Biomedical subjects

R R Weichselbaum

Publications and source records attributed to R R Weichselbaum.

At least 217 records · Page 12Linked to original sources

PubMed1989

Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation.

We report that tumor necrosis factor alpha (TNF-alpha) mRNA is increased after treatment with x-rays in certain human sarcoma cells. An increase in TNF-alpha mRNA is accompanied by the increased production of TNF-alpha protein. TNF-alpha enhances radiation lethality in both TNF-alpha-producing and -nonproducing tumor cells. These data suggest that, in addition to the direct cytotoxic effects of x-rays, production of TNF-alpha may add to radiation lethality through autocrine and paracrine mechanisms. Combinations of TNF-alpha and therapeutic radiation may be useful in clinical cancer therapy.

Cell Line↗

PubMed1989

Radiobiological characterization of 53 human tumor cell lines.

We investigated the in vitro radiobiological survival parameters of 53 human tumor cell lines studied in exponential growth. Epithelial cell lines derived from 24 patients with head and neck carcinoma, 15 patients with ovarian carcinoma, and mesenchymal tumor cell lines derived from 14 patients with bone and soft tissue sarcomas were studied. Survival data are analyzed using the multi-target and linear quadratic models. The head and neck and ovarian carcinoma tumor cell lines were more radioresistant as measured by D0, D, and alpha parameters, compared with the bone and soft-tissue sarcoma lines. The radiobiological parameters of tumor cell lines reported herein are similar to parameters of tumor cell lines derived from head and neck and soft tissue sarcoma patients presently being followed for clinical outcome following radiotherapy in our clinic.

Cell Line↗

PubMed1989

A randomized study of inpatient versus outpatient continuous intravenous infusion chemotherapy: psychosocial aspects.

This study was designed to test whether previously untreated patients with head and neck cancer could effectively manage home continuous infusion chemotherapy, and to compare their acceptance and adjustment to home versus inpatient treatment. Twenty-two patients received 3-4 cycles of induction chemotherapy and a 5-day continuous intravenous infusion (CVI). Patients were randomized to receive the CVI portion of cycle 1 either in the hospital via a standard chemotherapy delivery device or at home via the Travenol Infusor, a portable and disposable drug delivery system. For their second cycle of chemotherapy, patients crossed over to the alternate drug delivery method. Patients who did not want to receive their treatment at home received their chemotherapy as inpatients via the Infusor. Therefore, all patients received treatment with both drug delivery methods. Nineteen patients were evaluable for this study. Eleven patients received at least one cycle of home CVI chemotherapy, and adjusted well to this method of drug delivery. Levels of psychological distress decreased for this group of patients when receiving outpatient chemotherapy compared to their inpatient cycles. The eight patients who received all chemotherapy cycles as inpatients (refused home treatment) were found to be less educated and reported greater physical impairment prior to study entry than future home CVI acceptors. Levels of psychological distress in this group increased with each inpatient chemotherapy cycle. We conclude that home CVI chemotherapy may be an alternative to inpatient treatment for patients who have had at least one cycle of inpatient chemotherapy. The best candidates for home treatment are patients with unimpaired daily functioning and a minimum high school education.

Drug Therapy↗

PubMed1989

Comparative analysis of the inherent radiosensitivity of ovarian carcinoma.

Success or failure of radiation therapy in patients with ovarian carcinoma is due to the inherent radiosensitivity of both the tumor cell and the surrounding normal tissues. The D0 value were 1.65 Gy for benign mesothelium, 1.50 for the ovarian carcinoma, and 1.45 Gy for the fibroblasts. The ovarian carcinoma cells had a similar n value (1.7) to the mesothelial (n = 2.5) or fibroblast (n = 1.2) cells. Similarly, the 24-hour potentially lethal damage repair ratios were 2.26 for the tumor cells and 2.2 for the benign cells. The kinetics of the induction and repair of DNA strand breaks caused by X-ray irradiation were similar for the three cell types.

DNA Damage↗

PubMed1989

Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head and neck cancer: a phase I-II study.

Hydroxyurea and fluorouracil (5-FU) are active cytotoxic drugs in head and neck cancer and have shown synergistic activity in vitro. Both drugs also act as radiosensitizers. Therefore, we administered radiotherapy at daily fractions of 180 to 200 cGy with simultaneous continuous infusion 5-FU at 800 mg/m2/d and escalating daily doses of hydroxyurea for five days. Cycles were repeated every other week until completion of radiotherapy. Thirty-nine inoperable patients were treated at six dose levels of hydroxyurea ranging from 500 mg to 3,000 mg orally daily. Little effect of hydroxyurea on the WBC or platelet count was noted in patients receiving less than 2,000 mg daily, whereas both parameters decreased progressively in patients receiving 2,000 mg daily or more. Mucositis occurred at all dose levels, requiring frequent dose reduction of 5-FU; however, in patients receiving a daily hydroxyurea dose of 2,000 mg or less, the median weekly 5-FU dose administered was 1,725 mg/m2 (86% of the intended 5-FU dose), whereas at daily hydroxyurea doses exceeding 2,000 mg, the median weekly 5-FU dose decreased to 1,133 mg/m2 (57%) (P = .001). Of 15 evaluable patients with recurrent disease after prior local therapy only one failed to respond; six had a complete response (CR), and eight a partial response (PR). Of 17 evaluable patients without prior local therapy, 12 had a CR, with no patient developing recurrence in the irradiated field to date; five patients had a PR. We conclude that the recommended dose of hydroxyurea in this regimen is 2,000 mg daily. That dose will cause mild to moderate myelosuppression and will allow for delivery of greater than 80% of the intended 5-FU dose. The activity of this regimen in poor-prognosis head and neck cancer exceeds 90%; its further investigation in previously untreated patients is warranted.

Adult↗

PubMed1989

Neoadjuvant and adjuvant methotrexate, cisplatin, and fluorouracil in multimodal therapy of head and neck cancer.

To increase the complete response (CR) rate of patients with locally advanced head and neck cancer after three cycles of neoadjuvant chemotherapy, we added sequential methotrexate to the combination of cisplatin and continuous infusion fluorouracil (5-FU). We also evaluated the feasibility of administering three additional cycles of the same regimen as adjuvant chemotherapy. Thirty-eight patients were treated; the median age was 53 years and 36 patients had stage IV disease. Chemotherapy consisted of methotrexate 120 mg/m2 followed 24 hours later by cisplatin 100 mg/m2 and a five-day continuous infusion of 5-FU at 1,000 mg/m2/d. Of 34 patients evaluable for response to neoadjuvant chemotherapy, nine had a CR, 21 a partial response (PR), two a minimal response (MR), and one patient each stable disease (SD) and no response (NR). Of 31 patients who received local therapy, 15 were treated with surgery and radiotherapy and 16 with radiotherapy alone. Of 25 patients eligible to receive adjuvant chemotherapy only ten received all three intended cycles, while 15 received less or no adjuvant chemotherapy because of patient refusal, cumulative toxicity, or early disease progression. With a median follow-up time of 39 months, the median survival is estimated to be 20 months. Of eight patients with nasopharyngeal or paranasal sinus cancer, none has had disease recurrence. Patients with good initial performance status and low N-stage also had a significant survival advantage. Chemotherapy-related toxicities consisted mainly of mucositis, requiring 5-FU dose reduction in the majority of patients; similar toxicities were exacerbated in the adjuvant setting. The addition of methotrexate did not increase the CR rate over what has been reported for the combination of cisplatin and 5-FU alone. Certain subsets of patients appear to have a good prognosis when treated in this fashion. The administration of adequate adjuvant chemotherapy in patients with head and neck cancer remains difficult due to toxicity and poor patient compliance.

Adolescent↗

PubMed1989

Neoadjuvant vindesine, etoposide, and cisplatin for locally advanced non-small cell lung cancer. Final report of a phase 2 study.

We treated 27 patients with regionally advanced non-small-cell lung cancer (NSCLC) with two cycles of neoadjuvant chemotherapy with etoposide, vindesine, and cisplatin. Twenty-three patients were evaluable for response; 13 had a partial response while ten patients had stable disease or disease progression. Subsequent local therapy consisted of surgery followed by radiotherapy in four patients and of radiotherapy alone in 14 patients. Five patients did not receive local therapy. At completion of local therapy, seven patients were considered free of disease including all four who had undergone surgery. Median time to disease progression for the 13 patients who had a partial response to neoadjuvant chemotherapy was eight months (three to 51+ months). The median survival for all patients registered on study was eight months (three days to 53+ months). Chemotherapy induced toxicities included moderate myelosuppression, nausea and vomiting in all patients, and occasional ototoxicity, neurotoxicity, and wasting syndrome. One patient died of intracerebral hemorrhage due to thrombocytopenia. This trial shows that administration of neoadjuvant chemotherapy to patients with locoregionally advanced NSCLC is feasible and may yield an increased response rate compared to patients with stage IV disease. While no clearly beneficial effect of the use of chemotherapy on patient survival is apparent in this study, further studies utilizing neoadjuvant chemotherapy in patients with NSCLC are warranted and should attempt to identify more active combinations of drugs.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1989

Management of stage I and II Hodgkin's disease.

Early stage Hodgkin's disease is highly curable with radiation therapy alone. Some prognostic factors are associated with increased risk of relapse and may require combined modality treatment. The evolution of treatment of stage I and II Hodgkin's disease is presented.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1989

Substaging of stage III Hodgkin's disease.

Patients with stage III Hodgkin's disease require a staging laparotomy to accurately define two main subgroups of patients, III1 and III2. Selection of treatment modality for each group is very important. The majority of patients with pathological stage III Hodgkin's disease are treated with combined modality therapy; however, a subset of patients can be effectively treated with radiation therapy alone.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1988

X-ray and cis-diamminedichloroplatinum(II) cross-resistance in human tumor cell lines.

Clinical studies have suggested a close correlation between cis-diamminedichloroplatinum(II) (cisplatin) and radiation resistance. To determine whether this cross-resistance is due to an inherent cellular resistance to both agents, ten early passage human tumor cell lines were examined for their radiation and cisplatin sensitivity in vitro. Previous studies have suggested that these early passage tumor cell lines retain many of their in vivo characteristics and are therefore good models for tumor cells in vivo. Radioresistance was strongly associated with cisplatin resistance in these cell lines. Four of the cell lines examined were radioresistant, having Dos greater than 2.0 Gy. These four lines were also resistant to cisplatin, with the dose reducing survival to 10% greater than 1.29 microM. The remaining six cell lines had Dos ranging from 1.07 to 1.57 Gy of X-ray and doses reducing survival to 10% of less than 0.83 microM cisplatin. Because early passage human tumor cell lines were used, resistance or sensitivity to radiation and cisplatin most likely developed in vivo and was not due to selection in vitro. These results indicate that cross-resistance between cisplatin and radiation in vivo is probably due primarily to an inherent cellular resistance to these agents and not necessarily to the tumor microenvironment in situ.

Adenocarcinoma↗

PubMed1988

Synergistic cytotoxicity and DNA strand break formation by bromodeoxyuridine and bleomycin in human tumor cells.

5-Bromo-2'-deoxyuridine (BrdUrd) is a thymidine analogue whose cellular effects are related to its incorporation into DNA. BrdUrd is a known radiosensitizing agent that could potentially enhance the activity of chemotherapeutic agents that interact directly with DNA. Therefore we studied the interaction of BrdUrd and bleomycin in a human head and neck squamous carcinoma cell line, SQ20B. Using a colony-forming assay and analyzing results by the median-effect method, we have shown that there is synergistic cytotoxicity between BrdUrd and bleomycin. Synergism is evident when BrdUrd is administered prior to bleomycin or when the two drugs are applied simultaneously and is evident at a variety of BrdUrd:bleomycin concentration ratios. Alkaline elution of DNA from cells exposed to BrdUrd and bleomycin demonstrated greater single strand break formation than expected from the individual single strand break frequencies induced by each drug alone. BrdUrd did not affect the rate of repair of bleomycin-induced single strand breaks or the formation of double strand breaks. Although the mechanism of this interaction at the molecular level is unclear, our studies suggest that a direct interaction of bleomycin with BrdUrd-substituted DNA may be the cause of the synergism of these two agents.

Algorithms↗

PubMed1988

Southern analysis of human head and neck cancer cells for homologous sequences using yeast gamma repair genes.

We employed southern analysis to examine homology between yeast genes RAD 51, RAD 52, RAD 54, and RAD 55 for possible gamma repair genes in radioresistant or repair proficient human tumor cell lines and normal placental DNA. No homology wa observed; however, other strategies including further gene restriction and transfection are underway to identify repair genes in human tumors. Understanding mechanisms of radiation repair might lead to more effective clinical radiation treatment protocols.

Base Sequence↗

PubMed1988

Cytogenetic observations of a human ovarian carcinoma clinically resistant to therapy.

Resistance of a cancer cell to therapy represents an important problem in tumor biology. Hypotheses concerning the mechanism of resistance have included genetic instability, gene amplification, aneuploidy, and altered cell growth kinetics. Cytogenetic assays allow for the analysis of each of these parameters and provide important information concerning tumor heterogeneity. In using cytogenetic analysis, we have analyzed a human ovarian carcinoma clinically resistant to therapy. The ovarian carcinoma had a complex but stable karyotype with a mean chromosome number of 61.7 chromosomes/cell. Approximately 50% of the metaphase preparations examined had double-minute chromosomes, which have sometimes been associated with gene amplification. The frequency of double minutes varied from one pair to hundreds of pairs per cell. Cell cycle kinetic analysis revealed an average generation time of 38 hours. The cells were relatively resistant to doxorubicin in vitro, and the baseline sister chromatid exchange frequency, a measure of genetic instability, was elevated. These results suggest that cytogenetic assays have potential as predictive assays of tumor chemoresistance and may provide information regarding the biologic aggressiveness encountered clinically.

Cell Cycle↗

PubMed1988

Heterogeneity of radiation response of a parent human epidermoid carcinoma cell line and four clones.

We examined the radiobiological parameters of a parent tumor cell line and four tumor clones of a human skin squamous cell carcinoma. The parent line and all clones have a tumor morphology, aneuploid karyotype, and the ability to passage infinitely in vitro. The parent cell line and three of four clones formed tumors in nude mice. The parent line, SCC-12, has a D0 of 1.59 Gy and an n of 7.5. In the four clones, D0 ranges from 1.31 Gy to 2.66 Gy and n ranges from 2.1 to 22.8. Potentially lethal damage repair (PLDR) following 11 Gy ranges from 1.7 to 13.1, at 24 hours, however PLDR following equitoxic doses of radiation is similar. The mean inactivation dose value (D) in the parent tumor cell line is 3.48 and ranges from 3.31 to 4.17 in the tumor clones. Radiobiological interpretation of heterogeneity may complicate predictive assays for clinical radiotherapy.

Carcinoma, Squamous Cell↗

PubMed1988

Faster repair of DNA double-strand breaks in radioresistant human tumor cells.

To investigate the molecular basis of radiation resistance in human tumor cells, the induction and repair of radiation-induced DNA single- and double-strand breaks was determined by DNA elution analysis in two normal human cell lines and 12 early-passage human tumor cell lines of varying radiosensitivities. The radiosensitivities (D0) of the cell lines ranged from 1 to 2.9 Gy. Inherent cellular radiosensitivity was found to directly correlate with the rate at which the DNA double-strand breaks were repaired. Radioresistant cell lines repaired approximately 90% of their radiation-induced DNA double-strand breaks within 1 hr of irradiation while more radiosensitive cell lines required 2-4 hr to repair the same fraction of damage. Radioresistant cell lines also had lower initial DNA double-strand break frequencies. DNA single-strand break induction and repair was not found to be an important factor in the radiation response of human tumor and normal cell lines. Therefore, the rate at which DNA double strand breaks are repaired is a critical factor underlying radioresistance in human tumor cell lines.

Cell Line↗

PubMed1988

In vitro radiobiological parameters of human sarcoma cell lines.

In vitro radiobiologic survival parameters have been determined for 7 human osteosarcoma, 5 human soft tissue and bone sarcomas, and 4 Ewing's sarcoma cell lines. The mean D0 values were 99.5 +/- 11.6 cGy, 90.5 +/- 7.7 cGy and 95.8 +/- 7.9 cGy for osteosarcomas, soft tissue and bone sarcomas and Ewing's sarcomas, respectively. These in vitro survival data do not predict the clinical radiation resistance generally attributed to osteosarcomas and soft tissue and bone sarcomas, and do not differ substantially from the results obtained with the clinically radioresponsive Ewing's sarcomas.

Bone Neoplasms↗

PubMed1988

Radioresistant tumor cells are present in head and neck carcinomas that recur after radiotherapy.

We determined the in vitro survival parameters of 14 human head and neck squamous cell carcinoma tumor cell lines cultured from patients who suffered local failure after a curative course of radiotherapy. The radiobiological parameters determined included D, D0, n, and surviving fractions at 100, 200, and 300 cGy. When compared to in vitro radiobiological parameters of tumor cells cultured from head and neck cancer patients prior to radiotherapy, human sarcoma cell lines derived from patients not receiving therapeutic radiation, normal human diploid fibroblasts or other human tumor cell lines reported in the literature, the human tumor cells derived from radiotherapy failures are radioresistant.

Carcinoma, Squamous Cell↗

PubMed1988

Some retinoblastomas, osteosarcomas, and soft tissue sarcomas may share a common etiology.

DNA and RNA were extracted from primary human osteosarcomas and soft tissue sarcomas obtained from patients without retinoblastoma and were analyzed by hybridization with a cDNA probe for RB mRNA; absence or alterations of the RB gene are associated with development of retinoblastoma. Most of the osteosarcomas or soft tissue sarcomas examined by us did not express detectable levels of RB mRNA, whereas normal cells and epithelial tumor cells did. One osteosarcoma expressed a 2.4-kilobase transcript in addition to a normal 4.7-kilobase species. Our data suggest that transcriptional inactivation or post-transcriptional down-regulation of the RB gene may be important in the etiology of some osteosarcomas and soft tissue sarcomas as well as retinoblastomas.

Bone Neoplasms↗