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Biomedical subjects

M E Scheulen

Publications and source records attributed to M E Scheulen.

At least 55 records · Page 3Linked to original sources
PubMed1997

Tissue toxicity of doxorubicin in first and second hyperthermic isolated limb perfusion--an experimental study in dogs.

The aim of this experimental study in dogs was to assess the tissue toxicity of doxorubicin (DOX) and the impact of dose and pharmacokinetics after double isolated limb perfusion (ILP). Fifteen beagle dogs were assigned to three groups of five animals each. In the first ILP 0.75 mg/kg bodyweight (bw) DOX was given to all animals. In the second perfusion after an interval of 6 to 8 weeks the dosage was 0.5 mg/kg bw in group I, 0.75 mg/kg bw in group II, and 1.0 mg/kg bw in group III. At the same dosage tissue toxicity increased in comparison to the first ILP. At the second ILP there was a dose-toxicity relationship. At a dose of 0.75 mg/kg bw pharmacokinetics of DOX in the perfusate showed no significant differences between first and second perfusion. The mean muscle tissue levels during the second ILP were lower than during the first perfusion. However, in contrast to the first perfusion, they showed a further increase after perfusate eluation. A disturbed microcirculation caused by intima proliferations in arteries and arterioles fter the first ILP may impair the removal of DOX from the intravasal and interstitial compartment and can be assumed as a reason for increased tissue toxicity. Therefore, we recommend a reduction of DOX dose in the second ILP for clinical use.

Animals↗
PubMed1997

Does the multidrug-resistance modulator cyclosporin A increase the cardiotoxicity of high-dose anthracycline chemotherapy?

Cyclosporin A has heterogeneous effects on anthracycline-related cardiotoxicity and can prevent multidrug-resistance (MDR). The aim of this study was to explore whether the coadministration of cyclosporin A is accompanied by an increase in cardiotoxicity. Forty-three patients (27 male, 16 female, age: 18-67 yrs [mean: 47.5 yrs, SD: 11.6 yrs]) received 177 radionuclide ventriculography examinations (RNV 177 at rest, 133 at stress) before and during chemotherapy with either doxorubicin (n = 23) or epirubicin (n = 20). RNV studies were applied up to 11 times in the follow-up of the patients. A maximum of 10 courses of chemotherapy was performed. In the doxorubicin group only, the age of the patients and the cumulative dose of the chemotherapeutic agent had a significant negative impact on left ventricular ejection fractions, whereas cyclosporin A had a significant positive influence (multiple analysis of regression, p < 0.05). Cyclosporin A did not cause any significant increase in cardiotoxicity in our patients.

Adolescent↗
PubMed1997

A phase-II study with idarubicin, ifosfamide and VP-16 (IIVP-16) in patients with refractory or relapsed aggressive and high grade non-Hodgkin's lymphoma.

We report a phase-II study of idarubicin, ifosphamide and etoposide (IIVP-16) in heavily pretreated patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. The IIVP-16 regimen consisted of idarubicin (10 mg/m2 i.v. days 1 + 2 or days 1 + 8), ifosfamide (1000 mg/m2 i.v. days 1-5) and VP-16 (150 mg/m2 i.v. days 103). 40 patients were enrolled. Of 38 evaluable patients, 26 had centroblastic subtype, followed by lymphoblastic (6), immunoblastic (2), and other entities (4). 18 patients were primary resistant; 14 patients had early relapse (CR less than 12 months) and 8 patients late relapse (CR longer than 12 months). The median number of different prior chemotherapy regimens was 2 (range 1 to 6). 20 patients had received additional radiotherapy. The response-rate was 47.4% including 8 CR (21.1%) and 10 PR (26.3%). IIVP-16 was more effective in patients with relapsed disease when compared with patients with primary resistant disease (response rate 65% vs. 27.8%, p < 0.025). Leukopenia and thrombocytopenia were the major toxicities occurring in 73/107 (68.2%) and 57/107 (53.3%) of cycles (WHO grade IV). IIVP-16 is an effective regimen particularly in patients with unfavorable relapsed NHL.

Adult↗
PubMed1996

Modulation of multidrug resistance by BIBW22BS in blasts of de novo or relapsed or persistent acute myeloid leukemia ex vivo.

The phenylpteridine derivative BIBW22BS (BIBW22) is a potent modulator of multidrug resistance (MDR). We investigated BIBW22 in comparison to dexniguldipine and verapamil as modifier of MDR in blasts of de novo, relapsed or persistent acute myeloid leukemia (AML) in vitro. All patients with relapsed or persistent AML had been pretreated with idarubicin and cytosine arabinoside. The degree of MDR was determined by efflux kinetics of rhodamine 123 (R123), daunorubicin, and idarubicin measured by flow cytometry (FACS). A total of 51 patients with AML, 25 de novo and 26 relapsed or persistent, were investigated. While only 6 out of 25 de novo AML blast populations showed moderate efflux of R123 and daunorubicin, 17 out of 26 blast populations of relapsed or persistent AML had an efflux between 20% and 44% within 15 min ex vivo. This efflux could be significantly inhibited by 1 microM BIBW22, 1 microM dexniguldipine, or 10 microM verapamil. For idarubicin we found an effusion of 40+/-9% within 15 min in all blast populations that could not be inhibited by the modulators. Clinically achievable drug concentrations causing only moderate side-effects are in the range of 0.5 microM dexniguldipine and 3 microM verapamil. Up to now, BIBW22 has not been investigated clinically. Thus the potential toxicity of concentrations of 0.5-1 microM BIBW22, sufficient for an optimal efflux inhibition ex vivo, is not known yet. We conclude from our ex vivo investigations in blast populations of de novo, relapsed or persistent AML that BIBW22 is a potent modulator of MDR.

Antigens, CD34↗
PubMed1995

Pharmacokinetics of two different delivery regimens of doxorubicin in isolated hyperthermic limb perfusion.

Evaluation of doxorubicin (DOX) pharmacokinetics in hyperthermic isolated limb perfusion (HILP) is limited. In this study two administration regimens of DOX were compared in terms of area under the time concentration curve (AUC) in plasma. HILP was performed in 13 dogs. In group 1 (n = 7) four single doses of DOX were injected in intervals of 15 minutes, in group 2 (n = 6) DOX was administered continuously during the first 30 min. The total dose in both groups was 1 mg/kg body weight, and the perfusion lasted 60 min. Concentrations of DOX and its major metabolite doxorubicinol (DOXol) were measured in perfusate and muscle tissue by high performance liquid chromatography (HPLC). Pharmacokinetic estimates were calculated. The two investigated administration modes provided sufficient drug levels of DOX during the whole perfusion time. Maximum concentrations in the perfusate and areas under the time concentration curves were nearly the same. The tissue concentrations also did not show significant differences. Both regimens are practicable avoiding high peak levels of the drug in order to minimize toxic side effects.

Animals↗
PubMed1995

Activity of N-benzyl-adriamycin-14-valerate (AD198), a new anthracycline derivate, in multidrug resistant human ovarian and breast carcinoma cell lines.

The new lipophilic anthracycline N-benzyl-adriamycin-14-valerate (AD198) was evaluated for its activity in comparison to doxorubicin in P-glycoprotein (Pgp)-positive and -negative cell lines. AD198 and doxorubicin showed comparable antitumor activity in the Pgp-negative breast cancer cell line MCF-7 and the Pgp-negative ovarian carcinoma cell line A2780. By contrast, AD198 was significantly more active than doxorubicin in the Pgp-positive breast cancer cell line MCF7AD (IC50 values 2.5 and 0.15 microM for 96 h continuous exposure) and the Pgp-positive ovarian carcinoma cell line A2780 DX5 (IC50 values 0.6 and 0.07 microM, respectively). Unlike doxorubicin, the activity of AD198 was not increased by concommittant application of cyclosporin A in cell line MCF7AD. Flow cytometry studies showed that, in contrast to doxorubicin, AD198 was not transported by Pgp and that verapamil did not change the intracellular pharmacokinetics of this new anthracycline. These data provide evidence that AD198 possesses high activity in human solid tumor cell lines expressing the classical multidrug resistant phenotype. Its further clinical development appears to be warranted.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Efficacy of ifosfamide, dacarbazine, doxorubicin and cisplatin in human sarcoma xenografts.

The primary chemosensitivity of 16 highly malignant xenografted human soft-tissue sarcomas to ifosfamide, dacarbazine, adriamycin and cisplatin and the development of secondary drug resistance in two chemosensitive sarcoma cell lines was tested in the xenograft system. Single-dose, single-agent treatments with 350 mg kg-1 ifosfamide, 200 mg kg-1 dacarbazine, 10 mg kg-1 doxorubicin and 6.6 mg kg-1 cisplatin were administered and response measured as specific growth delay. Since ifosfamide induced unexpectedly higher toxicity, response was corrected based on the shape of the dose-response curve for ifosfamide. Taking a specific growth delay > 3 as the cut-off point for chemosensitivity, ifosfamide, dacarbazine, doxorubicin and cisplatin were effective in 10/16, 4/16, 2/16 and 1/16 sarcoma cell lines respectively. Five out of 16 sarcoma cell lines were resistant to all tested drugs. Ifosfamide-resistant sarcoma lines were also resistant to doxorubicin and cisplatin, indicating a high degree of cross-resistance. Dacarbazine was still effective in 1/6 ifosfamide-resistant sarcoma cell lines. Secondary drug resistance developed slowly after doxorubicin and ifosfamide pretreatments at moderate selection pressure and developed rapidly after dacarbazine pretreatment at high selection pressure.

Animals↗
PubMed1993

The neu-oncogene product in serum and tissue of patients with breast carcinoma.

BACKGROUND: A soluble 105 kD neu-related protein is detectable in conditioned medium from breast cancer cells expressing the neu-oncogene product and in serum of nude mice bearing tumors that overexpress neu-oncogene. PATIENTS AND METHODS: In 100 patients with primary (n = 33) relapse-free (n = 6) and metastatic (n = 61) breast carcinoma the serum levels of the soluble neu-related protein were investigated by ELISA techniques. Median age was 57 years, range 26-89 years. RESULTS: The neu-protein serum levels were below 40 HNU/ml (human neu-antigen unit) in 72 patients and 40 or more HNU/ml in 28 patients. In 30 patients with primary breast carcinoma, tested before mastectomy, all serum-neu-protein samples were negative. However, 26 of 61 metastasized patients (43%) were serum-neu-protein-positivity. In disseminated disease (n = 61), serum-neu-protein-positivity was more likely to be seen in patients with visceral metastases (18/33 = 54%), than in patients with nonvisceral metastases (8/28 = 28%). Furthermore, monitoring of the serum-neu-protein levels reflected clinical course. For 53 patients original paraffin-embedded tumor material was available for studying immunohistochemical neu-protein expression. In 39/53 (73%) patients immunohistochemical and ELISA data showed corresponding results. In 27/30 (90%) patients, from whom sera and tissue could be obtained at the same time at primary mastectomy, results of immunohistochemistry in primary tumor and serum ELISA were negative and mutually confirmatory. However, the other three patients were positive for immunohistochemical neu-protein expression in primary tumor but negative for serum-neu-protein expression. CONCLUSIONS: Our results suggest that patients with advanced breast cancer and an elevated serum-neu-protein level may have a poor clinical outcome. This test might be a useful tool for monitoring patients with advanced breast carcinoma, but not those with early disease. Further prospective studies are warranted to elucidate the question of whether this test can contribute to determining prognosis and treatment strategies.

Adult↗
PubMed1993

Constant intravenous pentoxifylline infusions in allogeneic marrow transplant recipients: results of a dose escalation study.

An uncontrolled open prospective dose escalation study of daily constant-rate 24-h i.v. pentoxifylline (PTX) infusions was performed in 24 consecutive adult patients with hematologic malignancies undergoing allogeneic BMT. The objective of this study was to determine the maximum tolerable dose and to evaluate steady-state plasma concentrations of PTX and its major active 5-hydroxylated metabolite (MI) with this application route. On each of three dose levels of PTX (10, 15 and 20 mg/kg/day), eight patients were enrolled in this study. The prominent dose-dependent and dose-limiting adverse effect attributable to PTX infusions was moderate to severe nausea and vomiting which occurred on the 15 mg/kg and 20 mg/kg dose levels. In addition, one patient on each of the higher doses developed central nervous system toxicity which manifested as acute obtundation and myoclonias. Monitoring of steady-state plasma concentrations revealed that metabolite MI contributed 70-80% to both active compounds with a dose-dependent increase of parent drug and metabolite MI concentrations. In patients pretreated by high-dose busulfan and cyclophosphamide (CY), steady-state plasma concentrations of metabolite MI were significantly increased on all dose levels over those of patients who received total body irradiation and CY as a preparative regimen. Furthermore, impairment of excretory liver function led to significant accumulation of parent drug and metabolite MI. In conclusion, constant i.v. PTX infusions in allogeneic marrow transplant recipients are limited by dose-dependent nausea and vomiting with an estimated maximum tolerable dose in the range of 10 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Drug- and radiation-induced resistance in a human neurogenic sarcoma xenografted in nude mice.

The in vivo development of radiation- and doxorubicin-induced resistance was studied in a chemosensitive and radiosensitive human neurogenic sarcoma (Essen neuroectodermal tumor line 2) xenografted in nude mice. Dose-response curves were generated for the parent tumor line, and growth delay (GD) and specific growth delay (SGD) were the study end points. An intravenous injection of doxorubicin at 10 mg/kg, the lethal dose for 10% of the study population (LD10) in nude mice, and a single dose of 12 Gy radiation were determined to be isoeffective and were thus maintained for all subsequent treatments. For the induction of resistance to both treatment modalities, regrowing tumors were transplanted into successive generations of nude mice and retreated. This procedure was repeated 13 and 9 times, respectively, for the doxorubicin and radiation treatments. The response was monitored in all passages. As compared with the parent tumor line, a 50% decrease in SGD was observed following 3.9 and 8.5 treatments with doxorubicin and radiation, respectively. Following four treatments with doxorubicin, SGD in tumors crossed over to radiation therapy declined by 50%. Radiation therapy, on the other hand, caused significant reductions in GD and SGD in tumors that were subsequently exposed to doxorubicin, but it did not induce a 50% decline in response. Overexpression of P-170-glycoprotein was not observed for either treatment modality. The data suggest that treatment with doxorubicin or radiation can potentially induce resistance to subsequent continued or crossover treatment and that this resistance develops gradually. The lack of P-170-glycoprotein over-expression in the resistant cell lines indicates the existence of alternative pathways that may lead to resistance.

Animals↗
PubMed1992

Treatment of high-risk, nonseminomatous testicular cancer with cisplatin, ifosfamide and bleomycin: long-term results.

Thirty-four patients with stage IIC (unresectable, retroperitoneal tumor mass (RTM) greater than 5 cm), stage IVC (minimal lung metastases less than 10 cm3 and RTM greater than 5 cm) and IVD (lung metastases greater than 10 cm3 and RTM greater than 5 cm), who had not received previous chemotherapy, were treated with cisplatin (40 mg/m2, on days 2-4), ifosfamide (5 g/m2, on days 1 and 5) and bleomycin (30 mg, on days 1, 8, 15) (PIB), every 21 days. Twenty of the 34 patients (59%) achieved a complete remission (CR). Furthermore, five patients (15%) showed no evidence of disease (NED) after surgical removal of residual tumor masses (NED rate of 74%). A tumor marker-negative partial remission (PR) occurred in 3/34 patients (9%), and a tumor marker-positive PR in another 3/34 patients (9%). Three patients did not respond to this regimen. At a median follow-up period of 38 months (range, 15-47 months), 26/34 patients (76%) were alive, 21 (62%) of them without evidence of disease and three with a stable tumor marker-negative remission. Major toxicity consisted of myelosuppression, neurotoxicity and nephrotoxicity. Chemotherapy-related mortality occurred in two patients (one septicemia and one bleomycin-induced lung fibrosis). In conclusion, PIB is an effective induction regimen in patients with high-risk NSTC. However, controlled clinical trials are necessary to prove the superiority of dose intensification schedules.

Adult↗
PubMed1991

Ifosfamide, methotrexate and 5-fluorouracil for pretreated advanced breast cancer.

A total of 51 fully evaluable patients with advanced and intensively pretreated breast cancer were treated with a combination chemotherapy of ifosfamide plus mesna, methotrexate and 5-fluorouracil. All patients had received at least one series of combined chemotherapy, 30 patients had received more than one combination and 41 patients had had anthracyclines before. Metastatic lesions in more than one site were found in 42 patients, and 24 patients had metastatic liver lesions. Partial remission was achieved in 10 patients (20%) and no change in 16 patients (31%). Survival was almost identical in both groups of responding patients and significantly shorter in treatment failures. Response was favorable in patients without pretreatment with anthracyclines. Two patients who received this protocol directly after progression with cyclophosphamide, methotrexate and 5-fluorouracil (CMF protocol) responded with a partial remission. Median time to progression was 7 months for partial responders and 4.5 months for patients achieving a no-change status. Median survival was 8 months for all patients. Toxicity was tolerable. Leukocytopenia and thrombocytopenia were treatment-limiting parameters. Overall, this protocol is well tolerable and effective in breast cancer patients with advanced disease and in intensively pretreated patients.

Adult↗
PubMed1990

Six weeks of continuous intravenous cyclosporine and short-course methotrexate as prophylaxis for acute graft-versus-host disease after allogeneic bone marrow transplantation.

The feasibility and toxicity of six-week continuous intravenous 3 mg/kg/day cyclosporine (CsA) treatment in conjunction with a short course of methotrexate (MTX) was studied in 69 consecutive patients after HLA genotypically identical bone marrow transplantation. In light of the uncertain efficacy of prolonged oral CsA immunoprophylaxis in preventing de novo chronic graft-versus-host disease (GVHD). CsA treatment was terminated three months after BMT. Sixty-one (88%) patients received the full intravenous regimen and no patient exclusions were necessary due to intolerable adverse effects. Weekly median blood CsA concentrations ranged between 820 ng/ml in the first and 648 ng/ml in the sixth week of treatment. No significant correlation existed between blood CsA concentrations and CsA dosages. Major adverse effects of the regimen included hypertension in 36%, acute nephrotoxicity in 36%, acute hepatotoxicity in 41%, and central nervous system toxicity in 4% of the patients. Since hepatotoxicity occurred predominantly in the early posttransplant period (median onset day 9), the relatively high incidence of this untoward effect might have been additionally caused by MTX and/or the preparative regimen. Blood CsA concentrations and CsA dosages did not significantly correlate with serum creatinine or total and conjugated bilirubin levels. In addition, blood CsA and serum creatinine levels did not differ between hypertensive and normotensive patients. Acute GVHD developed in 16% of the patients. Median CsA doses and blood CsA concentrations were identical for each week after BMT for patients contracting acute GVHD as compared with those without acute GVHD. In 55 patients surviving without acute or secondary chronic GVHD, the cumulative probability of de novo chronic GVHD after termination of CsA treatment was 13%. In conclusion, this regimen was tolerable and provided constant blood CsA concentrations for six posttransplant weeks that were not adversely influenced by the development of acute GVHD. Restriction of CsA treatment to the first three months after BMT appeared not to increase the risk of de novo chronic GVHD, which challenges regimens employing oral CsA immunoprophylaxis for 6-12 months after BMT.

Acute Disease↗