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Biomedical subjects

R Osieka

Publications and source records attributed to R Osieka.

At least 55 records · Page 3Linked to original sources
PubMed1988

Influence of ring substituents on the antitumor effect of dichloro(1,2-diphenylethylenediamine)platinum(II) complexes.

Diastereomeric para-substituted dichloro(1,2-diphenylethylenediamine)platinum(II) complexes were synthesized and tested for their antitumor activity on the human MDA-MB 231 breast cancer cell line and the P 388 leukemia of the mouse. An interaction with the DNA was demonstrated by UV difference spectroscopy. The D,L configurated, 4-fluoro-substituted complex was the most active.

Animals↗
PubMed1987

Treatment of chronic myelogenous leukemia with recombinant interferon alfa-2b.

Interferon alfa-2b (Intron A; Schering-Plough) was administered to 36 patients with chronic myeloid leukemia (CML) at an initial dose of 4 X 10(6) IU/m2 daily subcutaneously, adapted to changes in leukocyte counts during the course of treatment. Of 32 patients who could be fully evaluated (20 men and 12 women; median age, 34 years) 29 were in the chronic phase, one had a blast crisis and two had accelerated phase disease. Hematologic remission was achieved in 20 of the 32 patients, while a partial hematologic remission was obtained in 10. Elevated pretreatment white-cell counts returned to normal in 25 patients after 3-40 weeks. There was a parallel decrease in platelet counts after an average treatment time of six weeks and in lactate dehydrogenase, after 2-20 weeks. In conclusion, administration of interferon alfa-2b resulted in a relatively rapid cell reduction in chronic phase CML. The long-term effect of this treatment on the course of the disease and the place of interferon alfa-2b in the overall concept of CML treatment remains to be evaluated.

Adult↗
PubMed1987

Increased cytotoxicity of 1-(2-chloroethyl)-1-nitroso-3(4-methyl)-cyclohexylurea by pretreatment with O6-methylguanine in resistant but not in sensitive human melanoma cells.

Cells from a resistant ("Gr II") and a sensitive ("Str") human melanoma xenograft were incubated in vitro with O6-methylguanine for 2 h, subsequently treated with 1-(2-chloroethyl)-1-nitroso-3(4-methyl)-cyclohexylurea (MeCCNU) for 1 h and then plated in soft agar. In the resistant cells the O6-methylguanine pretreatment (2 mM) yielded an increase in sensitivity towards MeCCNU by a factor of 7.5. In the sensitive melanoma cells pretreatment with O6-methylguanine did not increase cytotoxicity. Human bone marrow cells from three normal donors were similarly pretreated with O6-methylguanine and MeCCNU. There was a clear increase in MeCCNU-induced cytotoxicity. We conclude, that while O6-methylguanine does potentiate the action of MeCCNU in resistant melanoma cells, the therapeutic usefulness of this treatment strategy may be limited.

Animals↗
PubMed1987

Clinical pharmacology of sodium butyrate in patients with acute leukemia.

Since cancer may be regarded as a disease of differentiation and sodium butyrate induces differentiation of malignant cells in vitro, a study of the clinical pharmacology of sodium butyrate was undertaken. Nine patients with acute myeloid (n = 1), acute monocytic (n = 1), acute myelomonocytic (n = 6) and acute undifferentiated (n = 1) leukemia were treated. Their median age was 52 (range, 27-78) years. Six of the nine patients were pretreated with cytostatic agents. Sodium butyrate was administered i.v. at a dosage of 500 mg/kg/day as continuous infusion over 10 days. A sensitive and reproducible high-performance liquid chromatographic separation was developed after derivatization of sodium butyrate with 2,4'-dibromoacetophenone employing crown ether catalysis. Plasma concentrations and urinary excretion of sodium butyrate were monitored during the 10 days of continuous infusion and for 2 days thereafter. During infusion, plasma concentrations increased 6-fold over the endogenous butyrate level and reached 39-59 microM. The area under the curve of the exogenous butyrate was 384 +/- 50 microM X day (mean +/- S.D.). After the end of infusion, concentrations declined rapidly with a half-life of 6.1 +/- 1.4 min, and reached pretreatment values within 1 hr. The total clearance rate was 83 +/- 12 ml/kg/min and the volume of distribution 738 +/- 245 ml/kg. The excreted amounts of butyrate in the urine were minimal as compared to the infused dose. Although excretion by other organs was not ruled out, it is suggested that the infused sodium butyrate was rapidly metabolized. A significant increase in peripheral blast cells was observed, whereas bone marrow cytologies before and after treatment did not reveal a significant change in blasts. Differential counts of peripheral white blood cells did not show significant changes. No toxicity was encountered. The apparent lack of clinical efficacy may be explained by the low plasma levels of sodium butyrate due to its short half-life in vivo. In comparison, concentrations reported for in vitro studies were at least 10 times higher.

Adult↗
PubMed1987

Interferon alfa-2b in the treatment of chronic myelogenous leukemia.

Thirty-six patients with Philadelphia chromosome-positive CML were treated with interferon alfa-2b for at least 3 months. Thirty-two of the patients had chronic phase disease and four had acute phase disease, one in blast crisis. Patients initially received a daily dose of 4 megaunits/m2 administered subcutaneously; outpatient self administration followed at a dosage decreased in accordance with serially determined blood cell counts. Treatment was continued for 0.5 to 15 months, with a median duration of 7 months. No complete remission was achieved, but hematologic remission occurred in 21 (58%) patients, with partial hematologic remission in an additional 12 (33%). All four patients with acute phase disease failed to respond. Adverse reactions were only significant during the first days of treatment and did not interfere with self administration of the drug. Interferon alfa-2b may prove to be an important alternative therapeutic modality in chronic phase CML.

Adolescent↗
PubMed1986

Enhancement of etoposide-induced cytotoxicity by cyclosporin A.

Following the clinical observation of enhanced antineoplastic action of etoposide in the presence of cyclosporin A (CyA), we investigated this drug interaction in several in vitro and in vivo tumor systems. Macromolecular DNA damage induced by etoposide at drug levels comparable to plasma AUC values achieved in patients was increased not only in leukemic peripheral blood cells from patients but also in mononuclear peripheral blood cells from a healthy donor. Intracellular retention of radioactivity from 3H-etoposide was increased by a factor of 1.5 at the most in the presence of CyA. The cytotoxicity of etoposide and adriamycin to L 1210 leukemic cells was clearly enhanced, whereas CyA had no effect on the action of cisplatin or ionizing irradiation. At CyA blood levels not exceeding 1.44 microgram/ml, increased tumor inhibition of etoposide was observed in a human embryonal cancer xenograft, but there was also higher lethality in normal mice. We conclude from our own data and from other recent findings that with respect to chemosensitization the effects of CyA resemble those of calcium channel blockers or anticalmodulin agents. In contrast to calcium channel blockers, however, adequate plasma levels of CyA can well be achieved in patients.

Animals↗
PubMed1986

Tumor biology and oncology.

The role of surgery in the management of human neoplasias is constantly undergoing reevaluation. Less surgical radicality reduces mutilating side-effects without a decrease in long-term survival if adjuvant chemotherapy is given. On the other hand, the surgical excision of isolated metastases helps to maintain curative intent even in the presence of residual disease after chemotherapy. Many experimental and clinical observations point to a predilection of circulating tumor cells for certain organs. Thus, the metastatic process is not simply a series of random events but rather governed by anatomical determinants such as venous and lymphatic drainage of the primary tumor and also by the intrinsic metastatic potential of the tumor cells themselves. The complex biology of metastasis is discussed with special reference to the surgical removal of isolated metastases.

Humans↗
PubMed1986

Enhancement of semustine-induced cytotoxicity by chlorpromazine and caffeine in a human melanoma xenograft.

Chlorpromazine (CPZ) and caffeine (CFN) enhance the cytotoxicity of nitrosoureas in conventional murine tumor systems, but this effect was not confirmed in a randomized clinical trial which compared the action of semustine (MeCCNU) against the combination of MeCCNU, CPZ, and CFN. Since differences in repair systems are known to exist between cells of human or murine origin, we have employed a human melanoma xenograft system to quantify the drug interaction. The enhancement in human melanoma cells was similar to that observed with conventional murine tumor systems. Alkaline elution studies and determination of radioactivity from labeled MeCCNU pointed to increased drug retention and fixation of DNA damage as the mechanism of enhancement. Although toxicity studies were limited to murine tissues, there was evidence of increased toxicity, especially if MeCCNU was combined with both CPZ and CFN. Thus, a true therapeutic synergism may not be present for the combination. Some explanations for the failure to detect such drug interaction in clinical trials and the relevance of advanced preclinical tumor systems are discussed.

Animals↗
PubMed1985

Interaction of cyclosporin A with antineoplastic agents.

A synergistic effect of etoposide and cyclosporin A was observed in a patient with acute T-lymphocytic leukemia in relapse. The concomitant administration of etoposide and cyclosporin A resulted in eradication of hitherto refractory leukemic infiltration of bone marrow. Severe side effects in terms of mental confusion and progressive hyperbilirubinemia, however, point to an enhancement not only of antineoplastic effects but also of toxicity in normal tissues. This report demonstrates for the first time that the pharmacodynamic properties of cyclosporin A may not be confined strictly to suppression of normal T-cell functions.

Adult↗
PubMed1985

[Effect of antineoplastic agents and ionizing radiation on a human testicular cancer heterograft].

Chemotherapy has afforded a high percentage of definitive cures in advanced testicular cancer. Nevertheless some patients with large tumor burden still succumb to chemorefractory disease. Therefore preclinical and clinical evaluation of new drugs and agents not primarily used against this type of disease are still mandatory. For preclinical drug screening purposes heterotransplantation of specific human tumors yields a model with high validity for tumor markers and drug response. Heterotransplantation of a human embryonal testicular cancer was used for simultaneous testing of established agents such as cisplatin, melphalan, bleomycin, vinblastine, etoposide and adriamycin and some newer derivatives such as PHM or mafosfamide. Furthermore agents such as procarbazine, dacarbazine and methyl-CCNU that cross the blood-brain-barrier displayed some interesting activity. The results hint at a unique chemosensitivity pattern of the xenograft line, with some accordance between clinical response to vinblastine and bleomycin and good response of the xenografts to bleomycin but not to vinblastine. Radiotherapy was also effective against this tumor line, but there was not much difference in response when the schedule of fractionation was changed. It is concluded that a combined modality approach might salvage patients with residual, chemorefractory disease.

Animals↗
PubMed1984

Primary and acquired resistance to antineoplastic chemotherapy. A preclinical and clinical study.

Due to ethical restrictions, dose-response relationships may not be appreciated in clinical trials as clearly as in preclinical tumor models. Furthermore, tumor heterogeneity sets the pharmacology of antineoplastic agents somewhat apart from general pharmacology, since for each individual tumor there may be a distinct dose-response curve describing tumor-inhibitory effects of a given drug. This has been documented by a panel of human tumor xenografts derived from patients with disseminated malignant melanoma who participated in an open Phase II clinical trial. Patients who were refractory to dacarbazine received the combination of ifosfamide and cisplatin and vice versa. In the xenograft model four additional DNA-damaging agents were tested. Heterogeneity of response to antineoplastic drug treatment was evident in three ways: (1) tumor volume responses of individual mice bearing a certain xenograft line varied considerably after exposure to a certain drug at a specified dose level; (2) at equitoxic dose levels response of a given xenograft line to different DNA-damaging agents was quite heterogeneous, covering a range of almost two decades; and (3) if the panel of xenograft lines derived from different donors was exposed to a battery of DNA-damaging drugs at the LD 10/30 level, some lines revealed unique chemosensitivity patterns in contrast to more uniform resistance displayed by a minority of lines. Preclinical and clinical responses correlated well, and thus the relevance of dose-response relationships observed in the xenograft model to clinical treatment strategies is discussed.

Animals↗
PubMed1984

Predictive tests in cancer chemotherapy. A reappraisal.

The evolution of medical oncology so far owes much to the preclinical and clinical development of antineoplastic agents. Prognostic factors and empiric treatment strategies have guided the clinician in his choice of drugs. In the light of increasing ethical restrictions met with phase I-II clinical trials and major advances in propagating human tumor cells outside the donor patient, a reappraisal of predictive tests in cancer chemotherapy is warranted. Among 'short-term assays' only the determination of steroid-hormone receptor content in tumor tissues has gained clinical acceptance, whereas other methods still suffer from theoretical or practical shortcomings. Both the human tumor stem cell assay and the xenograft model have revealed unique patterns of sensitivity for each individual tumor line. While interindividual heterogeneity among tumors sharing a common site of origin justifies efforts to develop predictive tests, microheterogeneity among tumor samples from the same donor patient limits the potential of this approach. Predictive tests should be performed in conjunction with clinical trials to ensure optimal extraction of information. As additional prognostic factors, they should in the near future accelerate drug development and reduce the hazard of unnecessary drug toxicity without therapeutic benefit.

Animals↗
PubMed1984

Macromolecular DNA-damage in murine and human leukemic and lymphoid cells after in vitro exposure to ASTA Z 7557 (INN mafosfamide).

Cyclophosphamide (CPA) is widely used against leukemic and lymphoproliferative diseases, but in vitro studies on response to this agent so far have been limited to instable derivatives with poor galenic properties. ASTA Z 7557 is a newly synthesized "activated cyclophosphamide" that circumvents the need for hepatic activation and has good stability. The critical cytotoxic lesions after exposure to bifunctional alkylating agents presumably are DNA interstrand crosslinks (ISC). We have, therefore, examined the formation and apparent removal of ISC after in vitro treatment with ASTA Z 7557 by use of the highly sensitive alkaline elution technique. Survival of murine L1210 cells was determined after 1 hour in vitro exposure with a D 37 value of 5.7 micrograms/ml (from the initial shoulder part of the survival curve) and a Do value of 1.5 micrograms/ml (from the exponential part of the curve). Previous labelling of L1210 cells by 125IUdR simplified the alkaline elution procedure but there was some cytotoxicity of the radiochemical itself with a reduction of cloning efficiency from 77% to 61%. The maximum of ISC was observed at 6 h after initiation of treatment with much of the damage apparently removed at 24 h. The simultaneous presence of DNA single strand breaks (SSB), however, confounds the analysis of DNA damage at 24 h and early cytolysis and unaided death of human lymphocytes often preclude the analysis of macromolecular damage at this time. Human peripheral blood cells isolated from patients with leukemic or lymphoproliferative diseases showed a remarkable heterogeneity with regard to the formation of ISC at 3 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Studies on drug resistance in a human melanoma xenograft system.

Alkylating agents and their functional analogues belong to the most useful antineoplastic drugs in the treatment of disseminated malignant melanoma. In conjunction with an open clinical phase II trial evaluating the combination of cisplatin and ifosfamide, 17 melanoma xenograft lines were established from patients often refractory to dacarbazine (DTIC). These xenograft lines were exposed to cisplatin, dacarbazine, dibromodulcitol, ifosfamide, methyl-CCNU, mitomycin C, and malonato-diaminocyclohexane-platinum II (PHM) at the respective LD 10/30 doses. Growth delay values less than 2 corresponded in 26/27 instances with progressive disease, whereas values greater than 2 corresponded in only 10/13 instances with achievement of a no-change status or a partial remission of the donor patient's disease. Among the panel of DNA-damaging agents tested, cross-resistance was incomplete. Some xenograft lines revealed unique chemosensitivity patterns in contrast to a uniform pattern of drug resistance in others (pleiotropic or multidrug resistance). The data confirm independently of results obtained in the phase II study that the combination of cisplatin and ifosfamide is effective against malignant melanoma refractory to dacarbazine. Suboptimal drug exposure, repeated up to 21 transplant generations, was employed to induce secondary resistance to either dacarbazine, melphalan or methyl-CCNU in a melanoma xenograft line originally quite sensitive to drug treatment. When the resistant sublines were exposed to the other agents, only partial cross-resistance was observed. Tumour volume responses to treatment with dacarbazine correlated with persisting DNA damage assayed 24 h after in vivo drug exposure in a sensitive line and the absence of such lesions in a resistant line.

Animals↗