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Biomedical subjects

C G Schmidt

Publications and source records attributed to C G Schmidt.

At least 145 records · Page 8Linked to original sources
PubMed1982

Covalent protein binding of reactive adriamycin metabolites in rat liver and rat heart microsomes.

Covalent binding of 3H-labeled adriamycin metabolites to bovine serum albumin and microsomal protein is demonstrated in an aerobic incubation system with rat liver and rat heart microsomes, respectively, using exhaustive organic solvent extraction and gel chromatography. Covalent protein binding was dependent on active microsomes, NADPH, and oxygen and was inhibited by reduced glutathione and other sulfhydryl compounds. The anthracycline moiety was spectrophotometrically evidenced in the adriamycin metabolite(s) covalently bound to protein. Thus, enzymatic activation of adriamycin in the heart with consecutive covalent protein binding of reactive adriamycin semiquinone radicals may contribute to adriamycin cardiotoxicity.

Animals↗
PubMed1982

Effects of cisplatin on different haemopoietic progenitor cells in mice.

The effects of Cisplatin on marrow haemopoietic progenitor cells, WBC and RBC were measured and compared in F1 (CBA x C57BL) female mice. Dose/survival curves of Cisplatin for CFU-S, CFU-C and BFU-E were found to be simply exponential, indicating that the effect of the drug has no cell-cycle dependency. BFU-E also appeared significantly (P less than 0.001) more sensitive to Cisplatin than CFU-S and CFU-C. After a single dose of 12 mg/kg of Cisplatin, WBC, MNC and CFU-E were seen to be markedly less reduced and to recover much earlier than CFU-C, and particularly BFU-E and CFU-S. Results suggest that the drug is more toxic for earlier haemopoietic progenitor cells than for the more mature cells, and that the latter are not reliable parameters for complete haemopoietic recovery in mice after treatment with this agent. In the animals treated, there was also a subsequent significant decrease of the RBC count, accompanied by a marked increase of the marrow CFU-E concentration. Possible underlying mechanisms (e.g. alterations of RBC after exposure to Cisplatin) were discussed.

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

[Comparison of the sensitivity of various mouse hematopoietic stem cells to cis-diamminodichloroplatinum (II)].

Recently, several investigators have reported on severe myelosuppression, particularly anaemia, in patients treated repeatedly with cis-diamminedichloroplatinum (II) (cisplatin). The aim of the present study was to evaluate the sensitivity of different haematopoietic stem cells to this agent in mice. Survival of CFU-S, CFU-C and BFU-E was determined 24 h after i.p. injection of increasing doses of the drug. All three stem cell types showed exponential survival curves without evidence of plateau phases indicating that the effect of cisplatin has no cell cycle dependency. In addition, BFU-E appeared to be significantly more sensitive to cisplatin than CFU-S and CFU-C. Doses required to reduce the stem cell compartment sizes to 37% were found to be 3.0, 4.9 and 5.4 mg/kg of cisplatin, respectively. In view of these data, the question arises whether the preferential toxicity of cisplatin for BFU-E is causatively involved in the development of anaemia induced by this agent.

Anemia↗
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↗
PubMed1981

[Individualized interval shortening in the chemotherapeutic induction treatment of solid tumors (author's transl)].

Sequential chemotherapy with vinblastin and bleomycin, as well as adriamycin and cis-platin, was administered to 29 patients with disseminated malignant testicular teratoma. In order to intensify the induction phase, the intervals between drug administrations were individually shortened, with the next course of treatment following directly after the phase of critical leucocyte depression. This method was pursued over four courses of chemotherapy without dose reduction, followed by courses of chemotherapy in a conventional three-weekly rhythm. A response was obtained in 28 patients, 18 of them achieving complete remission. Taking into consideration unfavourable prognostic factors in the treatment group, this result is better than after the same chemotherapy at three-weekly intervals. Induction treatment adapted to leucocyte response carries with it the risk of higher toxicity, but this would seem to be acceptable in view of the improved long-term prognosis. This or similar intensification of the first treatment phase, for a long time used with leukaemias, could also be considered in the management of various chemotherapy-sensitive solid tumours, especially in younger patients.

Adolescent↗
PubMed1981

[Chemotherapy in advanced sarcomas (author's transl)].

43 patients with metastasizing sarcomas were treated with a combination of either vincristin, adriamycin and cis-platinum (n = 21) or ifosfamide and cis-platinum at three weeks' intervals in each case. Ten patients responded to the first combination and nine to the second combination with objective tumor regression. Particularly the latter result is remarkable since 16 of the 22 patients had already been pretreated with combinations containing adriamycin. Obviously the combination of ifosfamide and cis-platinum is a promising alternative in metastasizing sarcomas of the bones and soft tissue, especially if the CYVADIC combination--which is often regarded as standard treatment--remained unsuccessful. This has no bearing on additional surgical measures or on radiotherapy which may be necessary in some patients.

Cisplatin↗
PubMed1981

Sister chromatid exchange and growth kinetics in untreated acute leukemia.

Sister chromatid exchange (SCE) frequency has been analyses after short-term culture of leukemic bone marrow cells of eight untreated patients with acute leukemia. Compared to normal bone marrow, results show a statistically significant decrease of SCE (p less than 0.001) in euploid as well as in aneuploid leukemias, ranging from 2.11 to 2.97 SCE per metaphase. The different SCE values were not related to contraction status of chromosomes and could not be explained by the age of patients. Therefore, low SCE may be a typical feature of leukemic cells. An examination of growth rates by the SCE technique revealed a high turnover of normal bone marrow cells. About 80% of the cells did not need more than 50 h to run two or three cell cycles. Leukemic cells, however, apparently divided more slowly, which is in good agreement with data obtained by autoradiographic methods.

Acute Disease↗
PubMed1981

Autonomous cortisol secretion by a metastatic Leydig cell carcinoma associated with Klinefelter's syndrome.

We present the case of a 39-year-old man with Klinefelter's syndrome and a metastatic Leydig cell carcinoma in whom autonomous cortisol production induced by the interstitial cell tumor was found. Apart from the Cushing's syndrome the endocrine activity of the tumor was demonstrated by the secretion of estradiol, estrone, alkaline phosphatase, and testosterone. This is, to our knowledge, the first description of a Cushing's syndrome not caused via ACTH production but directly induced by ectopic steroid production. While being resistent to chemotherapy and radiation, the tumor responded favorably to treatment with o,p'-DDD. The reduction of tumor size was accompanied by a continuous decrease of serum markers. The etiology of the tumor is discussed in the light of the hormonal derangement caused by the genetic abnormality of Klinefelter's syndrome.

Adult↗
PubMed1981

[Chemotherapy of bronchogenic cancer (author's transl)].

This report summarizes our experience with protocols "ACLI" and with alternative combinations such as ifosfamide plus etoposide in the chemotherapy of inoperable bronchogenic carcinoma. Using the "ACO"-protocols and consolidating irradiation, 77% complete remissions were achieved in patients with limited disease (median survival of 21 months). Patients with extensive disease (50% complete remissions) had a median survival of 10 months. The survival data point to a plateau after 30 months, suggesting that approximately 20% of limited disease patients may achieve long-term survival. Relapse patterns are analyzed.

Adenocarcinoma↗
PubMed1981

[Chemotherapy of soft tissue sarcomas].

Sixty-two patients with metastatic soft tissue sarcomas of various histological types were treated with Cyvadic. No chemotherapy had been given previously. Complete remission (CR) was obtained in 10% and complete plus partial remission (PR) in 20% of the patients. Mean duration of CR was 25 months, that of PR 2.5 months. Median survival time of responders was 28 months, that of nonresponders 14 months. Chemotherapy with a combination of ifosfamide plus cisplatin given to patients with primary or secondary resistance to Cyvadic led to CR + PR in 50% of the patients.

Antineoplastic Agents↗