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J Rotmensch

Publications and source records attributed to J Rotmensch.

At least 55 records · Page 3Linked to original sources
PubMed1991

Radiation-induced DNA double-strand break frequencies in human squamous cell carcinoma cell lines of different radiation sensitivities.

DNA neutral (pH 9.6) filter elution was used to measure radiation-induced DNA double-strand break (dsb) frequencies in eight human squamous cell carcinoma cell lines with radiosensitivities (D0) ranging from 1.07 to 2.66 Gy and D values ranging from 1.46 to 4.08 Gy. The elution profiles of unirradiated samples from more radiosensitive cell lines were all steeper in slope than the profiles from resistant cells. The shapes of the dsb induction curves were curvilinear and there was some variability from cell line to cell line in the dose-response for the induction of DNA dsb after exposures to 5-100 Gy 60Co gamma-rays. There was no relation between the shapes of the survival curves and the shapes of the dose-responses for the induction of DNA dsb. At low doses (5-25 Gy), three out of four of the more sensitive cell lines (D less than 2.5 Gy) had larger initial break frequencies than the more resistant lines (D greater than 3.0 Gy). Although the low-dose (5-25 Gy) elution results were variable, they do suggest that DNA neutral elution will detect differences between sensitive and resistant tumour cells in initial DNA dsb frequencies.

Carcinoma, Squamous Cell↗
PubMed1991

Differential locus sensitivity to mutation induction by ionizing radiations of different LETs in Chinese hamster ovary K1 cells.

Mutation induction after exposures to 250 kVp X-rays, alpha-particles from the radon daughter 212Bi, and fission-spectrum neutrons from the JANUS reactor was studied in Chinese hamster ovary (CHO) K1 cells and in CHO-10T5, a K1 derivative containing the bacterial gene xanthine-guanine phosphoribosyl transferase (gpt). Mutation induction was analyzed at three genetic loci: the gpt locus, the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus, and the thymidine kinase (tk) locus. After X-irradiation, mutants were induced at the tk loci at approximately 8-9 times the rate of mutant induction at the hprt locus, and the rate of mutant induction at the gpt locus was 8-10 times greater than that at the hprt locus. Neutron and alpha-radiation were more effective mutagenic agents. Mutant frequencies were approximately 4- to 6-fold higher than for X-rays at the hprt and gpt loci and greater than 12-fold greater than X-rays at the tk locus. The greater sensitivity of the tk locus to mutation induction by ionizing radiation (especially neutron and alpha-particle radiation) compared to the hprt locus is likely to be due to the recovery of an additional class of mutants, possibly ones containing larger-sized mutational events. Approximately half of the X-ray-induced tk-1- mutants were small-colony mutants, and 75% of the alpha- and neutron-induced tk-1- mutants were small-colony mutants. The increase in the proportion of small-colony mutants seen with increasing radiation linear energy transfer (LET) suggests that the radiation quality influenced the type of mutation recovered at this locus. There is probably a different reason for the hypersensitivity of the gpt locus because the frequency of gpt mutants, compared to the hprt locus, was independent of radiation quality. Therefore, the LET dependence of mutant induction is gene specific and not necessarily related to the size of deletion recoverable.

Animals↗
PubMed1991

Increased nuclear damage by high linear energy transfer radioisotopes applicable for radiodirected therapy against radiologic malignancies.

High linear energy transfer radioisotopes carried by appropriate agents have been proposed for receptor-directed radiotherapy. Two such classes of isotopes are Auger electron and alpha-emitting nuclides. To determine the relative cytotoxicity and nuclear damage to cells produced by these two classes of nuclides, we compared bromine-80m (80mBr), an Auger-electron-emitting radionuclide with a 4.4-hour half-life, with bismuth-212 (212Bi), an alpha-emitter with a 1-hour half-life. Because of the short path length of the Auger electrons, 80mBr was radiotoxic only when incorporated into DNA, such as in the form of [80mBr]bromodeoxyuridine ([80mBr]BrUdR). Both agents induced linear increases in chromosome aberration frequency, however, [80mBr]BrUdR caused multiple aberrations including the shattering of parts of the chromosomes. While, in contrast, a 2-hour exposure of cells to 212Bi, chelated to DTPA, a form which does not enter the cell, induced much less extensive chromosome damage. Exposure to equivalent activities of Auger electrons or alpha-particles results in 5 times more damage in Auger-electron-exposed cells. However, estimates of dose suggest they are equally toxic. Unlike Auger electrons, alpha-particles did not need to be in as close proximity to the DNA to have clastogenic and radiotoxic effects.

Alpha Particles↗
PubMed1991

In vitro exposure of mammalian cells to radon: dosimetric considerations.

We have developed a model to calculate the dose to the cell nucleus in cells exposed in suspension to radon and/or radon progeny. The model addresses the influence of (1) different radiation qualities and energies in the irradiation milieu; (2) the contribution to dose from radioactivity in the medium surrounding the cell after exposure to the radon gas as well as that from excess radon progeny associated with the cell; (3) the geometry of the cell and of the radiosensitive target, the cell nucleus; (4) the intracellular localization of the radionuclides; (5) attenuation of the alpha particles by the cytoplasm; (6) the radionuclide concentrations in the medium; and (7) the length of exposure. Investigation of the influence of these various parameters was made using an irradiation system in which cells were exposed to 212Bi, which decays to stability with the emission of an alpha particle (either 6.05 or 8.78 MeV). The information from these studies was then used to develop the system further for more complex systems in which 222Rn and its progeny are present. The model takes into account the contribution of dose from different radiation sources using scintillation counts of the medium and the cells, and it is useful for calculations of dose in situations where cells are exposed in suspension culture.

Animals↗
PubMed1990

Comparison of radon-daughter-induced effects in repair-proficient and repair-deficient CHO cell lines.

The radiobiological effects of the radon daughter 212Bi were investigated in the Chinese hamster ovary cell line AA8 and its radiosensitive derivative EM9. EM9 cells rejoin radiation-induced DNA strand breaks more slowly than do AA8 cells. Three endpoints were examined: cell killing, G2-induced chromosome aberration frequency, and mutation induction at the hypoxanthine (guanine) phosphoribosyltransferase (HGPRT) locus. Cells were exposed to the alpha-emitter 212Bi chelated to diethylenetriaminepentaacetic acid (212Bi-DTPA). As expected, 212Bi-DTPA was more effective than X-rays in producing cytotoxicity, chromosome aberrations, and gene mutations. The relative biological effectiveness (RBE) for all three endpoints ranged from about 2 for chromosome aberrations to 4.4 for mutation induction. EM9 was more sensitive than AA8 cells to the cytotoxic and clastogenic effects of both X-rays and 212Bi-DTPA, suggesting that the repair deficiency in EM9 cells affects response to low- and high-linear energy transfer (LET) radiation for these endpoints. There was no significant difference between these two cell lines in their mutagenic response to X-rays and AA8 was slightly more sensitive to the mutagenic effects of alpha radiation. These results suggest that alterations in DNA repair ability may affect response of cells to both low- and high-LET radiation-induced cytotoxicity and clastogenicity, but they appear to have little effect on gene mutation induction.

Animals↗
PubMed1990

Radiation therapy in the treatment of cervical cancer: the University of Chicago/Michael Reese Hospital experience.

A retrospective analysis was conducted on 307 patients referred for radiation therapy at The University of Chicago and Michael Reese Hospital between 1971 and 1986. Median follow-up was 6.4 years. Treatment techniques varied during the time of the study. Actuarial disease-free survivals were 78%, 64%, 55%, 33%, 41%, and 60% for stage IB, IIA, IIB, IIIA, IIIB, and IVA, respectively. Stage, size of the cervical lesion, and hemoglobin level during treatment were prognostic factors. Treatment technique as well as time dose factors were analyzed with respect to survival, failures, and complications.

Adult↗
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

Preoperative radiotherapy followed by radical vulvectomy with inguinal lymphadenectomy for advanced vulvar carcinomas.

A therapeutic alternative to exenteration for large locally advanced vulvar carcinoma involving the rectum, anus, or vagina is the use of preoperative radiation followed by radical surgery. Between 1980 and 1988, 13 patients with Stage III and 3 with Stage IV vulvar carcinoma involving the rectum/anus, urethra, or vagina were treated with 4000 rad to the vulva and 4500 rad to the inguinal and pelvic nodes followed by a radical vulvectomy and inguinal lymphadenectomy 4 weeks later. The overall 5 year cumulative survival was 45%. Twelve tumors regressed after radiation with 62.5% of the patients having visceral preservation while in 4 patients there was no major response to radiation and urinary or fecal diversion was required. Of the 6 recurrences 4 were central and 2 distant. Three patients with central recurrences had tumor within 1 cm of the vulvectomy margin. Complications included wet desquamation, inguinal wound separation, lymphedema, and urethral strictures. There were no operative deaths. It is concluded that the use of preoperative radiation followed by radical vulvectomy may be an alternative to pelvic exenteration in selected patients with advanced vulvar lesions.

Adult↗
PubMed1990

Modeling of dose to tumor and normal tissue from intraperitoneal radioimmunotherapy with alpha and beta emitters.

Dose distributions for normal and tumor tissues from intraperitoneally administered radiolabeled antibodies have been calculated for 90-Yttrium (90Y), 131-Iodine (131I), and 211-Astatine (211At). The dose calculations use data on the activity of intraperitoneal fluid administered, the percent injected dose/gm uptake by tumor, biological half life, and a model for diffusion of antibody/radionuclide complex into peritoneal tissues. Calculations are performed for planar and hemispherical tumor shapes, ranging in size to establish the influence of geometry on dose distribution. Calculations for tumor geometry obtained from biopsies are also performed. When the activity is concentrated on or near the tumor surface, the maximum dose to a planar tumor for a 20 mci administration of 90Y is approximately 60 Gy, and falls rapidly to 50% of this value within 1 mm. However, for a hemispherical tumor, the dose is a maximum of 26 Gy, with an average of approximately 20 Gy. The surface dose from 131I (130 mci) is 240 Gy, and diminishes to 20 Gy in .05 cm in the planar case, whereas a hemispherical tumor receives a dose of 90 Gy over a large fraction of the volume, with the distal portions receiving 40 Gy. The surface dose for an administration of 70 mci of 211 At is 450 Gy and decreases to 50% of this value in 30 microns. Both surface geometry and tumor size are important determinants in the heterogeneity of tumor dose, as are the dose administered, antibody uptake, biodistribution, and residence time factors. These initial studies suggest that the size of disease which may be effectively treated is much less than the range of the particle emitted by radiolabeled antibodies. Furthermore, therapy is ultimately limited by the degree to which the antibody/radionuclide complex can diffuse and permeate the tumor.

Antibodies, Monoclonal↗
PubMed1989

The development of alpha-emitting radionuclide lead 212 for the potential treatment of ovarian carcinoma.

alpha-Emitting radionuclides may be an effective alternative treatment against ovarian carcinoma because they have short half-lives and are densely ionizing, with high linear energy transfer to a depth of several cell diameters without requiring cellular oxygenation. One radionuclide that has been generated and tested in our laboratory in vitro and in vivo is lead 212 (212Pb). Intraperitoneal instillation of 212Pb prolonged survival and totally eradicated tumor in 24% of mice inoculated with the extremely virulent Ehrlich ascites-producing tumor. In vitro 212Pb was two to four times more effective in killing human ovarian cancer cells than x-rays. Irradiation with 212Pb increased the radiosensitivity and chromosomal aberrations of cells. In dogs, intraperitoneal instillation of 2.6 mCi of ferrous hydroxide tagged with 212Pb caused no significant toxicity. It appears that alpha-emitting radionucides such as 212Pb have the potential to be a new and potent treatment of ovarian carcinoma and could be effective in cases that are resistant to conventional chemotherapy or x-ray therapy.

Animals↗
PubMed1989

The inherent cellular radiosensitivity of epithelial ovarian carcinoma.

Ovarian carcinomas of similar histology have variable responses to radiation therapy. It has been suggested that inherent cellular resistance to radiation may in part underlie radiotherapy failure. To determine in vitro radiobiological parameters of papillary serous adenocarcinoma of the ovary, we investigated the cellular responses of 16 early-passage ovarian carcinoma cell lines to radiation. The radiosensitivity, as measured by D0, ranged from 1.05 to 2.40 Gy (mean 1.70 Gy), and, as measured by D, ranged from 1.65 to 3.54 Gy (mean 2.38 Gy). The extrapolation number -n ranged from 1.1 to 2.0 (mean 1.5). The cells had a 1.3- to 5.4-fold (mean 2.8) ability to recover from potential lethal damage (PLDR) 24 hr after irradiation and subculture from plateau-phase cultures. Their inherent radioresistance may be one factor in the failure of some ovarian cancers to be sterilized by radiation.

Carcinoma↗
PubMed1989

Comparison of short-lived high-LET alpha-emitting radionuclides lead-212 and bismuth-212 to low-LET X-rays on ovarian carcinoma.

We are investigating the potential use of short-lived alpha-emitting radionuclides for the treatment of ovarian carcinoma. These radionuclides transfer dense high ionizing linear energy (high LET) over a short path length without dependence upon cellular oxygen. The alpha-emitting radionuclides chosen were lead-212 and bismuth-212 which are readily available. The radiosensitivities of two ovarian carcinoma cell lines (OVC-1 and OVC-2) was greater with 212Pb and 212Bi than with X-ray therapy. D0, inversely related to the radiosensitivity, was 155 and 240 rads for OVC-1 and OVC-2, respectively. With 212Pb or 212Bi, the slope of the survival curves was steeper. The D0 was 75 and 70 rads after 212Pb and 85 and 95 rads after 212Bi treatment for OVC-1 and OVC-2, respectively. The relative biological effectiveness with alpha irradiation was two to four times greater than with X rays. Unlike low-LET irradiation (i.e., X rays and gamma emitters) the cells had no ability to accumulate or repair sublethal damage. From these experiments it is concluded that a greater therapeutic advantage may be gained with alpha-emitting radionuclides than X rays. Further development of these nuclides may provide for a new form of therapy.

Bismuth↗
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↗
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

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

Characterization of a human ovarian carcinoma.

An epithelial ovarian carcinoma from a patient with progressive disease who had received combination chemotherapy was established as a cell line and characterized. The doubling time of the cell line was seven days. The subcutaneous inoculation with 10(6) cells into an athymic nude mouse produced a 5 X 5-mm nodule with a histology similar to that of the original tumor. The malignant epithelial cells were aneuploid and varied in chromosome numbers from 50 to 115; double minutes were present in 25% of the cells. Antibodies specific for keratin showed a dense filamentous keratin network within the cells. No estrogen receptors were identified by immunocytochemistry. A heterogeneous tumor population in the sixth passage was suggested by flow cytometric analysis. This cell line may be a useful in vitro model for studying the biology and mechanisms of radiation and/or chemotherapy resistance of ovarian carcinomas.

Animals↗
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↗