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R R Weichselbaum

Publications and source records attributed to R R Weichselbaum.

At least 127 records · Page 7Linked to original sources
PubMed1994

Patterns of failure of complete responders following high-dose chemotherapy and autologous bone marrow transplantation for metastatic breast cancer: implications for the use of adjuvant radiation therapy.

PURPOSE: To determine the pattern of failure and outcome of patients achieving a complete response following high-dose chemotherapy and autologous bone marrow transplantation for metastatic breast cancer, and to evaluate the use of involved field radiation therapy in this setting. METHODS AND MATERIALS: Thirty-one patients with metastatic breast cancer treated on three successive high-dose chemotherapy and autologous bone marrow transplantation trials between January 1987 and March 1992 who achieved a complete response were evaluated. Twenty-three patients (74.2%) had initially Stage I-II disease. Initial therapy consisted of mastectomy in 19 (74.2%), adjuvant chemotherapy in 19 (61.3%), and adjuvant radiation therapy in 11 (35.5%). All patients underwent induction chemotherapy prior to high-dose intensification. High-dose chemotherapy consisted of cytoxan, thiotepa +/- carmustine. Fourteen patients received radiation therapy prior to (7) or following the high-dose chemotherapy (7) with either the intent to palliate a symptomatic disease site (4) or to attain/maintain a complete response (10). The four palliatively treated sites received 30 Gy in 3.0 Gy fractions, the sites treated definitively received a mean dose of 43.9 Gy (range, 18-64.8 Gy) in 1.5-2.0 Gy fractions. Seventy-two disease sites were present in the 31 patients. The most common sites involved were nodal (23), bone (14), and chest wall/breast (11). Nineteen sites were bulky (> 2 cm in size). Twenty-three sites were irradiated (19 definitively, 4 palliatively). Median follow-up was 18 months (range, 2-49 months). RESULTS: Twenty (64.5%) of the 31 patients relapsed. Eleven of the 17 patients not receiving radiation failed. Seven (63.6%) failed first solely in sites of previous disease involvement and four (36.4%) failed in new sites. This failure pattern was reversed in the patients receiving radiation therapy. Nine of the 14 (64.3%) patients relapsed. Two (22.2%) failed solely in old sites and six (66.7%) solely in new sites. One patient (11.1%) failed simultaneously in both old and new sites. Patients receiving radiation therapy had a similar 2-year actuarial disease-free survival compared to those not treated with radiation (28.3% vs. 32.1%) (p = 0.14). However, patients with less than three sites of disease had a better disease-free survival at 2 years with the addition of radiation therapy (30.0% vs. 17.6%) (p = 0.03). Patients with locoregional disease only had a lower rate of local failure (one out of four vs. three out of five) and a longer mean time to any failure (4.0 months vs. 17.5 months) with the addition of radiation therapy. Of the 72 sites identified, 59 (81.9%) were amenable to radiation therapy either prior to or following the transplant. The use of radiation therapy resulted in a borderline significant improvement in 2-year actuarial control of all sites (82.4% vs. 64.3%) (p = 0.09) as well as of bulky sites (80.0% vs. 51.4%) (p = 0.08). Excluding the four sites treated with palliative intent only, the 2-year actuarial local control of the irradiated sites was 92.8%. None of the 14 treated patients experienced untoward sequelae. CONCLUSION: The predominant site of initial failure in patients with metastatic breast cancer achieving a complete response following high-dose chemotherapy and autologous bone marrow transplantation is in sites of previous disease involvement. Radiation therapy given in conjunction with the high-dose chemotherapy is capable of improving the control of these sites, the majority of which are amenable to treatment with radiation therapy. Our data suggests that patients with less than three sites of disease, bulky disease, and locoregional disease only should be considered for radiation therapy in addition to high-dose chemotherapy.

Adult↗
PubMed1994

Radiation induction of immediate early genes: effectors of the radiation-stress response.

Recent studies have demonstrated that the early response genes c-jun, Egr-1, c-fos, and NF kappa B are induced following exposure of mammalian cells to ionizing radiation. We propose that the products of these early response genes regulate downstream genes that are important in the adaptation of cells and tissues to radiation-induced stress. Potential downstream targets include cytokine and growth factor genes as well as deoxyribonucleic acid (DNA) repair genes. Early response gene products may also regulate cell cycle progression following cellular x-irradiation. Signal transduction pathways that allow cells to adapt to radiation may provide molecular targets to modify tumor and normal responses to radiotherapy.

Animals↗
PubMed1994

Gene therapy targeted by radiation preferentially radiosensitizes tumor cells.

Transcriptional regulation of the promoter/enhancer region of the Egr-1 gene is activated by ionizing radiation. We linked DNA sequences from the promotor region of Egr-1 to a complementary DNA sequence which encodes human tumor necrosis factor (TNF) alpha, a radiosensitizing cytokine. The Egr-TNF construct was transfected into a human cell line of hematopoietic origin, HL525, which was used in an experimental animal system. HL525 (clone 2) cells containing the Egr-TNF construct which exhibits radiation induction of TNF-alpha were injected into human xenografts of the radioresistant human squamous cell carcinoma cell line SQ-20B. Animals treated with radiation and clone 2 demonstrated an increase in tumor cures compared with animals treated with radiation alone or unirradiated animals given injections of clone 2 alone. No increase in local or systemic toxicity was observed in the combined treatment group. The combination of gene therapy and radiation therapy enhances tumor cures without increasing normal tissue toxicity and is a new paradigm for cancer treatment.

Animals↗
PubMed1994

Ketoconazole attenuates radiation-induction of tumor necrosis factor.

PURPOSE: Previous work has demonstrated that inhibitors of phospholipase A2 attenuate ionizing radiation induced arachidonic acid production, protein kinase C activation and prevent subsequent induction of the tumor necrosis factor gene. Because arachidonic acid contributes to radiation-induced tumor necrosis factor expression, we analyzed the effects of agents which alter arachidonate metabolism on the regulation of this gene. METHODS AND MATERIALS: Phospholipase A2 inhibitors quinicrine, bromphenyl bromide, and pentoxyfylline or the inhibitor of lipoxygenase (ketoconazole) or the inhibitor of cyclooxygenase (indomethacin) were added to cell culture 1 h prior to irradiation. RESULTS: Radiation-induced tumor necrosis factor gene expression was attenuated by each of the phospholipase A2 inhibitors (quinicrine, bromphenyl bromide, and pentoxyfylline). Furthermore, ketoconazole attenuated X ray induced tumor necrosis factor gene expression. Conversely, indomethacin enhanced tumor necrosis factor expression following irradiation. CONCLUSION: The finding that radiation-induced tumor necrosis factor gene expression was attenuated by ketoconazole suggests that the lipoxygenase pathway participates in signal transduction preceding tumor necrosis factor induction. Enhancement of tumor necrosis factor expression by indomethacin following irradiation suggests that prostaglandins produced by cyclooxygenase act as negative regulators of tumor necrosis factor expression. Inhibitors of tumor necrosis factor induction ameliorate acute and subacute sequelae of radiotherapy. We propose therefore, that ketoconazole may reduce acute radiation sequelae such as mucositis and esophagitis through a reduction in tumor necrosis factor induction or inhibition of phospholipase A2 in addition to its antifungal activity.

Arachidonic Acid↗
PubMed1994

Radiation oncology.

Radiosurgery has been effective in the treatment of otherwise inaccessible arteriovenous malformations. Perhaps the most exciting developments in dose optimization are in conformal radiation therapy. The use of radiation therapy and concomitant chemotherapy has been shown to improve survival in some patients with carcinoma of the anus, rectum, and head and neck.

Humans↗
PubMed1994

Membrane-derived second messenger regulates x-ray-mediated tumor necrosis factor alpha gene induction.

Cells adapt to adverse environmental conditions through a wide range of responses that are conserved throughout evolution. Physical agents such as ionizing radiation are known to initiate a stress response that is triggered by the recognition of DNA damage. We have identified a signaling pathway involving the activation of phospholipase A2 and protein kinase C in human cells that confers x-ray induction of the tumor necrosis factor alpha gene. Treatment of human cells with ionizing radiation or H2O2 was associated with the production of arachidonic acid. Inhibition of phospholipase A2 abolished radiation-mediated arachidonate production as well as the subsequent activation of protein kinase C and tumor necrosis factor alpha gene expression. These findings demonstrate that ionizing radiation-mediated gene expression in human cells is regulated in part by extranuclear signal transduction. One practical application of phospholipase A2 inhibitors is to ameliorate the adverse effects of radiotherapy associated with tumor necrosis factor alpha production.

Amino Acid Sequence↗
PubMed1994

Time-dose relationship for local tumor control following alternate week concomitant radiation and chemotherapy of advanced head and neck cancer.

PURPOSE: To analyze the time-dose relationship for local control of disease in patients with advanced head and neck neoplasms enrolled in two sequential Phase I dose escalation studies in which concomitant chemotherapy and radiotherapy were delivered on an alternate week schedule (i.e., 1 week of concomitant therapy alternated with 1 week of rest). METHODS AND MATERIALS: From 1986-1988, 65 patients were enrolled in two Phase I clinical trials. In trial one, 5-fluorouracil and hydroxyurea were administered concomitantly with radiation on an alternate week schedule (39 pts). In trial two, cisplatin was added to 5-fluorouracil and hydroxyurea (26 pts). Fifty-seven patients were evaluable for local control, including 26 patients who had failed prior local therapy and were retreated (group A), and 31 patients who had received no prior local therapy (group B). The median dose of RT and the median duration of therapy were 59.7 Gy and 12 weeks for group A, and 70.2 Gy and 14 weeks for group B, respectively. The biological effective dose of radiation therapy (RT) was calculated using the equation based on the linear quadratic model as proposed by J. Fowler. Univariate and multivariate logistic regression analyses were performed to evaluate prognostic factors for local control. RESULTS: Six of 26 patients in group A and 30 of 31 patients in group B had local control of disease. The 2-year Kaplan-Meier local failure rates were 84% for group A and 4% for group B, respectively. Despite the doubling of treatment duration compared to conventional daily radiotherapy and the low biological equivalent dose calculated (median biological equivalent dose for patients with local control of disease were 50.3 Gy and 48.8 Gy in groups A and B, respectively), local control was achieved in 5/17 patients in group A and 30/31 patients in group B who received RT dose of 59.4 Gy or higher. In multivariate logistic regression analysis, the only significant predictor for local control of disease was RT dose (p = 0.004). Treatment duration, chemotherapy dose intensities, age, and performance status were not significant variables. Decreasing the RT dose by 10 Gy would increase the rate of local failure by 24%. CONCLUSION: Our data suggest that prolongation of treatment duration to twice the normal duration of conventional once-a-day radiotherapy does not result in loss of local control when aggressive cell-cycle specific chemotherapy is given concomitantly with radiotherapy. The usual time-dose relationship based on RT alone does not appear to be applicable when concomitant chemotherapy is added. The clinical significance of biological equivalent dose calculation based on radiotherapy alone is unclear when chemotherapy is given with radiation.

Adult↗
PubMed1994

Intensified concomitant chemoradiotherapy with and without filgrastim for poor-prognosis head and neck cancer.

PURPOSE: We previously demonstrated high locoregional control rates in patients with poor-prognosis head and neck cancer using fluorouracil (5-FU), hydroxyurea (HU), and concomitant radiotherapy (FHX). In two trials reported here, we added cisplatin with and without granulocyte colony-stimulating factor (G-CSF) to 5-FU, HU, and concomitant radiotherapy. PATIENTS AND METHODS: Eligible patients had failed to respond to prior local therapy (group 1); previously untreated patients with unresectable and/or metastatic disease and a projected 2-year survival rate less than 10% were also eligible (group 2). Chemoradiotherapy consisted of 1.8 to 2.0 Gy on days 1 to 5 with simultaneous infusional 5-FU at 800 mg/m2/d and HU administered every 12 hours for 11 doses at escalating doses. Cisplatin was administered at 100 mg/m2 during every other cycle. Cycles were repeated every 14 days until completion of radiotherapy. In study 2, G-CSF was added on days 6 to 13 at 5 micrograms/kg/d. RESULTS: Acute and cumulative myelosuppression limited the feasibility of adding cisplatin to FHX without G-CSF. G-CSF allowed for escalation of HU to 1 g orally every 12 hours without dose-limiting acute toxicity during cycles 1 and 2. Dose-limiting cumulative toxicity consisted of severe or life-threatening myelosuppression and mucositis. To decrease total treatment duration and, thus, cumulative toxicity, a hyperfractionated radiation therapy schedule was investigated using the established chemotherapy doses with 1.5 Gy twice daily on days 1 to 5 (75 Gy over five treatment cycles). No increase in acute toxicities was seen; cumulative toxicities remained frequently severe or life-threatening. Thirty-eight of 45 assessable patients responded. The median survival duration was 12 months for both groups. Median time to treatment failure was 8 months for group 1 and has not been reached for group 2. At 1 year, local control rates were 74% and 91% for groups 1 and 2, respectively. CONCLUSION: The addition of cisplatin to 5-FU, HU, and concomitant radiotherapy is feasible using G-CSF. The high locoregional control rate and failure-free interval justify further investigation of this regimen in previously untreated patients.

Adult↗
PubMed1994

The role of intracellular calcium in the cellular response to ionizing radiation.

Calcium is required as a cofactor by primer recognition proteins involved in DNA synthesis and by protein kinase C (PKC), which is activated by ionizing radiation. Because these processes may be involved in radiation-mediated regulation of the progression of cells through the phases of the cell cycle, we studied the effects of the intracellular Ca2+ chelator, acetoxymethyl-1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (AM-BAPTA), on PKC activation, expression of c-jun and Gadd45 and distribution of cells in the phases of the cell cycle after irradiation. AM-BAPTA prevented ionizing-radiation-induced activation of PKC and expression of c-jun in cells of human tumor cell lines. Conversely, calcium chelation had no effect on X-ray-induced expression of the Gadd45 gene. To determine whether changes in the intracellular Ca2+ concentration ([Ca2+]i) occurred during irradiation, we measured [Ca2+]i in single cells using fura-2-based microfluorimetry. There was no increase in [Ca2+]i during or after irradiation of cells of the human tumor cell lines RIT-3, SQ-20B or HL-60 or normal human fibroblast strain IMR-90. The percentage of human tumor cells crossing the G1/S-phase border was reduced by pretreatment with AM-BAPTA. These data indicate that calcium is required for ionizing radiation-induced cell cycle regulation and PKC activation, but that increases in [Ca2+]i do not occur in cells of the cell lines irradiated in this study.

Amino Acid Sequence↗
PubMed1993

Chromosome changes characterizing in vitro response to radiation in human squamous cell carcinoma lines.

We have analyzed the karyotypes of a series of 16 cell lines derived from human squamous cell carcinomas of the head and neck. When the cell lines were grouped according to their in vitro response to radiation, it was observed that some recurrent chromosomal changes occurred with differing frequencies between groups. Radiation resistance was associated with clusters of breakpoints in bands 1p22, 3p21, and 8p11.2 and deletion of distal 14q, while relative radiation sensitivity was associated with a high frequency of breakpoints in 11q13 and duplication of distal 14q. The regions identified point to the possible locations of genes involved in the response to radiation and could provide a series of markers with which to predict response to radiation therapy.

Carcinoma, Squamous Cell↗
PubMed1993

p53 mutation does not correlate with radiosensitivity in 24 head and neck cancer cell lines.

The molecular basis of tumor response to therapeutic radiation is poorly understood. Recent evidence suggests the p53 tumor suppressor gene may be involved in production of the G1 arrest seen following DNA damage by X-irradiation. It has further been proposed that tumor cells lacking the p53 checkpoint function are likely to be more sensitive to cell killing by X-irradiation because these cells enter S phase despite unrepaired DNA damage. We tested the hypothesis that tumor cells with p53 mutations are more radiosensitive by correlating the in vitro surviving fraction at 2 Gy with the mutational status of 24 head and neck squamous cell cancer cell lines. p53 mutations were present in 15 of 24 (63%) of tumors; all were homozygous changes occurring within exons 5-9. The surviving fraction at 2 Gy for the group with mutations was 0.568 compared to 0.507 for tumors without mutations (P = 0.28, Mann-Whitney test). Furthermore, no association between radiosensitivity and mutational type, codon location, or predicted amino acid alteration was noted. Our data do not support the hypothesis that p53 gene alteration predisposes tumor cells to increased cell killing via radiation.

Carcinoma, Squamous Cell↗
PubMed1993

Footprinting of individual tumors and their variants by constitutive cytokine expression patterns.

We have examined the cytokine mRNA expression profile of six different human cell lines derived from Ewing sarcomas using polymerase chain reaction and found each to constitutively express a characteristic pattern. Furthermore, each cell line differed in the levels of secreted cytokines. We also analyzed the expression of several cytokines in murine UV-induced sarcomas and their heritably stable progressive variants. Each murine tumor also constitutively expressed a large number of cytokines, and in some cases, the more malignant variants differed from their parental tumors. These results demonstrate that tumors of the same type, and even in the same lineage, can have distinct cytokine expression and/or secretion profiles. Some cytokines may stimulate tumor growth while others may have antitumor effects. Cytokine therapy may be tailored depending upon the cytokine profile of the individual malignancy.

Animals↗
PubMed1993

Radiation signaling mediated by Jun activation following dissociation from a cell type-specific repressor.

The promoter regions of several radiation-inducible genes contain AP-1 cis-acting regulatory elements that are dependent upon protein kinase C signaling. We analyzed nuclear protein from irradiated human tumor cell lines for binding to the AP-1 consensus sequence. The increase in nuclear protein binding following irradiation was specific for the AP-1 sequence and was reduced by antibodies to c-Jun and c-Fos. The AP-1 DNA binding sequence was found to regulate transcription in irradiated cells and mutation of the AP-1 site within the c-jun promoter abolished transcriptional induction by radiation. The gene encoding the chimeric transcription factor Gal4-Jun5-253, which includes the DNA binding region of Gal4 and the transcriptional regulatory region of c-Jun, was cotransfected with the reporter plasmid with Gal4 binding sequences (G5B-CAT). Transfection of RIT-3 and HeLa cells revealed that the regulatory region of Jun was sufficient to activate transcription following irradiation. Conversely, Hep G2 cells, which do not contain the cell type-specific Jun repressor, were not responsive to radiation-induced Jun activation. The c-Jun repressor was found to regulate Jun activation by experiments using the expression vector CMV-jun, which competes for Jun inhibitor and eliminates radiation-induction of Jun. We propose transcription factor dissociation from inhibitor proteins may participate in the initiation of cellular responses to ionizing radiation.

Chloramphenicol O-Acetyltransferase↗
PubMed1993

Head and neck cancer.

Explore the source record for details and available documents.

Carcinoma, Squamous Cell↗
PubMed1993

Locoregionally advanced paranasal sinus carcinoma. Favorable survival with multimodality therapy.

To determine the efficacy of multimodality treatment for stage III and IV, advanced paranasal carcinoma, we have retrospectively reviewed local control rate and disease-free survival in patients treated at the University of Chicago (Ill). Twelve consecutive patients with stage III or IV, newly diagnosed paranasal sinus carcinoma treated between 1984 and 1991 were included in this study. Multimodality therapy was composed of a sequence of fluorouracil-cisplatin-based neoadjuvant chemotherapy (in 12 of 12 patients) followed by standard surgical resection (11 of 12 patients) and radiotherapy (12 of 12 patients, 45 to 73 Gy) with or without concomitant chemotherapy. Eleven patients (92%) are currently alive and free of disease, with a median follow-up of 55 months (range, 13 to 105 months). One patient died of persistent disease. Failure was attributed to incomplete surgical resection. There was only one major irreversible treatment complication (cisplatin ototoxic reaction). Our preliminary data suggest improved local control and survival with multimodality therapy that includes systemic neoadjuvant chemotherapy and standard tumor resection in patients with advanced paranasal sinus carcinoma. These results are superior to the reported 40% survival with bimodal therapy and are better than those achieved in our institution for other head and neck primaries with the same treatment regimens.

Adult↗