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Biomedical subjects

D Glaubiger

Publications and source records attributed to D Glaubiger.

32 records · Page 2Linked to original sources
PubMed1980

Haemopoietic recovery in Ewing's sarcoma after intensive combination therapy and autologous marrow infusion.

After the completion of combination therapy designed to achieve local control of Ewing's sarcoma, 13 patients with either truncal primary lesions or proven metastases were given 150 rad of total body irradiation over 5 weeks followed by cyclophosphamide, doxorubicin, imidazole carboxamide, and vincristine. 11 patients received autologous cryopreserved marrow infusions. In 2 patients marrow collections were not attempted. Two patterns of haemopoietic recovery were observed: 8 patients, who had received marrow infusions, showed leucocyte, granulocyte, and platelet recovery by 27, 28, and 30 days. 5 patients, 3 of whom had also received marrow, showed more delayed recovery with leucocyt, granulocyte, and platelet recovery at 45, 53, and 77+ days. Delayed recovery in patients receiving marrow seemed to correlate with aberrations in marrow freezing-rate during phase change, and these aberrations could be shown to diminish post-freeze recovery of marrow granulocyte-monocyte precursor cells.

Adolescent↗
PubMed1980

Result of attempted hematopoietic reconstitution using isologous, peripheral blood mononuclear cells: a case report.

In order to test the effect of peripheral blood mononuclear cell infusions on hematopoietic recovery in man we intensively leukapheresed a normal identical twin and obtained 9.8 x 10(10) peripheral blood mononuclear cells containing 4 x 10(5) CFU-C. These isologous cells were infused into his identical twin brother who had received 150 rad of total body irradiation and intensive combination chemotherapy as adjuvant therapy for Ewing's sarcoma. When compared to other patients receiving similar treatment, leukocyte recovery was accelerated by 3-4 wk, and occurred at a rate comparable to that induced by infusion of autologous cryopreserved marrow. Recovery of granulocytes, monocytes and platelets was not accelerated. The low number of CFU-C present in the preparation used ((one-eighth the number of CFU-C we usually obtain from bone marrow autograft collections) may have led to the pattern of hematopoietic recovery we observed in this patient.

Adolescent↗
PubMed1979

Qualitative and quantitative aspects of intercalator-induced DNA strand breaks.

The intercalating agents, adriamycin and ellipticine, were previously found to produce DNA strand breaks associated with DNA-protein crosslinks in mouse leukemia L1210 cells. The current work explores the nature of the agents that produce this effect and the quantitative relationship between the breaks and crosslinks. The protein-associated DNA breaks were produced by a wide variety of intercalators in addition to the above-mentioned compounds: actinomycin D, daunoycin, ethidium and lucanthone (miracil D). Treatment with several drugs that bind to DNA without intercalation, or that inhibit DNA synthesis without binding to DNA, did not cause DNA breaks. The strand break and crosslink frequencies were quantitated by means of alkaline elution methods. The strand break and crosslink frequencies were found to be within a factor of 2 of each other over a range of concentrations of adriamycin and ellipticine. It is proposed that intercalation-induced distortion of the DNA helix leads to strand scission by a nuclease which becomes bound to one terminus of the break so as to form a DNA-protein crosslink.

Alkaloids↗
PubMed1978

Structural limitations on the bifunctional intercalation of diacridines into DNA.

An homologous series of diacridines containing two 9-aminoacridine chromophores linked via a simple methylene chain has been studied in order to investigate the minimum interchromophore separation required to permit bifunctional intercalation. Viscometric, sedimentation, and electric dichroism experiments show that compounds having one to four methylene groups in the linker are restricted to monofunctional intercalation, whereas the interaction becomes bifunctional when the chain length is increased to six carbons or more. The results indicate that bifunctional reaction occurs with an interchromophore distance not exceeding 8.8 A, implying that intercalation by these compounds is not subject to neighbor exclusion if the mode of binding is of the classical intercalation type.

Acridines↗
PubMed1978

Phase I study of methanesulfonamide, N-[4-(9-acridinylamino)-3-methoxyphenyl]-(m-AMSA) using a single-dose schedule.

Methanesulfonamide, N-[4-(9-acridinylamino)-30methoxyphenyl]-(NSC-249992), an acridine derivative with significant antitumor activity in animal tumor systems, was administered to 29 patients in a phase I clinical trial. The dose ranged from 10 to 160 mg/m2 with a single dose given every 28 days. The toxic effects included moderate to severe leukopenia and mild thrombocytopenia. Myelosuppression was more severe in patients with prior whole abdominal or pelvic radiotherapy. Superficial phlebitis occurred when the drug was diluted in a volume of less than 500 ml of 5% dextrose in water. Antitumor activity was detected in one patient with ovarian carcinoma. Phase II studies are indicated with this compound since it has reproducible and reversible toxicity with some evidence of antitumor activity. The starting dose of the drug for phase II trials should be 120 mg/m2 as a single iv dose repeated at 4-week intervals.

Acridines↗
PubMed1975

Intercalative binding of ellipticine to DNA.

Ellipticine (NSC 71795), a plant alkaloid with antitumor activity, is a weakly basic polycyclic molecule with dimensions similar to those of proflavin. Like proflavin, ellipticine exhibits hypocromic and bathochromic changes in absorption spectrum in the presence of DNA. It binds preferentially to helical DNA by intercalation, but the strength of binding is substantially greater than that of proflavin. The evidence for intercalation is based on effects on the sedimentation and viscosity of sheared DNA fragments, removal and reversal of the supercoiling of closed circular DNA, and electric dichroism measurements. The sedimentation and viscosity changes are quantitatively similar to those produced by proflavin. The unwinding angle on binding to supercoiled DNA is estimated to be 7.9 degrees, similar to that of proflavin. Electric dichroism shows the plane of the bound ellipticine molecule to be oriented parallel (plus or minus 7 degrees) to the plane of the bases in helical DNA. Ellipticine differs from proflavin in that it is uncharged at neutral pH and becomes protonated under mildly acid conditions. This feature may influence the intracellular distribution of the drug. Ellipticine bound to DNA is probably in its protonated form.

Alkaloids↗
PubMedDate not supplied

Pharmacokinetics of leucovorin rescue using a new methotrexate-independent biochemical assay for leucovorin and N5-methyltetrahydrofolate.

A rapid biochemical assay for leucovorin (LV) and N5-methyltetrahydrofolate (mTHFA) has been developed, using a cell-free extract of Escherichia coli. The reaction used was the formylation of [14C]methionyl-tRNA fMet E. coli, in which product formation is dependent on added folate derivatives. The actual formyl donor, N10-formyltetrahydrofolate, is generated from LV in the presence of ATP or from mTHFA in the presence of NAD+ or NADP+. The assay is sensitive to approximately 5 X 10(-8) M l-LV and 5 X 10(-7) M l-mTHFA in serum. There is no cross-reactivity between LV and mTHFA. The presence of methotrexate (MTX) has no effect on assay results. This assay has been used to determine LV and mTHFA levels in patients receiving LV rescue after high-dose MTX infusions. Patients received 96 mg/m2 of LV as a single iv dose at the conclusion of the MTX infusion. Serum levels of LV and mTHFA were followed for the next 6 hrs. The initial (5-min) level and LV was about 10(-5) M, and its concentration in the serum decreased rapidly. The alpha-phase half-life of LV was about 15 mins, but LV was readily detectable by the assay for 3-4 hrs. There was rapid apparent conversion to mTHFA, as this compound was also detectable at the initial time point. The level of mTHFA increased for at least 60 mins, being equimolar with LV by 30 mins, and then decreased slowly with an apparent half-life of 2-3 hrs.

Adenosine Triphosphate↗
PubMedDate not supplied

Tolerance to single-dose dactinomycin in combination chemotherapy for solid tumors.

We have reviewed our experience using single-dose dactinomycin (Act D). Twenty-nine patients with Ewing's sarcoma or rhabdomyosarcoma received 114 courses of Act D (2 mg/m2) in combination with vincristine, cyclophosphamide, or DTIC with or without radiotherapy. Side effects included nausea and vomiting (100% of the courses), severe thrombocytopenia (16%), granulocytopenia (18%), and mucositis (25%). In addition, skin reactions were observed in 74% of the courses following concomitant radiotherapy. These results were compared with those following 152 courses of combination chemotherapy which contained doxorubicin in place of Act D and which were administered to these same patients. It is concluded that single-bolus Act D is no more toxic, is at least as effective, and is more conveniently administered than the traditional divided daily dose of Act D.

Adolescent↗