Biomedical subjects

R Weichselbaum

Publications and source records attributed to R Weichselbaum.

At least 73 records · Page 4Linked to original sources

PubMed1992

cis-Diamminedichloroplatinum(II) induces c-jun expression in human myeloid leukemia cells: potential involvement of a protein kinase C-dependent signaling pathway.

cis-Diamminedichloroplatinum(II) (CDDP) is a chemotherapeutic agent known to inhibit DNA, RNA, and protein synthesis. The cytotoxicity of this drug is thought to result from the formation of DNA intrastrand cross-links. The present work demonstrates that treatment of human myeloid leukemia cells (HL-60, U-937, and KG-1) with CDDP is associated with increased expression of the c-jun gene and that this effect is related to activation by a transcriptional mechanism. The results also demonstrate that treatment with CDDP is associated with increases in protein kinase C (PKC) activity. Furthermore, the finding that pretreatment with H7, an inhibitor of PKC, abrogates the effect of CDDP on c-jun expression suggested the involvement of PKC in this process. Down-regulation of PKC by prolonged pretreatment with 12-O-tetradecanoylphorbol-13-acetate was also associated with inhibition of CDDP-induced c-jun expression. The results further demonstrate that there is a temporal relationship between the CDDP-induced increase in c-jun expression and the occurrence of internucleosomal DNA cleavage characteristic of programmed cell death. These findings suggest that c-jun may be involved in the cellular response to DNA-damaging agents, such as CDDP, and that this effect may be mediated by a PKC-dependent pathway.

Actins↗

PubMed1992

Protection against AZT-induced mutagenesis at the HGPRT locus in a human cell line by WR-151326.

The anti-AIDS agent, AZT (3'-azido-3'-deoxythymidine), is mutagenic in a cultured human hepatoma cell line designated HepG2 at the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) locus. Using an exposure time of 3 hr, the number of mutants per 10(6) surviving cells increased as a function of AZT dose from 125 to 520. Chinese hamster ovary cells, in contrast, are not affected with respect to this endpoint when similar concentrations of AZT are used (i.e., 0.1 to 10 mg/ml). The aminothiol WR-151326 [3-(3-methylaminopropylamino) propanethiol dihydrochloride] was evaluated as a possible antimutagen for use with AZT. At a concentration of 4 mM, WR-151326 was added either concomitantly or following exposure of HepG2 cells to a 5 mg/ml concentration of AZT. Regardless of the treatment condition, WR-151326 was effective in reducing the mutagenic effects of AZT by about a factor of 2. Correcting for background mutations, the mutation frequencies determined were: AZT only for 3 hr, 110 x 10(-6) (S.E.M. +/- 6.0 x 10(-6)); AZT together with WR-151326 for 3 hr, 57 x 10(-6) (S.E.M. +/- 3.0 x 10(-6)); and AZT for 3 hr followed by WR-151326 for 3 hr, 68 x 10(-6) (S.E.M. +/- 5.0 x 10(-6)). This study demonstrates that AZT is mutagenic to a cell line of human origin and that WR-151326 can protect against this mutagenic process.

Humans↗

PubMed1992

Down-regulation of cell cycle control genes by ionizing radiation.

The cellular responses to ionizing radiation include growth arrest, DNA repair, and lethality. However, little is known about the signaling events responsible for these responses. The present studies have examined the effects of ionizing radiation on the expression of genes involved in cell cycle control. The results demonstrate that the treatment of asynchronous cells with 20 Gy ionizing radiation is associated with transient down-regulation of the cdc2, cyclin A, cyclin B, and cdc25 genes. This effect was associated with transient induction of the c-jun gene. RNA stability studies demonstrate that the down-regulation of gene expression following ionizing radiation exposure is at least in part due to a decrease in transcript half-life. Other studies were performed with elutriated cells enriched for populations in G1 and S phases. Treatment of G1 enriched cell populations with 10 Gy resulted in a selective decrease in cyclin B mRNA levels, whereas this effect on cyclin B expression was less pronounced at 5 Gy and undetectable at 1 Gy. Similar results were obtained with S phase enriched cells. Taken together with clonogenic survival studies, these findings indicate that down-regulation of cell cycle control gene expression is associated with lethality, whereas lower doses of ionizing radiation have little, if any, effect on the expression of these genes. The findings also suggest that DNA damage may activate signaling events which regulate expression of cell cycle control genes.

CDC2 Protein Kinase↗

PubMed1991

Vascular events in patients receiving high-dose infusional 5-fluorouracil-based chemotherapy: the University of Chicago experience.

In a retrospective review, 22 of a total of 244 patients (9%) patients with head and neck or gastrointestinal cancer who were treated with infusional 5-fluorouracil (5-FU)-based chemotherapy regimens experienced thrombotic vascular events. These events occurred concurrently with treatment or several months following the completion of therapy and consisted mainly of cardiac arrhythmias, myocardial infarction, sudden death, and thromboembolism. The temporal relationship of these vascular events to the time of treatment suggests that infusional 5-FU may have been the underlying cause.

Adult↗

PubMed1991

Ionizing radiation induces expression and binding activity of the nuclear factor kappa B.

Recent studies have demonstrated that treatment of mammalian cells with ionizing radiation is associated with activation of gene expression. Although the signal transduction pathways stimulated by ionizing radiation remain unclear, our previous findings indicate that radiation induces specific genes at the transcriptional level. The present work has examined the effects of ionizing radiation on the transcription factor NF-kappa B. The results demonstrate that ionizing radiation activates DNA binding of nuclear factor (NF)kappa B. This effect was detectable at 2 grays (Gy) and reached a maximum at 5-20 Gy. At a dose of 20 Gy, the increase in NF-kappa B binding activity was maximal at 2-4 h and then declined to pretreatment levels. The results also demonstrate that ionizing radiation transiently increases NF-kappa B mRNA levels. However, the finding that induction of NF-kappa B binding to DNA occurs in the presence of cycloheximide indicates that ionizing radiation activates preexisting NF-kappa B protein. NF-kappa B exists as a cytoplasmic protein before activation. Thus, our results suggest that ionizing radiation induces transduction pathways which include cytoplasmic signaling events.

Base Sequence↗

PubMed1991

Sex or survival: trade-offs between quality and quantity of life.

Patients with localized prostate cancer may be treated with either surgery (radical prostatectomy) or radiotherapy. Although controversial, many physicians believe that surgery offers a higher survival rate. However, the surgical treatment may also produce a higher rate of sexual impotency. Our study assessed how men value survival and sexual potency when asked to trade off one for the other. Using the treatment-choice technique, we interviewed 50 men aged 45 to 70 years without known prostate cancer. At hypothetical rates of survival (90% at 5 years for surgery) and impotency (90% for surgery and 40% for radiotherapy) representing published estimates, 32% of respondents were unwilling to trade off any survival, but 68% were willing to trade off a 10% or greater advantage in 5-year survival (by choosing radiotherapy) to maintain sexual potency. The median 5-year survival traded off was 10% (range, 0% to 80%). Willingness to trade off survival for sexual potency was significantly related to level of education, but not to age, interest in sex, frequency of sexual intercourse, or ability to achieve erection. We conclude that some men may choose treatment with lower long-term survival to increase their chance of remaining sexually potent. Because these men may be difficult to identify in clinical practice, physicians should thoroughly discuss both surgery and radiotherapy options with patients who have localized prostate cancer.

Aged↗

PubMed1990

Estimates of dose to intraperitoneal micrometastases from alpha and beta emitters in radioimmunotherapy.

Intraperitoneal metastases from ovarian and other gynecologic tumors are a significant source of treatment failure. In recent years, investigators have used radiolabeled monoclonal antibodies to treat this disease with encouraging results. We have developed a dose calculational technique which generates isodose distributions from intraperitoneally administered alpha and beta particle emitters. In this study we apply the calculations to tissue biopsy samples to determine the adequacy of dose to ovarian micrometastases. Tissue samples from staging biopsies at the time of surgical debulking are scanned to identify small metastases. The patient population studied comprised those with ovarian disease who based on clinical criteria would be considered good candidates for intraperitoneal radioimmunotherapy. The regions of interest (which include the tumor and surface of the peritoneum) are digitized and tumor volumes are contoured. Dose calculations based on the modeling of intraperitoneally administered antibodies radiolabeled with various isotopes is performed and the minimum dose to tumor and normal tissue is assessed. For example, with tumor uptake of 0.1% injected dose per gram of tissue, the surface tumor dose from alpha emitters is up to 45,000 rads. The dose falls to 6000 rads at approximately 40 microns from the peritoneal surface. The surface dose from 20 mCi 90Y administered in 1500 ml saline is up to 10,000 rads, and at a 2-mm depth, approximately 2000 rads. From our calculation dose distribution from radioimmunotherapy varies as a function of physical characteristics of the isotope, absorption of activity, and amount of disease being treated.

Alpha Particles↗

PubMed1990

Is pelvic irradiation necessary in stage III1A Hodgkin's disease?

Eighteen patients with pathologic Stage (PS) III1A Hodgkin's disease were treated with mantle and para-aortic field radiation therapy alone between 1973 and 1988. The median follow-up time is 84 months (range 20-174 months). The 5-year survival and relapse-free survival rates are 76 and 82%. Six patients had extensive splenic involvement or bulky mediastinal adenopathy, and three have relapsed and are dead of disease. Of the other 12 patients, only one has had recurrence of disease and died. Patients with PS III1A Hodgkin's disease are good candidates for mantle and para-aortic radiation therapy only, provided that they do not have extensive splenic involvement or large mediastinal adenopathy.

Adult↗

PubMed1988

Extended mantle radiation therapy for pathologic stage I and II Hodgkin's disease.

Between 1968 and 1983, 135 patients with pathologic stage (PS) I and II Hodgkin's disease were treated with extended mantle radiation technique (EMRT) at Michael Reese Hospital and the University of Chicago Center for Radiation Therapy. EMRT combines both standard mantle and para-aorta fields (M-PA) in one port. Actuarial disease-free survival at 5 and 10 years was 82.5%. Actuarial overall survival was 96% and 83% at 5 and 10 years, respectively. Acute complications were evaluated in 112 patients available for analysis. Severe nausea and vomiting occurred in 13%, weight loss of greater than 10% of body weight in 19%, and acute hematologic toxicity in 4% of patients. Bone marrow suppression was transient and did not interfere with subsequent delivery of salvage treatment with either chemotherapy or radiation therapy in 22 patients who relapsed. The cost of EMRT is 40% lower than the cost of treatment with M-PA. The median treatment time was 38 days, 33% less than the 56 days for M-PA field assuming no interruptions. These results suggest that the EMT is a safe and effective treatment tolerated by most patients. The advantages of this method are eliminating the possibility of technical error of matching between mantle and para-aortic field, decreasing overall treatment time, and reducing the cost.

Adult↗

PubMed1988

Radiotherapy of the resected mandible following stainless steel plate fixation.

There is general concern among otolaryngologists that irradiation of a stainless steel prosthesis used in mandibular reconstruction may cause irradiation overdosage to adjacent tissues. A tissue-equivalent plastic/steel model, simulating the characteristics of a stainless steel, reconstructed mandible, was irradiated and measurements were made with a parallel plate ionization chamber. The results of our measurements show that irradiation of an implanted steel plate results in an overdosage (120%) "in front" and an underdosage (80%) "behind" the steel plate. The regions of overdosage and underdosage are 2 to 3 mm thick. The overall dose modification is greatly reduced when two opposing fields are used. We conclude that irradiation of a stainless steel, reconstructed mandible with a 6-mV photon beam through opposing fields does not significantly alter the amount of radiation delivered to surrounding tissues.

Bone Plates↗

PubMed1987

Prophylactic cranial irradiation in adenocarcinoma of the lung. A possible role.

Seventy-eight patients with modified Stage II or Stage IIIM0 adenocarcinoma of the lung were evaluated retrospectively with regard to the impact of prophylactic cranial irradiation (PCI) (30 Gy in 15 fractions) in preventing central nervous system (CNS) metastases. Twenty patients received PCI and 58 did not. There were no significant differences between these groups with respect to age, sex, stage, or median survival (17.4 months with PCI versus 16.9 months without PCI; P = 0.6). One (5%) of 20 patients receiving PCI developed CNS metastases, compared with 14 (24%) of 58 patients not receiving PCI (P = 0.06). The time from diagnosis to development of CNS metastases and survival after CNS involvement was 51 weeks and 14 weeks, respectively, for the patient who received PCI; and a median time of 50 weeks and 26 weeks, respectively, for the patients not receiving PCI. In nine (64%) of the 14 non-PCI patients the CNS was the first and only site of relapse. A Cox regression analysis demonstrated that nodal involvement was significantly associated with an increased risk of CNS metastases. These data suggest that PCI may decrease the incidence of CNS metastases, and that it may be beneficial in the management of patients with N1 or N2 disease.

Adenocarcinoma↗

PubMed1986

Chromosome 13 homozygosity in osteosarcoma without retinoblastoma.

We provide evidence that some human osteosarcomas arise subsequent to the development of homozygosity at loci on the long arm of chromosome 13. The resulting chromosome 13q homozygosity allows the phenotypic expression of any recessive allele on that chromosome. Clinical evidence suggests that it is the retinoblastoma locus within 13q14 that is involved in the formation of these bone tumors.

Alleles↗

PubMed1984

Chromosome 13 restriction fragment length polymorphisms.

The gene locus for hereditary retinoblastoma is on human chromosome 13, band q14. With this gene localization in mind, we cloned DNA fragments from this chromosome. Three of the fragments identify restriction fragment length polymorphisms. These three fragments are from the region 13q12-13q22, the chromosome region which contains the retinoblastoma locus. We expect that these restriction fragment length polymorphisms will be linked to the retinoblastoma locus, and that they will serve in certain retinoblastoma families as predictors of retinoblastoma gene carriers. They will also be useful in studies of other gene loci thought to be on chromosome 13.

Alleles↗

PubMed1984

Cellular X-ray repair parameters of early passage squamous cell carcinoma lines derived from patients with known responses to radiotherapy.

We have investigated X-ray survival parameters and repair of potentially lethal damage ( PLDR ) in ten early passage squamous cell carcinoma cell lines derived from patients who were biopsied before initiation of radiotherapy or after radiation therapy failure. Radiosensitivity (D0) ranged from 1.07 to 1.93 (Gy), extrapolation numbers (-n) from 1.17 to 2.14 and PLD recovery at 24 h from 1.4 to 20.3. Despite significant differences in these parameters amongst the cell lines, a firm correlation between radiocurability and any individual radiobiological parameter could not be established. Our data suggest that the mechanisms associated with radioresistance are complex and that any single radiobiological parameter may not predict clinical success or failure.

Carcinoma, Squamous Cell↗

PubMed1984

Lethal effects of 1-beta-D-arabinofuranosylcytosine incorporation into deoxyribonucleic acid during ultraviolet repair.

We have previously demonstrated that 1-beta-D-arabinofuranosylcytosine (ara-C) incorporates into leukemic cell DNA and that the extent of this incorporation correlates significantly with loss of clonogenic survival. These studies have now been extended by monitoring the incorporation of ara-C in DNA undergoing repair of UV-induced damage. The present studies have been performed using human foreskin diploid fibroblasts that undergo density-dependent growth arrest. The results demonstrate that ara-C incorporates specifically into DNA undergoing repair of damage by UV light. The extent of ara-C incorporation in AG1522 DNA during UV repair correlates significantly (p less than 0.0006) with cell lethality. These findings confirm that incorporation of ara-C into DNA undergoing either semiconservative or unscheduled DNA synthesis results in lethal cellular events. The present findings may provide the experimental basis for the development of new therapeutic approaches using ara-C in combination with agents that damage DNA.

Cell Survival↗

PubMed1983

The effect of aging on the density and distribution of oral mucosal Langerhans cells.

Previous studies localizing the Langerhans cells in the hamster cheek pouch by ATPase staining have shown these cells to be distributed in a nonrandom pattern. The Langerhans cells have been found in both focal and interfocal arrangements. In this study we utilized two groups, Group 1 (six animals), was 5-6 weeks old, and Group 2 (six animals), was 78-80 weeks old. The Langerhans cells were stained for ATPase, following the epidermal stripping of the cheek pouch with 1% glacial acetic acid. The number of Langerhans was statistically decreased interfocally and there was a decrease in the number of focal aggregations, while there was a concomitant increase in the number of Langerhans cells in each unit. These alterations in the density and distribution of the Langerhans cells may suggest a lowering of the immune response, and increase susceptibility to irritants and carcinogenic agents in the oral cavity.

Adenosine Triphosphatases↗

PubMed1983

Platelet-derived growth factor stimulates bone resorption by monocyte monolayers.

Resorption of devitalized bone particles by monocytes grown in culture was stimulated by platelet-derived growth factor (PDGF) in a dose-dependent manner. Bone resorption in response to PDGF was time-dependent with a significant increase over control cultures evident by 72 hours. These data are the first to demonstrate stimulation of bone resorption by PDGF in a specific cell type known to resorb bone in vivo and in vitro.

Bone Resorption↗

PubMed1983

An epidermoid carcinoma cell line derived from hamster 7,12-dimethylbenz[a]anthracene-induced buccal pouch tumors.

w cell line, HCPC I, was established from an epidermoid carcinoma of the Syrian golden hamster cheek pouch. The carcinoma was induced by applications three times a week of a 0.5% solution of 7,12-dimethylbenz[a]anthracene (DMBA) in heavy mineral oil. The HCPC I cell line has been maintained through 60 passages over 15 months. Electron microscopy of the cell line revealed tonofilaments and desmosomes, thereby confirming its epithelial nature. Presence of keratin in the HCPC I cells was demonstrated by both histochemical and indirect immunofluorescence studies. The population-doubling time of HCPC I, estimated from the exponential growth phase of the growth curve established for the cell line, was 12 hours. The plating efficiency of the cell line was estimated at 35%. When an inoculum size of HCPC I, numbering 2.4 X 10(7) cells, was transplanted to the cheek pouch of an immunosuppressed inbred hamster, a papillary tumor, measuring 5 X 1 mm and microscopically diagnosed as a well-differentiated epidermoid carcinoma, developed 1 week post transplantation. Further successful transplantation was achieved with 1.8 X 10(7) HCPC I cells inoculated into the cheek pouch of a nonimmunosuppressed inbred hamster. A raised plaquelike mass, microscopically diagnosed as invasive epidermoid carcinoma, developed in the hamster cheek pouch 5 weeks post transplantation. Furthermore, 5 nonimmunosuppressed hamsters that received 1 X 10(6) HCPC I cells on their cheek pouches developed tumors microscopically diagnosed as anaplastic carcinomas 14 weeks post transplantation. The largest of these tumors measured 2 cm in diameter.

9,10-Dimethyl-1,2-benzanthracene↗