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Biomedical subjects

W E Ross

Publications and source records attributed to W E Ross.

At least 55 records · Page 3Linked to original sources
PubMed1983

Intensive 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), NSC #4366650 and cryopreserved autologous marrow transplantation for refractory cancer. A phase I-II study.

One hundred forty-three patients with refractory cancer were treated with intensive BCNU (600-2850 mg/m2) and autologous marrow transplantation to determine the maximum tolerated dose and antitumor effects of this regimen. Recovery from severe pancytopenia in less than 4 weeks after transplantation occurred in 92.8% of evaluable patients, suggesting the efficacy of the autologous marrow in limiting the prolonged myelosuppression anticipated with intensive BCNU. Serious extramedullary toxicity was encountered at BCNU 1200 mg/m2, where a 9.5% incidence of fatal interstitial pneumonitis and a 3.0% incidence of fatal hepatic necrosis was observed. Higher BCNU doses, 1500 to 2850 mg/m2, were associated with a 35.3% incidence of fatal hepatotoxicity. Fatal encephalomyelopathy was encountered in two patients given BCNU 2250 and 2850 mg/m2. One patient who received the highest cumulative dose of BCNU (3450 mg/m2 in 2 courses) died of cardiac necrosis. Other serious extramedullary toxicities were not encountered, even in the 14 patients who survived from 1 to nearly 5 years after BCNU therapy. Antitumor responses occurred in 40.0% of evaluable patients; a dose effect could not be evaluated due to patient heterogeneity. The BCNU doses associated with acceptable toxicity, 600 to 1200 mg/m2, produced a 37.5% total and an 11.3% complete response (CR) rate, including five patients with prolonged CRs of 1 to nearly 5 years. Notable among the CRs was the 25.0% CR rate in previously untreated metastatic melanoma, and the production of CRs in malignant disease in the central nervous system (CNS) including melanoma, lung cancer, adenocarcinoma of unknown primary, acute leukemia and glioblastoma multiforme. It is concluded that augmented doses of BCNU can be given when autologous marrow transplantation is used to limit myelosuppression. Lung and liver toxicity prevent the use of BCNU doses greater than 1200 mg/m2; neurotoxicity, and perhaps cardiotoxicity, are manifestations of the highest doses used in this study. The antitumor activity of BCNU 600 to 1200 mg/m2 remains to be determined for most neoplasms; these results suggest improved results in melanoma and CNS malignancy compared to conventional-dose BCNU therapy.

Adolescent↗
PubMed1983

DNA damage as a basis for 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyranoside) (etoposide) cytotoxicity.

The precise mechanism of action of 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyranoside) (VP-16), an important chemotherapeutic agent, has yet to be determined. VP-16 has been shown to cause single-strand breaks (SSBs) in DNA, but their relationship to cytotoxicity has not been determined. We have investigated the action of VP-16 using mouse leukemia L1210 cells in culture. By using the alkaline elution technique, we reaffirmed the occurrence of SSBs in DNA over the drug concentration range 1 to 60 microM. We were able to demonstrate additional types of DNA damage in the form of DNA double-strand breaks and DNA-protein cross-links within the same dose range. The number of double-strand breaks formed per SSB was consistent over this dose range and greater than that found after exposure of L1210 cells to gamma-irradiation. DNA SSBs and double-strand breaks were also shown to occur in isolated nuclei, indicating that cytoplasmic components are not required for this drug action. Colony formation by L1210 cells in soft agar decreased over a drug concentration range similar to that which produced DNA damage. The correlation between the effective dose range in the colony-forming assay and the DNA scission experiments supports the hypothesis that DNA breakage is responsible for drug cytotoxicity. The demonstration of strand scission in isolated nuclei may provide an experimental model for elucidating the exact mechanism of action of VP-16.

Animals↗
PubMed1982

Repair of deoxyribonucleic acid lesions caused by adriamycin and ellipticine.

The intercalating agents adriamycin and ellipticine caused DNA single and double strand breaks and DNA-protein crosslinks in mammalian cells. Ellipticine caused a much higher frequency of each of these lesions than adriamycin, at equitoxic doses. However, adriamycin-induced DNA effects were slowly and incompletely repaired over 24 hr after drug removal while the effects of ellipticine were virtually completely repaired within 30 min. Repair of ellipticine-induced lesions was observed only if cells were diluted ( 100-fold) after drug treatment, suggesting that significant amounts of drug may have been sequestered in the cellular membranes. Cell dilution did not alter the effects of adriamycin. Removal of the DNA lesions was temperature dependent. Finally, the similarity in the rates of repair for DNA single and double strand breaks and DNA-protein crosslinks supports the hypothesis that they are functionally related.

Alkaloids↗
PubMed1982

A pilot investigation of the psychologic functioning of patients with anticipatory vomiting.

A pilot investigation of nine cancer patients receiving chemotherapy on an outpatient basis at the University of Florida's Shands Teaching Hospital is reported. The focus of the study was comparing patients with anticipatory vomiting symptoms with patients who did not exhibit prechemotherapy vomiting on measures of affect and coping style. The data indicated that patients exhibiting prechemotherapy vomiting, compared with the other patients, were more anxious and depressed; additionally, they exhibited a coping style which was inhibitive rather than facilitative in nature. A theoretical context for defining and treating prechemotherapy vomiting is offered.

Antineoplastic Agents↗
PubMed1982

Potentiation of bleomycin toxicity by oxygen.

The clinical usefulness of bleomycin is limited by pulmonary toxicity. Recent clinical observations indicate that the pulmonary toxicity is potentiated in patients who are exposed to elevated but nontoxic concentrations of O2. We studied the interactions of O2 and bleomycin using a murine model. Mice were divided into two groups. One group was continuously exposed to 40% O2 at 1 atmosphere while the other group breathed compressed room air. The elevated O2 concentration alone was not toxic to animals. Mice in each group received either 40 mg/kg of bleomycin or normal saline twice a week sc. Median survival of mice receiving bleomycin was shortened from 8.24 to 4.35 weeks when the animals were maintained on 40% O2 (P = 0.0001). We conclude that exposure to a nontoxic but elevated O2 concentration can potentiate the toxic effects of bleomycin.

Animals↗
PubMed1981

DNA double-stranded breaks in mammalian cells after exposure to intercalating agents.

Previous work has shown that exposing mouse L1210 cells to intercalating agents such as adriamycin, ellipticine and actinomycin D results in DNA single-stranded breaks and DNA-protein crosslinks. To characterize further the interaction between these drugs and intracellular DNA we have employed a modification of the alkaline elution technique which allows the detection of DNA double-stranded breaks. Ellipticine (1.25-5.0 microgram/ml) adriamycin (0.5-3.0 microgram/ml) and actinomycin D (1.5-3.0 microgram/ml) all caused double-stranded breaks in DNA from L1210 cells following a 1 h treatment. The number of double-stranded breaks found per single strand break was highest for ellipticine, despite the fact that this is least cytotoxic of the three drugs. By comparing the single and double strand break frequency caused by radiation to that caused by ellipticine, it appears that most if not all of the drug-induced single strand breaks observed actually represent double-strand breaks. We suggest that these double-strand breaks may result from the action of an intracellular enzyme, perhaps topoisomerase, which breaks both strans in concert to relieve the topological strain caused by drug intercalation.

Alkaloids↗
PubMed1981

Comparison of DNA damage by methylmelamines and formaldehyde.

The cytoxicity and DNA damaging activity of S9-activated hexamethylmelamine (HMM) and pentamethylmelamine (PMM) were compared with suspected active metabolites in mouse leukemia L1210 cells. The presence of semicarbazide hydrochloride did not alter the cytotoxicity of S9-activated HMM and PMM or that of their hydroxylated analogs monomethylolpentamethylmelamine (MPM) and trimethyloltrimethylmelamine (TTM), which have been suggested as active metabolites. Following treatment of L1210 cells with high concentrations of activated HMM and PMM, there were no DNA single-strand breaks or interstrand cross-links observed by DNA alkaline elution and only a low frequency of DNA-protein cross-links. Formaldehyde (FA) at nonlethal concentrations caused far greater DNA-protein cross-linking. In contrast, the polyfunctional TTM produced both DNA-protein cross-linking and DNA interstrand cross-linking. The cytotoxicities of HMM and PMM were found unlikely to be related to extracellular or intracellular release of FA.

Altretamine↗
PubMed1980

A study of drug-induced kinetic perturbations in the marrow of a patient with neuroblastoma.

The kinetic perturbations induced by vincristine, cyclophosphamide, and adriamycin were studied in the bone marrow of a patient with neuroblastoma. Serial marrow samples were studied by dual parameter (Coulter volume and DNA content), flow cytometry, and radioautography, and findings were correlated with cytomorphologic changes. Multiparameter studies were useful in sorting out the various sequences of drug-induced kinetic changes. Distinctive effects of vincristine were observed at 2 and 24 hours after drug administration. An early drug-induced proliferative response was observed between 2 and 48 hours after initiation of therapy. Cell damage was apparent on day 4, with recovery in cell proliferative rate observed on days 6 through 9. The kinetics of perturbation may be useful in identifying temporal windows for optimum scheduling of chemotherapeutic agents in man.

Adolescent↗
PubMed1980

Relationship between DNA damage and survival in formaldehyde-treated mouse cells.

Mouse cells exposed to formaldehyde (FA) were examined for colony-forming ability and DNA synthesis as well as the induction of DNA damage. Cell survival was unaffected until the FA concentration exceeded 150 microM after which there was an exponential decay in survival. Formaldehyde-treated cells studied by the DNA-alkaline-elution technique exhibited a low frequency of single-strand breaks but extensive DNA-protein crosslinking. These crosslinks were repaired following removal of the drug. The DNA damage was accompanied by inhibition of DNA synthesis.

Animals↗
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↗
PubMed1979

Isolation and purification of large quantities of DNA replication intermediates by pH step alkaline elution.

The alkaline elution technique has been modified to be used in the isolation of DNA replication intermediates and in the study of the process of DNA replication. In this procedure pulse labeled CHO cells are layered onto a membrane filter, lysed with detergent, and the nascent DNA eluted in step-wise fashion with tetrapropylammonium hydroxide at pH 11.0, 11.3, 11.5 and 12.1. Alkaline sucrose sedimentation of the eluted DNA shows that the pH 11.0 material consists of less than 9S fragments consistant with those described by Okazaki and others. DNA eluting at pH 11.3 has a molecular weight of 8-12 million daltons, DNA which elutes at pH 11.5 sediments with a molecular weight of 20-30 million daltons. Two independent lines of evidence suggest that the pH 11.3 material includes DNA sequences synthesized at replicon origins. (1) Exposure of cells to low doses of X-ray prior to pulse labeling reduces the pH 11.3 fraction by 40-50% while there is little change in the other fractions. (2) Synchronization of cells by inhibiting DNA synthesis with FdU, followed by a 2 min pulse label, yields approximately 50% of the incorporated 3H-thymidine in the pH 11.3 fraction. The pH step elution technique has the following advantages: 1. Intermediates of high specific activity can be isolated from 10(6) cells per filter; 2. By lysing cells on a filter, proteins, nucleases, and other cellular materials are eliminated; 3. DNA in the lysate is never handled, thus eliminating shearing; 4. Eluted DNA may be instantaneously neutralized by collecting into a buffer to protect it from alkaline degradation.

Animals↗
PubMed1979

Beyond kinetics: the study of DNA damage and repair in bone marrow cells.

The response of the bone marrow to cytotoxic agents is a prime determinant of differential toxicity in cancer chemotherapy. Previous attempts to characterize drug effects on the bone marrow have largely been concerned with the proliferative status of the marrow cells. The DNA alkaline elution technique has recently proven to be a simple, sensitive technique for the study of drug-induced DNA damage and repair. The potential for applying this technique to mechanisms of bone marrow toxicity is discussed.

Animals↗
PubMed1978

Protein-associated DNA breaks in cells treated with adriamycin or ellipticine.

The effect of intercalating agents on mammalian DNA in vivo was examined by the technique of alkaline elution. Adriamycin and ellipticine were found to produce large numbers of single-strand breaks. These breaks appeared to be intimately associated with protein to the extent that enzymatic deproteinization of the DNA was necessary to reveal the breaks. The frequency of breaks and cross-links increased with concentration and time of exposure to the drugs. These data suggest that DNA single-strand scission may be a feature common to intercalators. The association with a cellular protein is previously undescribed and suggests possible mechanisms for the strand scission.

Alkaloids↗
PubMed1978

Glycogen-containing neuroblastoma with clinical and histopathologic features of Ewing's sarcoma.

The differential diagnosis is difficult in cases of metastatic neuroblastoma, Ewing's sarcoma, lymphoma, and rhabdomyosarcoma, the common so-called small round cell tumors of childhood. The distinction between Ewing's sarcoma and neuroblastoma in bone with no soft tissue mass in the adolescent is especially difficult. Ewing's tumor is usually characterized by its content of glycogen, neuroblastoma by its absence. A case of glycogen-containing neuroblastoma initially misdiagnosed as Ewing's tumor is presented. Diagnostic implications, including the role of electron microscopy in diagnosis, are discussed. Glycogen alone is unreliable as a diagnostic aid due to 1) its presence in several tumors other than Ewing's including neuroblastoma, and 2) its absence in some cases of Ewing's sarcoma.

Adolescent↗
PubMed1978

Differences between melphalan and nitrogen mustard in the formation and removal of DNA cross-links.

The formation of DNA cross-links is thought to represent the lethal lesion following exposure of cells to bifunctional alkylating agents. Since differences in rates of formation and repair of cross-links may explain differences in activity of these agents, we have studied these events following exposure of L1210 cells to nitrogen mustard (HN2) and melphalan. With the technique of alkaline elution, it was possible to measure cross-linking at doses that result in relatively little cell kill. Following a 30-min exposure to HN2, DNA cross-links increased for 1 to 2 hr and were then removed by a process that was virtually complete in 24 hr. In contrast, following a 30-min exposure to melphalan, cross-link formation increased for 12 hr and removal was much slower than it was for HN2. Comparison of cell survival with cross-linking kinetics suggests that persistence of the cross-links with time is an important factor in determining lethality.

Animals↗