Biomedical subjects

R R Weichselbaum

Publications and source records attributed to R R Weichselbaum.

At least 199 records · Page 11Linked to original sources

PubMed1990

Radiobiological characterization of head and neck and sarcoma cells derived from patients prior to radiotherapy.

The radiobiological parameters of 33 tumor cell lines were studied in biopsy samples obtained from patients prior to radiotherapy. Epithelial tumor cells derived from head and neck cancer patients were more radioresistant than tumor cell lines derived from patients with sarcoma regardless of method of analysis. The presence of radioresistant tumor cell lines was associated with local failure in some patients. However, the presence of radiosensitive tumor cells did not necessarily predict local control. Our data suggest radiocurability is complex and inherent radiobiological parameters of tumor cells may be only one factor in radiotherapy outcome.

Carcinoma, Squamous Cell↗

PubMed1990

Ionizing radiation regulates expression of the c-jun protooncogene.

There is little known about the regulation of gene expression by ionizing radiation exposure. The present studies demonstrate transcriptional activation of a mammalian gene, the c-jun protooncogene, by x-rays. The c-jun gene encodes a component of the AP-1 protein complex and is important in early signaling events involved in various cellular functions. The increase in c-jun transcripts by ionizing radiation was time- and dose-dependent as determined by Northern blot analysis. Transcriptional run-on analysis demonstrated that ionizing radiation stimulates the rate of c-jun gene transcription. Furthermore, the half-life of c-jun RNA was prolonged in the absence of protein synthesis. These findings indicate that the increase in c-jun RNA observed after irradiation is regulated by transcriptional and posttranscriptional mechanisms. Moreover, the induction of c-jun by ionizing radiation was associated with an inverse dose rate effect in that decreasing the dose rate resulted in increased c-jun expression. The present results similarly demonstrate that ionizing radiation increases levels of c-fos transcripts as well as that of jun-B, another member of the jun family. Taken together, these results suggest a role for induction of early response genes in the pathophysiologic effects of ionizing radiation.

Blotting, Northern↗

PubMed1990

Radioresistant derivatives of an X-ray-sensitive CHO cell line exhibit distinct patterns of sensitivity to DNA-damaging agents.

X-ray-resistant clones of the xrs-5 radiosensitive derivative of the CHO-K1 cell line were generated by transfecting cosmid library DNAs into the X-ray-sensitive cells. Transfectants were selected for both a dominant drug resistance marker present in the vector sequences and return to wild-type survival. Three cell lines were isolated which show X-ray survival characteristics similar to parental K1 cells. These revertant lines were examined for their cross-sensitivity to cis-diamminedichloroplatinum(II) (cisplatin) and bleomycin. Although these cell lines reverted with regard to X-ray sensitivity, they retained their sensitivity to cisplatin. Furthermore, changes in bleomycin and X-ray sensitivity did not correlate. There was a positive correlation between return to wild-type radiosensitivity and an increase in the rate of DNA double-strand break rejoining.

Animals↗

PubMed1990

Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for locally advanced head and neck cancer: a clinical and pharmacologic analysis.

Both cisplatin and leucovorin (LV) interact with fluorouracil (5-FU) by increasing intracellular reduced folate levels and thereby the inhibition of thymidylate synthase. Therefore, the addition of LV to cisplatin and 5-FU (PFL) may increase the activity of that combination in head and neck cancer. We treated 31 patients with locally advanced head and neck cancer with two cycles of neoadjuvant PFL consisting of 100 mg/m2 of cisplatin on day 1 followed by a 5-day continuous infusion of 5-FU at 1,000 mg/m2/day and oral LV at 100 mg administered every 4 hours during the entire duration of chemotherapy infusion. Two patients died during neoadjuvant chemotherapy of sudden death and sepsis, respectively, and were not evaluated for response. Of 29 evaluable patients, nine had a complete response (CR), 17 had a partial response (PR), and three had stable disease. Toxicities consisted of mild to moderate myelosuppression and moderate to severe mucositis, necessitating reduction of 5-FU on cycle 2 to less than or equal to 80% of the intended dose in 22 of 29 patients. Administration of LV by repeated oral dosing resulted in total reduced folate plasma concentrations of 5.3 (+/- 2.9) and 6.7 (+/- 3.4) mumol on days 2 and 4 of the 5-FU infusion. The sum of 1-LV and its metabolite 5-CH3-tetrahydrofolate exceeded the concentration of d-LV, consistent with selective absorption of the biologically active 1-stereoisomer from the gastrointestinal tract.

Adult↗

PubMed1990

Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors.

Concomitant chemoradiotherapy can be used in order to increase both the local and systemic control of solid tumors. The rationale for its use and experimental data for selected chemotherapy drugs are reviewed. Clinical trials have focused on increasing complete response (CR) and survival rates; in addition, improved quality of life by decreasing the use of conventional surgical procedures is being pursued. Both of these goals may have been achieved for some tumors, most notably for anal cell carcinoma. Improved survival with concomitant chemoradiotherapy has also been shown for patients treated on randomized studies for pancreatic, colorectal, small-cell lung, head and neck, and cervical cancer. These results call for the continued investigation of this approach in the laboratory and in the clinic.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

Palliative radiotherapy.

We have reviewed the role of radiation therapy in the palliative treatment of patients with non-small cell lung cancer. The use of radiation treatment results in effective palliation of chest symptoms such as dyspnea, cough, hemoptysis, and chest pain. In addition, the pain and suffering associated with skeletal and hepatic metastases are effectively alleviated by radiation therapy with minimal morbidity. Devastating neurologic complications can be avoided or alleviated in a great proportion of patients undergoing radiation therapy for cerebral metastases and spinal cord compression. Therefore, radiation therapy is a potent modality in relieving or reducing the suffering of patients with lung cancer. This is also a modality that has wide applicability; very few patients are not suitable candidates for that has wide applicability; very few patients are not suitable candidates for treatment regardless of their performance status. The aim of the treatments should always be prompt intervention using radiation therapy schedules that will minimize treatment time yet produce the desired results in a high proportion of patients. Protracted radiation schedules are not warranted in such patients except in special clinical situations. Palliation with radiation therapy is achieved quite promptly, with minimal side effects and a very small risk of any long-term consequences in patients who have a limited life expectancy.

Bone Neoplasms↗

PubMed1990

Prediction of the radiation sensitivity of human squamous cell carcinoma cells using DNA filter elution.

Radioresistant tumor cells are found in tumor specimens from patients in whom radiotherapy has failed or whose tumors have recurred after therapy. This suggests that inherent cellular radioresistance may in part underlie the failure of radiotherapy, and therefore determination of the presence of resistant cells within a tumor might be a useful predictor of response to radiation therapy. Most standard clonogenic assays of radiation response are time-consuming, and alternative assays of radiation response are being sought. In an earlier publication (J. L. Schwartz et al., Int. J. Radiat. Oncol. Biol. Phys. 15, 907-912, 1988), we reported that radioresistant human tumor cells rejoin DNA double-strand breaks, as measured by DNA neutral filter elution (pH 9.6), faster than more sensitive cell lines. To determine whether DNA elution might have potential as a rapid predictive assay, we examined the relationship between the rate of DNA double-strand break rejoining and radiosensitivity in nine first-passage-after-explant squamous cell carcinomas under conditions that minimized the influence of nontumor and nonclonogenic cells. The frequency of DNA double-strand breaks measured 1 h after irradiation with 100 Gy 60Co gamma rays was used as an estimate of relative rejoining rate. This number is a reflection of both the initial DNA double-strand break frequency and the amount of repair that occurs in 1 h. The relative break frequency was compared to radiosensitivity as measured by standard clonogenic survival assays in later passages (p3-p14) of these same cells. A significant relationship (r = 0.61, P less than 0.01) was found between break frequency measured in first-passage cells and radiosensitivity measured in later passages, suggesting that the neutral elution assay as described here has some promise as a relatively rapid assay of the radiosensitivity of human tumor cells.

Carcinoma, Squamous Cell↗

PubMed1989

Sensitivities of NIH/3T3-derived clonal cell lines to ionizing radiation: significance for gene transfer studies.

Rodent cells are frequently used as recipients in experiments involving gene transfer, isolation, and characterization. The present studies were designed to investigate the clonal responses to ionizing radiation of NIH/3T3 cells subjected to DNA-mediated gene transfer. Radiation sensitivity (D0) values were determined for the parental NIH/3T3 cell strain, six clonal cell lines transfected with DNA from radiation-resistant human tumor cells, and six nontransfected clonal cell lines. The radiation sensitivities of four transfected and two nontransfected clonal cell lines differed significantly from parental NIH/3T3 cells (P less than 0.05). Detailed karyotype analysis of two nontransfected clonal cell lines with differing radiation sensitivities showed variation in chromosomal composition. Specifically, a minute chromosome was observed to segregate consistently (in 49 of 50 metaphases) with the genome of one NIH/3T3 clone (D0 2.07 Gy) and was completely absent (from 50 metaphases) in another NIH/3T3 clone (D0 1.06 Gy). In the parental NIH/3T3 strain (D0 2.02 Gy) 10% of cells (3 of 30 metaphases) had such minute chromosomes. These findings demonstrate that the clonal cellular heterogeneity of NIH/3T3 cells is characterized by genotypic and phenotypic variations which must be considered in the experimental design involving gene transfer and expression.

Animals↗

PubMed1989

Cisplatin, 5-fluorouracil, and high-dose oral leucovorin for advanced head and neck cancer.

Both cisplatin and leucovorin may increase the activity of 5-fluorouracil (5-FU) by increasing the intracellular concentration of reduced folates. Therefore, a Phase I study was conducted in patients with recurrent or metastatic head and neck cancer in which high doses of oral leucovorin were added to the combination of cisplatin and 5-FU. Patients received intravenous cisplatin 100 mg/m2 on day 1, followed by a continuous intravenous infusion of 5-FU at 600 mg/m2/day for 5 days. Leucovorin 50 mg/m2 orally was administered from the start of the cisplatin infusion and then every 6 hours throughout the 5-FU infusion. The dose of 5-FU was increased to 800 mg/m2/day and 1 g/m2/day according to observed toxicity. In a second phase of the study, the dose of leucovorin was increased to 50 mg/m2 orally every 4 hours. Twenty-five patients were registered: 23 had recurrent head and neck cancer after extensive treatment; two had newly diagnosed metastatic disease. The maximum tolerated dose of 5-FU was 800 mg/m2/day with leucovorin administered every 6 hours. Toxicities at that level included mild-to-moderate myelosuppression. Mucositis in the previously irradiated field prevented the further increase of the 5-FU dose to 1 g/m2/day. Identical toxicities were observed when administering 5-FU at 800 mg/m2/day with 50 mg/m2 of leucovorin every 4 hours. Eighteen patients were evaluated for response: one had a pathologic complete response; nine had a partial response (including four who had previously received cisplatin and 5-FU as induction chemotherapy). Eight patients did not respond. The median survival for all 25 patients was 6.5 months. It was concluded that the combination of cisplatin, 5-FU, and leucovorin is active in the treatment of recurrent head and neck cancer. The maximum tolerated dose of 5-FU in previously treated patients is 800 mg/m2/day, with mucositis being the dose-limiting toxicity. Further investigation of this regimen as neoadjuvant chemotherapy in previously untreated patients with locally advanced head and neck cancer is in progress.

Adult↗

PubMed1989

Effect of antisense c-raf-1 on tumorigenicity and radiation sensitivity of a human squamous carcinoma.

Antisense RNA-mediated inhibition of gene expression was used to investigate the biological function of the c-raf-1 gene in a radiation-resistant human squamous carcinoma cell line, SQ-20B. S1 nuclease protection assays revealed that transfection of full-length raf complementary DNA in the antisense orientation (AS) leads to a specific reduction (greater than tenfold) of steady-state levels of the endogenous c-raf-1 sense (S) transcript in SQ-20B cells. In nude mice, the malignant potential of SQ-20B cells transfected with raf (S) was significantly increased relative to that of SQ-20B cells transfected with raf (AS). SQ-20B cells containing transfected raf (S) maintained a radiation-resistant phenotype as compared to those cells harboring the AS version, which appeared to have enhanced radiation sensitivity. These data indicate that the reduced expression of endogenous c-raf-1 is sufficient to modulate the tumorigenicity and the radiation-resistant phenotype of SQ-20B cells, thus implicating c-raf-1 in a pathway important to the genesis of this type of cancer.

Animals↗

PubMed1989

A randomized study of inpatient versus outpatient continuous infusion chemotherapy for patients with locally advanced head and neck cancer.

This study was designed to evaluate the safety, reliability, and patient acceptance of outpatient continuous intravenous infusion (CVI) chemotherapy. Twenty-two patients with locally advanced head and neck cancer received induction chemotherapy with methotrexate, cisplatin and a 5-day CVI of 5-fluorouracil (5-FU). Patients were randomized to receive the 5-FU portion of cycle 1 either by a standard inpatient CVI chemotherapy delivery device (standard pump) or by the Infusor (Baxter Healthcare Corporation, Deerfield, IL), a portable chemotherapy delivery system that provides a constant flow of drug over a period of 24 hours. For cycle 2, patients crossed over to the alternative drug delivery method. Patients receiving chemotherapy via the Infusor could choose to be either inpatients or outpatients. Daily plasma concentrations of 5-FU were determined during the first two cycles of chemotherapy. There was no significant difference in the mean steady state plasma 5-FU levels achieved with either drug delivery method (329.7 +/- 95.8 ng/ml for infusor cycles vs. 352.8 +/- 114.9 ng/ml for standard pump cycles). Clinical toxicities consisted primarily of mucositis for both methods of drug delivery. Eight patients declined to receive CVI chemotherapy as outpatients citing as reasons fear of malfunction of the device, inconvenience of the frequent clinic visits necessitated by daily monitoring of plasma 5-FU concentrations, and restrictions in daily home activities. Eleven patients underwent CVI chemotherapy via Infusor as outpatients. All reported outpatient CVI chemotherapy as convenient and effective and, when eligible, chose it again in subsequent cycles. A comparison of estimated costs revealed reductions in daily costs of +366.00 (+2,200.00 per cycle) for outpatient chemotherapy. Outpatient CVI chemotherapy is a reliable drug delivery method that was accepted by a majority of patients in this study. These factors may help to establish outpatient CVI chemotherapy as a viable alternative to hospitalization.

Ambulatory Care↗

PubMed1989

The transfacial approach for combined anterior craniofacial tumor ablation.

The transfacial approach to the anterior cranial fossa for tumor removal provides for excellent surgical exposure, improved postoperative appearance, and a minimum of complications. The technique is different from previously reported combined craniofacial ablative procedures in that the head and neck surgeon and the neurosurgeon approach the anterior fossa mass through the same facial incision, thus avoiding the need for a separate craniotomy incision. The formation of a vascularized nasofrontal bone flap allows for better wound healing regardless of preoperative and postoperative radiotherapy and/or chemotherapy. This report presents 42 cases in which the transfacial approach was exclusively used in a combined manner to remove nasal, paranasal sinus, and nasopharyngeal neoplasms. The transfacial technique offers a significant advantage over previously described approaches to the anterior skull base.

Facial Bones↗

PubMed1989

Chromosomal sensitivity of lymphocytes from individuals with therapy-related acute nonlymphocytic leukemia.

A small fraction of those individuals exposed to cytotoxic chemotherapy or radiation for the treatment of a primary malignant disease will develop a second malignancy some time later. Although exposure to the cytotoxic agents is believed to be the causative factor, the reason only certain individuals develop the second malignancy is unknown. Some studies have suggested that these individuals might be predisposed to cancer because of an inherent sensitivity to the alkylating agents used in cancer therapy. We have reported that these individuals with therapy-related acute nonlymphocytic leukemia (t-ANLL) have reduced endogenous levels of the repair protein O6-alkylguanine alkyltransferase (AGT). To further investigate the etiology of this disease, alkylation-induced sister-chromatid exchange (SCE) formation in individuals who developed second malignancies, was compared to other patient groups and normal controls. Peripheral blood lymphocytes from patients with (1) t-ANLL, (2) primary forms of acute nonlymphocytic leukemia (ANLL de novo), (3) patients with primary malignancies at risk of developing secondary disease, and (4) unexposed, healthy controls were treated in vitro with N-methyl-N'-nitro-nitrosoguanidine or mitomycin C. Baseline and mutagen-induced frequencies of SCEs were determined. These studies failed to detect any increased sensitivity in those patients who developed second malignancies as compared to controls or patients with de novo forms of the same disease. Also, no correlation between sensitivity to the alkylating agent N-methyl-N'-nitro-nitrosoguanidine and endogenous levels of the AGT repair protein was found. These results suggest that t-ANLL patients are not sensitive to SCE induction by either MNNG or MMC.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗

PubMed1989

An important step in radiation carcinogenesis may be inactivation of cellular genes.

The loss of genetic material may result in a predisposition to malignant disease. The best studied example is retinoblastoma where deletion or transcriptional inactivation of a specific gene is associated with the development of the tumor. When hereditary retinoblastoma patients are treated with radiation, the incidence of osteosarcoma within the treatment field is extremely high compared to other cancer patients treated with radiotherapy. These data, together with cytogenetic and molecular data on the development of acute non-lymphocytic leukemia secondary to radiotherapy and chemotherapy treatment suggest that radiation-induced deletions of critical DNA sequences may be an important event in radiation carcinogenesis. Therefore, we propose that radiation-induced tumors may result from deletion of tissue specific regulatory genes. Base alterations caused by radiation in dominantly transforming oncogenes may also contribute to radiation carcinogenesis.

Genes↗

PubMed1989

Radiation therapy for pathologic stage III Hodgkin's disease with and without chemotherapy.

Ninety-eight patients with pathological Stage (PS) III Hodgkin's disease treated between 1969 and 1984 were retrospectively analyzed. Treatment consisted of radiation therapy (RT) alone in 46 patients and combined radiation therapy and chemotherapy (CMT) in 52 patients. The median follow-up was 10 years (range 3-19 years). Fifteen-year year survival for patients with Stage III1-is better than for Stage III2 patients (82% vs 53%; p = .014). Patients with Stage III1A have a favorable prognosis regardless of treatment modality. The probability of freedom from relapse at 15 years for patients with pathological Stage III1A treated with radiation therapy is 70%, compared to 83% for pathological Stage III1A patients treated with combined modality therapy (p = .56). In patients with pathological Stage III2A, III1B, and III2B relapses were less frequent with the use of combined modality therapy compared to radiation therapy. We conclude that pathological Stage III1A patients may be treated with radiation therapy alone; the other subsets of patients benefit from combined radiation and chemotherapy.

Adult↗

PubMed1989

The patterns of failure in patients with pathological stage I and II diffuse histiocytic lymphoma treated with radiation therapy alone.

Radiation therapy was used to treat 36 patients with pathological Stage I and II diffuse histiocytic lymphoma at The University of Chicago Hospitals from 1970 to 1986. Twenty-two patients had pathological Stage I and 14 had pathological Stage II diffuse histiocytic lymphoma. The patients were treated with a median tumor dose of 50 Gy (range of 40-60 Gy). Therapy consisted of extended field radiation therapy in 27 patients (extended mantle or total nodal irradiation) and involved field irradiation in nine patients. The 10-year actuarial relapse-free survival for pathological Stage I and pathological Stage II patients was 91% and 35%, respectively (median follow-up of 7 years). None of the 22 pathological Stage I patients had bulky mediastinal or abdominal disease. Of the 22 pathological Stage I patients, one failed in an unirradiated contiguous lymph node and one relapsed with disseminated disease. Of the 14 pathological Stage II patients, two patients with bulky disease failed in field, one patient failed in a contiguous node, three patients failed within the abdomen, and three patients failed with disseminated disease. To better evaluate the efficacy of staging laparotomy, we analyzed the patterns of failure of 17 clinical Stage I and II diffuse histiocytic lymphoma patients. Four of these patients failed in field (three in sites of bulky disease), and five patients relapsed in the abdomen (three with disseminated disease). Salvage treatment with multiagent chemotherapy resulted in second complete responses in seven of ten patients; however, all but one have recurred and are dead of disease. Radiation therapy may be used as the sole treatment in patients with pathological Stage I diffuse histiocytic lymphoma without bulky disease. Patients with pathological Stage II diffuse histiocytic lymphoma and clinically staged patients have a higher incidence of dissemination and relapse within the abdomen. A benefit resulting from the administration of extended field irradiation was not revealed by this study.

Adolescent↗

PubMed1989

Breast conserving surgery and definitive irradiation for early stage breast cancer.

Breast conserving surgery and postoperative breast radiotherapy were used to treat 219 cases of AJCC Stage I and II breast carcinoma at the Michael Reese and University of Chicago Hospitals. Most patients were treated with lumpectomy and axillary sampling followed by breast irradiation to a dose of 46 Gy followed by a boost dose of 14-16 Gy to the surgical bed. The 5-year actuarial local control is 92%. Follow-up is 1 to 10 years and the median follow-up is 36 months. Of the seven patients who recurred in the breast, three failed in the boost site and three failed adjacent to the boost site. The seventh patient recurred diffusely in the breast and skin. Four of the seven recurrences were in patients with positive surgical margins. The 5-year actuarial relapse-free survival is 80%. Factors which had an adverse affect on the cosmetic results were a scar length greater than 8 cm and a volume of resected breast tissue greater than 100 cm3. Treatment related complications were minor and infrequent. Breast conserving surgery followed by radiation therapy is effective in achieving local control with good to excellent cosmetic results.

Adult↗

PubMed1989

The effect of the alpha-emitting radionuclide lead-212 on human ovarian carcinoma: a potential new form of therapy.

To improve response and survival of patients with ovarian carcinoma noncross-resistant forms of therapy must be developed. alpha-emitting radionuclides may be therapeutically useful since they can directly ionize with energies of 5 to 9 MeV, penetrate only a few cell diameters, and transfer a high amount of energy. The purpose of this study was to determine the effect of the alpha-emitter, lead-212 (212Pb), complexed to sulfur in a nude athymic mouse model (NIH:OVCAR-3) containing human ascites and solid epithelial ovarian carcinoma. Thirty-six nude mice 28 to 32 days old were injected with 10(7) to 10(8) carcinoma cells from donor mice. After 4 weeks, six groups of six nu/nu athymic BALB-C mice were intraperitoneally injected with 70, 50, 20, 5 microCi of 212Pb sulfur colloid, sulfur colloid, or saline. Tumor necrosis with a decrease in ascites and a dose-related survival were noted with doses of 50, 20, and 5 microCi. With 70 microCi acute gastrointestinal toxicity developed. These experiments form the basis for further investigations and the development of alpha-emitting radiocolloids which may be of therapeutic efficacy in the treatment of intraperitoneal ovarian carcinoma.

Animals↗