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Biomedical subjects

R Osieka

Publications and source records attributed to R Osieka.

At least 73 records · Page 4Linked to original sources
PubMed1984

Continuous infusion versus intermittent bolus injection of bleomycin in a human embryonal testicular cancer xenograft.

In vivo experiments with bleomycin in conventional murine tumor systems indicate a superiority of continuous-infusion schedules over daily intermittent bolus injections. This schedule of administration has been incorporated into many clinical trials, especially in testicular cancer, on the basis of in vitro and in vivo experiments as well as favorable comparisons with historical controls. Since mechanisms linked to a superiority of continuous-infusion schedules may not be operative in every individual tumor line, we have compared both schedules of administration in a human testicular cancer xenograft. We found no significant difference with respect to antineoplastic response.

Animals↗
PubMed1984

[Comparison of a continuous infusion with a daily bolus injection of bleomycin in a heterotransplanted human testicular cancer].

Continuous Infusion vs. Bolus Injection of Bleomycin in a Human Testicular Cancer Xenograft System Bleomycin ( Bleomycinum Mack ) ranks among the most effective agents against non-seminomatous testicular cancer. The cytocidal effects of this drug are cell cycle dependent and increase with duration of exposure. Schedule dependency has been demonstrated in conventional murine tumor systems and recently superiority of continuous infusion over bolus injection has been claimed using the "Lewis lung carcinoma". The continuous infusion of bleomycin has found entry into many successful combination chemotherapy regimens without definitive proof of its superiority by a randomized clinical phase II trial. Presently, however, any clinical study comparing single agent activity in untreated patients with testicular cancer would meet ethical restrictions since combination chemotherapy affords cures in 30-80% of all cases. The human tumor xenograft model employing congenitally athymic (nu/nu) mice preserves salient features of the original tumor specimen with remarkable fidelity. Thus structural similarity at the microscopic level ("embryonal carcinoma with choriocarcinoma") and production of beta-HCG both in the donor patient and the subsequent xenograft line "Ma" could be demonstrated. The overall correlation between serum beta-HCG levels and tumor volumes was significantly positive (r = 0.85; p = 0.001), but varied among individual tumor-bearing mice. Covering a total dose range from 10.5-42 mg/kg given over 7 days no difference was found between daily bolus injections and continuous infusion of bleomycin. These data allow for the first time a direct comparison of both schedules of administration in a testicular cancer of human origin. On the basis of these findings the clinical preference for continuous administration of bleomycin is questioned, especially since it may cause considerable discomfort to the cancer patient.

Animals↗
PubMed1984

Human malignant melanoma: preclinical and clinical drug evaluation.

A panel of 17 melanoma xenograft lines was exposed to various DNA reactive agents. Growth delay values were calculated from tumor volume responses of xenograft bearing mice and correlated with donor patient's response as determined by standard clinical criteria. Most donor patients were refractory to dacarbazine and received the combination of ifosfamide and cisplatin as secondary treatment. Clinical and preclinical responses correlated well for resistance in 26/27 instances, whereas sensitivity was observed consistently in only 9/12 instances. Incomplete cross-resistance among cisplatin, dacarbazine, dibromodulcitol, ifosfamide, methyl-CCNU, mitomycin C, and PHM has been observed after sequential drug exposures in clinical trials and was confirmed by simultaneous drug exposures in this panel of melanoma xenografts. Most xenograft lines revealed unique chemosensitivity patterns, which offer a therapeutic potential yet to be fully exploited in clinical therapy guided by predictive tests. Macromolecular DNA damage was compared in xenograft lines differing at least 100-fold in sensitivity to dacarbazine. Removal of DNA damage 24 hours after in vivo treatment with dacarbazine paralleled in vivo sensitivity. The preclinical and clinical data on responses to various DNA reactive drugs validate the xenograft model for therapeutic purposes. The model has found an additional application in analysis of the molecular pharmacology of response to in vivo drug treatment.

Animals↗
PubMed1983

Therapeutic evaluation of five nitrosoureas in a human melanoma xenograft system.

The development of nitrosoureas has switched from more lipophilic derivatives to congeners with higher water-solubility, since this property was presumably associated with a decrease in myelosuppression. We have compared the therapeutic efficacy of clinically well-known lipophilic nitrosoureas BCNU, CCNU, and MeCCNU with the recently introduced water-soluble nitrosoureas chlorozotocin (CZT) and hydroxyethyl-CNU (HeCNU), using a human melanoma xenograft system. There were considerable differences in tumor-inhibitory activity, with HeCNU ranking first and CZT last, and the rank order was similar for drug-induced lethality or bone marrow damage (in terms of reduced cellularity or macromolecular DNA damage). When the doses are expressed as percentages of the corresponding LD10/30 values, CZT ranks last and HeCNU low among conventional nitrosoureas. We conclude that water-solubility is not associated with reduced myelosuppression and that other guidelines will have to be adopted for rational development of nitrosoureas.

Animals↗
PubMed1982

In vivo resistance towards anthracyclines, etoposide, and cis-diamminedichloroplatinum(II).

From a single wild-type strain of Ehrlich ascites tumor, sublines resistant to daunorubicin, etoposide, and cis-diamminedichloroplatinum(II) have been developed in vivo. Different levels of resistance were achieved after 4 to 8 months for anthracyclines (greater than 32-fold), cis-diamminedichloroplatinum(II) (4-fold), and etoposide (greater than 6-fold). Anthracycline resistance was associated with decreased nuclear steady-state concentration of anthracyclines, increased content of high-molecular-weight membrane glycoproteins, and glucose-dependent drug extrusion after metabolic blockade with sodium azide. A similar "pump" system which was apparently not drug specific was also documented in etoposide resistance. Resistance towards cis-diamminedichloroplatinum(II) was accompanied by decreased cis-diamminedichloroplatinum(II)-induced DNA damage in vitro when proteinase K-resistant interstrand cross-links were measured by alkaline elution. Parallel in vivo studies revealed cross-resistance of various degrees among a number of anthracycline analogs, complete cross-resistance among daunorubicin, doxorubicin, and 4'-(9-acridinylamino)methanesulfon-M-anisidine (amsacrine), and partial cross-resistance between daunorubicin and etoposide. However, cis-diamminedichloroplatinum(II) was curative in anthracycline- and etoposide-resistant cells, as daunorubicin and etoposide were curative in acquired resistance towards cis-diamminedichloroplatinum(II). cis-Diamminedichloroplatinum(II) resistance was also overcome by the derivative 1,2,diaminocyclohexylplatinum malonate. The Vinca alkaloid vindesine, although only marginally active in the control tumor, was highly active in cells selected for cis-diamminedichloroplatinum(II) resistance. These in vivo patterns of cross-resistance and collateral sensitivity may be related to observations in clinical chemotherapy.

Animals↗
PubMed1982

[Enhancement of MeCCNU potency (chemosensitization) by misonidazole in a human melanoma xenograft system].

In addition to the well-known radiosensitizing properties of misonidazole its potential for chemosensitization has been investigated recently. According to results obtained mostly with conventional murine tumor systems, the degree of such chemosensitization depends on the particular tumor system, the type of antineoplastic agent and the dose of misonidazole employed. Our experiments were conducted with a human melanoma transplanted onto (nu/nu) mice. At the dose level of 1 g/kg misonidazole toxicity was enhanced by a factor of about 3, whereas antineoplastic activity was enhanced only by a factor of about 1.8. Therefore, the usefulness of such chemosensitization remains limited, especially since under clinical circumstances this dose of misonidazole would cause unacceptable neurotoxicity. The retention of radiotivity from 14C-MeCCNU is increased in neoplastic as well as in normal tissues by a factor of 1.3.DNA interstrand crosslinks measured 24 hours after drug exposure, however, are increased by a factor of about 2. Despite their nonselective reaction at the level of molecular pharmacology, drugs with sensitizing or protective properties may well constitute a valuable addition to the serial synthesis of chemical congeners in drug development. The use of oxazaphosphorines is quoted as an example where selective protection from urotoxicity is afforded by sodium-2-mercaptoethanesulfonate.

Animals↗
PubMed1980

Peripheral neuropathy and ophthalmologic toxicity after treatment with cis-dichlorodiaminoplatinum II.

A 57-year-old woman with inoperable bladder cancer received radiation treatment. Thirteen years later she relapsed at locoregional, retroperitoneal, and mediastinal sites. During treatment with cis-dichlorodiamineplatinum II (DDP) (30 mg/day for 5 days repeated every 4 weeks) she achieved a partial remission. After seven courses of DDP-chemotherapy she complained of numbness of her hands and legs and of diminished visual acuity of both eyes. After 4 weeks these symptoms grew less but intensified severely after another DDP-treatment. The temporal relationship of neurologic symptoms and their intensification by the last administration of DDP suggest this drug to be the causative agent for peripheral neuropathy and ophthalmologic toxicity.

Cisplatin↗
PubMed1979

[Cis-diamminedichloroplatinum(II). A new antineoplastic agent derived from the group of heavy metal complexes (author's transl)].

Platinum coordination complexes represent a new class of antineoplastic agents among which only cis-diamminedichloroplatinum(II) (cis-DDP) has undergone extensive clinical trials. Cis-DDP and some of its congeners share the potential to form DNA-crosslinks with the group of bifunctional alkylating agents, yet cross-resistance is incomplete. The prominent dose-limiting nephrotoxicity can be effectively circumvented by forced diuresis. Cis-DDP not only displays outstanding activity against non-seminomatous testicular cancer but also has a broad spectrum of clinical activity. It ranks very high in activity against bladder cancer and head and neck tumors. Since myelosuppression by cis-DDP is mild, it combines well with other antineoplastic agents. Synergism has been experimentally shown for cyclophosphamide and several other antineoplastic agents. For testicular cancer combination chemotherapy including cis-DDP has become accepted treatment. The simple geometry of platinum coordination complexes allows substitutions of leaving and remaining ligands with anorganic or organic moieties thus altering pharmakokinetic, antineoplastic, and toxic properties in comparison to the parent compound. Mechanism of action, pharmacology, and clinical use of cis-DDP as well as of potentially useful congeners are discussed in this review, since cis-DDP is expected to be available for general use in medical oncology in the near future.

Animals↗
PubMed1978

Bleomycin: effect on satellite DNA in mouse fibroblasts.

The effect of Bleomycin on the semiconservative replication of mouse nuclear DNA has been studied. When asynchronously dividing mouse fibroblasts (L-cells) were grown in the presence of 5-bromodeoxyuridine (25 mg/l medium) for 18 h, three hybrid DNA bands with densities of 1.722, 1.752, and 1.761 kg/l appeared after caesium chloride density gradient centrifugation of nuclear DNA. In cells exposed to Bleomycin (100 mg/l) however, replication of satellite DNA is more strongly inhibited than is the replication of the main band DNA; preferentially the thymidinerich hybrid duplex at 1.761 kg/l could no longer be detected.

Animals↗
PubMed1978

Differential repair of 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea-induced DNA damage in two human colon tumor cell lines.

Two human colon tumor cell lines were examined for their responses to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea treatment when maintained as cultured cell lines and xenograft tumors in nude mice. One tumor line, HT, was resistant to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea treatment both in tissue culture and in vivo. The other tumor line, BE, was sensitive to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea treatment in vitro and in vivo. The DNA of tissue-cultured cells treated with 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea was examined by alkaline elution for DNA damage. 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea was found to produce DNA strand breaks and DNA cross-links in both cell types. The DNA cross-links appear to be completely repaired in the resistant HT line over the 48-hr period following drug removal, but in the sensitive BE line little or no cross-link repair was observed during this interval.

Animals↗
PubMed1978

DNA cross-linking by in vivo treatment with 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea of sensitive and resistant human colon carcinoma xenograms in nude mice.

The DNA alkaline elution technique provides a sensitive assay for the effects of DNA-damaging drugs in mammalian cells. We have adapted this method to permit measurements of effects on DNA in solid tumors. Human colon carcinoma xenografts in nude mice were treated with a single i.p. injection of 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, and the effects on the DNA were followed for 19 hr. Drug doses in the pharmacological range produced significant reductions in DNA alkaline elution rates in assays in which X-ray was used to introduce a standard frequency of single-strand breaks. These changes in alkaline elution rate were attribute to the production of both DNA interstrand and DNA-protein cross-links, which were distinguished from each other on the basis of the extent to which the effect on elution could be reversed by proteinase K. Crosslinking increased for about 8 hr after treatment with little change thereafter up to 19 hr. A drug-resistant tumor line exhibited substantially less cross-linking than did a drug-sensitive line at all time points examined.

Alkalies↗
PubMed1977

The combined modality approach in the treatment of inoperable small-cell anaplastic carcinoma of the lung.

The combined modality approach with combination chemotherapy ("Comb" or "BACO") and radiotherapy was used in a pilot study comprising 35 evaluable patients with inoperable small-cell anaplastic carcinoma of the lung. Treatment strategy was based on prior assessment of prognostic factors such as histology, performance status and extent of disease. Median survival time was 39.8 weeks for "COMB" treated patients and 21.2 weeks for "BACO" treated patients. Although the combined modality approach has been very helpful against a variety of human cancers it should be used with caution since not all combination chemotherapy regimens are compatible with radiotherapy. Mechanisms of interactions between cytostatic agents and X-rays are discussed with regard to enhanced tumor cell kill and possible toxic side effects.

Alopecia↗
PubMed1977

[Integrated treatment of the inoperable bronchial carcinoma (author's transl)].

The inoperable bronchial carcinoma tends to early formation of metastases. If the tumor responds well to different cytostatic drugs, chemotherapy is absolutely necessary. In this case, combined therapy has better results than monotherapy. We use chemotherapy prior to radiotherapy in order to prevent hematogenic extension of the disease and to ameliorate the receptiveness of the primary tumor. In order to avoid local recurrence it is necessary to submit the primary tumor and the mediastinum to radiotherapy. A focal dose of 3000 rd within three weeks is considered to be sufficient. This dose generally does not cause severe myelosuppression, so that the chemotherapy can be continued. A report is given on the provisional results of different chemotherapeutic combinations. Further studies, however, are absolutely necessary in order to be in a position to give recommendations of common validity.

Bronchial Neoplasms↗
PubMed1976

The effect of hyperthermia on DNA repair.

In the past there were many individual observations on the value of hyperthermia in the treatment of human neoplasia but most of the information about the value of hyperthermia as a single agent or in the combined modality approach has come from laboratory investigations. Dose response curves for cell survival after exposure to heat are similar in shape to cell survival curves obtained after irradiation or treatment with some cytostatic agents. The shoulder in such curves suggests that repair of sublethal or potentially lethal damage takes place after hyperthermic treatment. On the level of molecular biology the process of cellular repair should correspond to repair of damage inflicted on deoxyribonucleic acid (DNA). We have shown by means of the BUdR assay that such DNA-repair synthesis does take place upon exposure to heat. Many investigations have provided evidence of a synergism between hyperthermia and ionizing irradiation or some cytostatic agents. It was suggested that such synergism might be caused by the inhibition of repair of sublethal damage by heat. After inflicting DNA damage by a strong alkylating agent (NA-AAF) we could demonstrate DNA-repair synthesis by means of the BUdR-assay during exposure to heat. At the present time results obtained by assaying DNA repair on the basis of cell survival and by means of the BUdR-assay are difficult to reconcile.

Acetoxyacetylaminofluorene↗
PubMed1976

The effect of bleomycin on mitochondrial DNA.

Covalently closed circular mitochondrial DNA (mt-DNA) from mouse fibroblasts (L-cells) forms a separate band from nicked circular or linear DNA molecules in ethidium bromide-cesium chloride byoyant density gradient analysis. The conversion of covalently closed circular mt-DNA to nicked circular or linear DNA may serve as a sensitive method of detecting DNA strand breaks induced by bleomycin (BLM). At a very high concentration BLM induces the conversion of closed circular mt-DNA to nicked circular or linear DNA, however even after 24 h of exposure to BLM at a high concentration a considerable amount of closed circular mt-DNA molecules remains intact.

Animals↗