + chemotherapy arm). The patients then receive optimal local treatment using adequate surgery immediately followed by radiotherapy. Thereafter an additional four cycles of EIA chemotherapy are given with or without RHT according to the initial randomization. At present more than 150 patients have been recruited for this trial. The integration of RHT as a new potent treatment modality if combined with EIA chemotherapy as first-line treatment for well-defined risk groups is based upon encouraging long-term results of phase II studies both in pretreated patients with HR-STS and in those with locally advanced disease. CONCLUSIONS: In summary, significant prognostic variables recognized for patients with STS have been addressed in the design of two open phase III clinical trials on adjuvant and neoadjuvant chemotherapy. The best chance for offering such treatment strategies following evidence-based medicine criteria to eligible patients with HR-STS depends upon early contact with the coordinator of the individual protocol prior to any treatment.

Adult↗
PubMed2001

The role of heat shock protein (hsp70) in dendritic cell maturation: hsp70 induces the maturation of immature dendritic cells but reduces DC differentiation from monocyte precursors.

Members of the heat shock protein (hsp70) family are either constitutively expressed (hsc70) or can be induced by hyperthermic stress (hsp70). Recombinant hsp70 (rhsp70) stimulates cytokine production from monocytes and enhances NK cell proliferation and cytotoxicity. Here we demonstrate that rhsp70 binds to immature dendritic cells (DC) derived from monocyte precursors and induces their maturation as evidenced by an increase in CD40, CD86 and CD83 expression. Immature DC stimulated to mature with rhsp70 show an enhanced ability to present tyrosinase peptide to specific CTL. Mature DC did not bind rhsp70, suggesting a down-regulation in the expression of its receptor. When rhsp70 was added to monocyte precursors at the same time as GM-CSF and IL-4 it reduced the differentiation of monocytes into DC as shown by a decrease in the level of CD40, CD83, CD86 and HLA-DR expression and an increase in CD14 expression. The constitutively expressed hsc70 had neither a stimulatory effect on the maturation of immature DC nor did it reduce the differentiation of monocytes into DC. These findings demonstrate the specific ability of rhsp70 to induce the maturation of immature DC. Therefore rhsp70 may be useful for its adjuvant like properties in DC based immunotherapy of certain tumors.

Antigens, CD↗
PubMed2001

Neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for locally advanced primary or recurrent high-risk adult soft-tissue sarcomas (STS) of adults: long-term results of a phase II study.

In this phase II study, activity and safety of neoadjuvant regional hyperthermia (RHT) combined with chemotherapy was investigated in 59 patients with primary advanced or recurrent high-risk soft-tissue sarcoma (STS). Patients received four EIA cycles consisting of etoposide, ifosfamide and doxorubicin combined with RHT followed by surgical resection and adjuvant treatment. The overall objective response (OR) rate was 17%, with one complete (2%) and eight partial (15%) responses. In addition, 13 minor responses (25%) were seen. At time of surgery, complete necrosis (pCR) occurred in 6 patients and >75% necrosis (favourable histological response (FHR)) in 12 patients. At the completion of protocol treatment, 36 patients were rendered disease-free which was significantly associated with the initial radiographic and/or pathological tumour response (P=0.004). Treatment-related toxicity was acceptable overall. At a medium follow-up of 82 months, local treatment failure occurred in 33 patients, median overall survival (OS) was 52 months, and the 5-year survival rate was 49% (95% confidence interval (CI): 36-61%). OS which did not differ for extremity versus non-extremity STS (P=0.21) was better for patients responding to EIA combined with RHT (P<0.01).

Adult↗
PubMed2001

Treatment of primary, recurrent or inadequately resected high-risk soft-tissue sarcomas (STS) of adults: results of a phase II pilot study (RHT-95) of neoadjuvant chemotherapy combined with regional hyperthermia.

The efficacy of thermochemotherapy in adult patients with primary, recurrent or inadequately resected non-metastatic high-risk soft-tissue sarcomas (STS) was assessed. 54 patients were prospectively treated with four cycles of etoposide, ifosfamide and doxorubicin (EIA) combined with regional hyperthermia (RHT) followed by surgery, another four cycles of EIA without RHT and external beam radiation. The objective response rate was 16% and at a median follow-up time of 57 months, the 4-year estimated rates of local failure-free survival (LFFS), distant metastasis-free survival (DMFS), event-free survival (EFS) and overall survival (OS) were 59% (95% confidence interval (CI) 45-73%), 59% (95% CI 44-73%), 26% (95% CI 14-38%) and 40% (95% CI 27-53%), respectively. OS was in favour of patients responding to neoadjuvant treatment (P=0.073). In comparison to a preceding phase II study including pre- and postsurgical thermochemotherapy (RHT-91), at a 4-year follow-up the RHT-95 study cohort showed an inferior LFFS rate (P=0.027), but this did not affect DMFS (P=0.558) or OS (P=0.126). Hence, postsurgical thermochemotherapy seems critical for local tumour control without affecting survival.

Adult↗
PubMed1998

Apoptosis in Burkitt lymphoma cells is prevented by promotion of cysteine uptake.

Burkitt lymphoma (BL) cells are highly sensitive to suboptimal growth conditions and undergo apoptosis when seeded at reduced serum concentration or low cell density. Irradiated fibroblasts can protect BL cells from apoptosis induced by lowering the serum concentration or cell density through secretion of a survival- and proliferation-promoting activity which is soluble and labile. Murine B cells have a restricted uptake capacity for cystine and require cysteine for proliferation, which can be supplied efficiently by feeder cells. Therefore, we have studied the role of cysteine and other compounds with free thiol groups for survival and proliferation of BL cells. Cysteine, when added alone, exerted strong toxicity on BL cells. This toxicity could be counteracted by the addition of catalase, pyruvate or bathocuproine disulfonate (BCS), all of which interfere with the production of hydrogen peroxide. Inhibition of the toxicity of cysteine was necessary to unravel the survival- and growth-promoting activity of cysteine at low cell density. Alpha-thioglycerol, beta-mercaptoethanol and dithiothreitol had similar toxic activity in the absence of catalase, pyruvate and BCS and, through stimulation of cysteine uptake and glutathione synthesis, displayed a similar survival- and growth-promoting activity in the presence of the protective agents. The survival- and proliferation-inducing activity of thiol compounds in the presence of catalase, pyruvate and BCS was not associated with induction of BCL-2 or BAX. Cysteine/cystine uptake and the intra/cellular glutathione level are thus important parameters, determining the susceptibility vs. resistance of BL cells to apoptosis.

Apoptosis↗
PubMed1998

Definition of extracellular localized epitopes of Hsp70 involved in an NK immune response.

In order to define extracellular localized epitopes of Hsp70 on human tumor cells which are accessible to the immune system, six commercially available Hsp70-specific monoclonal antibodies (mAb) with different recognition sites were examined by immunological approaches. The recognition pattern of these antibodies was analyzed on purified recombinant Hsp70 proteins (rHsp70, Hsc70, DnaK), on lysates of Hsp70-expressing colon carcinoma cells (CX+) and on lysates of M21 rat-1 cells that overexpress human Hsp70 or Hsp70 fragments: ABgl (del 120-428) consisting of the C-terminal part and ASma (del 438-618) consisting of the N-terminal part of human Hsp70. All antibodies reacted equally well with rHsp70 and cytoplasmic Hsp70 derived from human tumor cells or M21 rat-1 cells. Only one antibody (MA3-007; Hsp70, Hsc70) detects a region localized within the ATPase domain of Hsp70 (amino acid 122-264) and reacts positively with the C-terminal deletion mutant ASma. All other antibodies, including RPN1197 are directed against the C-terminal peptide binding domain of Hsp70 and react positively with the N-terminal deletion mutant ABgl. Although all six antibodies detect full-length Hsp70 protein, derived from plasma membrane fractions of CX+ tumor cells, cell surface expressed Hsp70 on viable CX+ tumor cells, as determined by flowcytometry, is only recognized with the antibodies MA3-006 (Hsp70, Hsc70; 504-617), MA3-009 (Hsp70; 504-617) and RPN1197 (Hsp70). An estimation of the ratio of membrane-bound to cytoplasmic Hsp70 molecules revealed that 15-20% of total Hsp70 molecules are expressed on the plasma membrane. This tumor-selective cell surface expression of Hsp70 correlates with an increased sensitivity to lysis mediated by non-MHC restricted natural killer (NK) cells. We demonstrate that only antibodies directed against membrane-bound Hsp70 (MA3-006, MA3-009, RPN1197) inhibit NK-killing activity against Hsp70-expressing tumor cells. Taken together our data indicate that at least the C-terminal region 504-617, that contains at least one single alpha-helix (amino acid 512-536), has to be localized extracellularly and might be of importance for an NK-mediated anti-tumor immune response.

Animals↗
PubMed1996

Noncytotoxic alkyl-lysophospholipid treatment increases sensitivity of leukemic K562 cells to lysis by natural killer (NK) cells.

Alkyl-lysophospholipids (ALP) are a group of anti-cancer compounds tha t have previously been shown to have the unique feature of being selectively toxic to neoplastic tissues. Because alkyl-lysophospholipids target the cell membrane as their site of action, our aim was to analyse the immunological effects of a nonlethal ALP treatment on leukemic K562 cells. In this in vitro study we used ET-18-OCH3, one of the most potent ALP derivatives, at different concentrations ranging from 25 up to 100 microgram/ml. By measurement of cell viability and of apoptosis, we determined a concentration of 25 microgram/ml ET-18-OCH3 and an incubation period of 2 hr as nonlethal for K562 cells; higher concentrations markedly reduced cell viability and led to induction of apoptosis. Similar to the effects induced by nonlethal heat shock, a nontoxic ET-18-OCH3 treatment led to a significant increase in the sensitivity of K562 cells to lysis by interleukin-2 (IL-2) stimulated natural killer (NK) cells. With respect to these results, we investigated the influence of nonlethal ALP treatment on the cell surface expression patterns and compared it to the results obtained with nonlethal heat shock. ALP treatment does not induce major histocompatibility complex (MHC) expression; however, a significant increase in the cell surface expression of HSP72 was shown by immunoblot analysis of membrane lysates of either untreated or ET-18-OCH3 treated K562 cells. The increased sensitivity of ET-18-OCH3 treated K562 cells to lysis by NK cells could be correlated with the elevated cell surface expression of HSP72.

Antineoplastic Agents↗
PubMed1995

Degradation of 2-(3-aminopropylamino)-ethanethiol (WR-1065) by Cu-dependent amine oxidases and influence on glutathione status of Chinese hamster ovary cells.

The radioprotective drug 2-(3-aminopropylamino)ethanethiol (WR-1065) can be degraded when incubated in cell culture medium in vitro. The degradation reaction consumes oxygen and results from the action of Cu-dependent amine oxidases present in the serum content of the medium. Analysis of the degradation products of WR-1065 demonstrates the formation of cysteamine, acrolein and H2O2. WR-2721, the inactive prodrug of WR-1065, is not a substrate for these enzymes. Extracellular degradation of WR-1065 by Cu-dependent amine oxidases leads to an intracellular depletion of glutathione (GSH) in Chinese hamster ovary (CHO) cells and to reduction of clonogenic cell survival. Addition of aminoguanidine, an inhibitor of Cu-dependent amine oxidases, protects CHO cells from the toxic effects of WR-1065 and under these conditions an increase of intracellular GSH levels occurs. These data demonstrate that WR-1065 can be degraded to toxic compounds by the presence of Cu-dependent amine oxidases which might have further implications for the clinical use of WR-2721.

Acrolein↗
PubMed1995

Differential effects of ifosfamide on the capacity of cytotoxic T lymphocytes and natural killer cells to lyse their target cells correlate with intracellular glutathione levels.

We established an in vitro model to study the influence of ifosfamide treatment on intracellular glutathione (GSH) levels in activated human effector cells with specific phenotypes and immunologic functions. Besides its role as the major intracellular reductant, GSH has been shown to affect the initiation and progression of lymphocyte activation after stimulation with lectins. An incubation of activated human peripheral blood lymphocytes (PBL) with 4-hydroxyifosfamide, the activated form of ifosfamide (4-OH-IF), resulted in a depletion of the intracellular GSH levels and a significant inhibition of the proliferative capacity in a dose-dependent manner. The cytotoxic activity of separated CD3- natural killer (NK) cells and CD3+ allospecific, cytotoxic T lymphocytes (CTL), either untreated or treated with 4-OH-IF at different concentrations, was compared in a standard 51chromium release assay (CML). There were three major findings. (1) The capacity of CD3+ major histocompatibility complex (MHC)-restricted CTL to lyse their specific allogeneic target cells was substantially reduced by preincubation of the effector cells with 4-OH-IF. This inhibition of the lytic activity in CD3+ CTL correlated with a substantial depletion of the intracellular GSH levels in this population. Rapid reconstitution of depleted GSH levels and restoration of cytotoxic activity of CTL was achieved by incubation of the effector cells with thiols, eg, glutathione ester (GSH-ester) or 2-mercaptoethanesulfonate (mesna). (2) In contrast, the lytic activity in CD3- NK cells was not substantially affected (up to 100 mumol/L 4-OH-IF). This result correlates with the capacity of NK cells to maintain their intracellular GSH levels after an ifosfamide treatment. (3) In comparison with CD3+ CTL, CD3- NK cells are more resistant to an ifosfamide treatment because they have higher initial GSH levels and a more than fourfold higher relative rate of GSH synthesis.

Antibodies, Monoclonal↗
PubMed1995

A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells.

It is suggested that members of the heat-shock protein (HSP) 70 and 90 families are involved in intracellular antigen processing and the presentation of cell-membrane-anchored antigens. We show that non-lethal heat shock (41.8 degrees C) causes comparable rates of HSP72 (about 20x) and HSP73 (about 3x) synthesis in both tumor (including human Ewing's sarcoma, ES and osteosarcoma cells, HOS58) and normal cells (including EBV-transformed B-LCL, PBL and fibroblasts derived from healthy human volunteers). However, following non-lethal heat stress and a recovery period at 37 degrees C, flow cytometric analysis with a specific MAb showed HSP72 to be expressed only on the cell surface of tumor cells. The cell-surface localization of HSP72 was confirmed by Western-blot analysis of separated membranes and by immunoprecipitation with the HSP72-specific MAb. In addition, co-incubation of untreated tumor cells with supernatants from lethally heat-shocked cells, which contain HSP72, did not lead to HSP72 cell-surface expression. Thus, non-specific association of HSP72 molecules with the outer plasma membrane is unlikely. In conclusion, despite comparable cytoplasmic HSP72 induction, human tumor cells differ from normal cells in their capacity to express HSP72 on their surface. This might imply clinical application as a means to target a stress-inducible, tumor-specific immune response.

Animals↗