Biomedical subjects
R R Weichselbaum
Publications and source records attributed to R R Weichselbaum.
Fraction size and the repair of potentially lethal radiation damage in a human melanoma cell line. Possible implications for radiotherapy.
Studies performed on a human melanoma line in exponential growth showed radiation survival parameters similar to those of other tumors (n = 1.2, D0 = 151). In plateau-phase cultures, however, this tumor cell line was efficient in the repair of potentially lethal radiation damage, especially when large dose fractions were employed (there was a 48-fold recovery after 1,200 rad [12 Gy]). Thus, extrapolation from survival data generated only on exponentially growing cells may be misleading when determining the ultimate surviving fraction in some tumors. Large-fraction radiotherapy may not be effective in tumors that contain cells analogous to plateau-phase cells.
Radioresistance in some human tumor cells conferred in vitro by repair of potentially lethal X-ray damage.
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Heterogeneous response to X-ray and ultraviolet light irradiations of cultured skin fibroblasts in two families with Gardner's Syndrome.
A heterogeneous response to X-ray and far UV (254 nm) light irradiations was found in cultured skin fibroblast lines from 2 separate families with Gardner's syndrome. When compared to 2 normal control cultures and cultures from 2 patients with nonfamilial colon cancer, cultures from 4 clinically affected members of family 1 showed increased sensitivity to the lethal effects of both X-ray and UV light irradiations. These cells also showed a delayed pattern of X-ray potentially lethal damage repair (PLDR) and absent UV PLDR. In contrast, cultures from 3 members of family 2 (2 of whom were clinically affected) showed a normal response of survival and PLDR to both X-ray and UV light irradiations. Thus increased sensitivity of cultured skin fibroblasts to X-ray and UV light irradiations was not a consistent in vitro finding in patients with Gardner's syndrome. However, in families with Gardner's syndrome who demonstrate in vitro radiosensitivity, additional studies are needed to assess the usefulness of these techniques in detecting affected individuals prior to the development of colon carcinoma and other manifestations.
Importance of repair of potentially lethal damage in assays of cytotoxic agents.
Most in vitro assays expose growing cells to cytotoxic agents for a fixed period of time. However, these assays fail to account for repair of potentially lethal damage, the enhancement in survival that occurs when cells are maintained under nongrowth conditions after treatment with cytotoxic agents. This study extends previous observations of the repair of potentially lethal damage in human melanoma cells to parallel in vitro and in vivo experiments with the F10 subline of B16 melanoma. An in vivo (in C57BL/6 mice) and in vitro (in plastic plates) radiation dose-response relationship for the F10 subline of B16 melanoma was determined (200 to 1100 rads). Time delay until explant, allowing repair of potentially lethal damage, resulted in a significant and progressive enhancement of survival, five- to sixfold, both in vivo and in vitro. Survival with 700 rads and 24-hour delay was equivalent to that after treatment with 300 rads and no delay. Repair of potentially lethal damage, demonstrated in human cells in vitro and in animal preparations in vitro and in vivo, may account for the lack of clinical efficacy of some cytotoxic agents. Our results suggest that repair of potentially lethal damage should be taken into consideration in the design of in vitro chemotherapy and radiation therapy assays.
Effects of dexamethasone and cortisone with x-ray irradiation on transformation of C3H 10T 1/2 cells.
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Abnormalities of human chromosome 13 and in vitro radiosensitivity; a study of 19 fibroblast strains.
The in vitro X-ray sensitivity of 19 fibroblast strains derived from patients bearing a deletion, trisomy, inversion, or translocation of all or part of chromosome 13 were determined with a clonogenic survival assay. The results were compared with data from similar experiments involving strains from normal controls and from individuals trisomic for 3 other autosomes. The results suggest the involvement of this chromosome with hypersensitivity to the cytotoxic effects of X-irradiation. Experiments involving the partial monosomies and trisomies seem to implicate a locus on 13q14.
Radiation therapy in the treatment of aggressive fibromatoses.
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The repair of potentially lethal damage in x-irradiated cultures of normal and ataxia telangiectasia human fibroblasts.
The repair of potentially lethal damage (PLD) after X-rays was studied in plateau phase cultures of nine normal and five ataxia telangiectasia (AT) strains of human fibroblasts. In the normal strains PLD repair was complete after 6 hours of post-irradiation incubation. There were differences in the form of the survival curves of normal strains after maximum PLD repair but the extent of post-irradiation recovery was similar in all strains. In contrast all AT strains were almost completely deficient in PLD repair even when post-irradiation incubation was extended to 18 or 24 hours. The relevance of the PLD repair-deficiency in cultured AT strains to in vivo radiotherapeutic observations in AT patients is briefly discussed.
Effects of 17 beta-estradiol on radiation transformation in vitro; inhibition of effects by protease inhibitors.
We have investigated the effects of 17 beta-estradiol, given both alone and with X-irradiation, on the induction of malignant transformation in vitro. Treatment with 10(-6)M 17 beta-estradiol for 6 weeks, or 10(-5)M 17 beta-estradiol for only 5 days, induced malignant transformation in C3H 10T1/2 cells. Estradiol also acted as a cocarcinogen for X-ray induced transformation; the results indicate an additive effect when the cells were exposed to both agents together. The protease inhibitors antipain and leupeptin suppressed estradiol induced transformation as well as the additive effect observed for estradiol-radiation transformation.
In vitro radiosensitivity of human leukemia cell lines.
The in vitro radiobiologic survival values (n, D0) of four tumor lines derived from human hematopoietic tumors were studied. These cell lines were HL50 (n = 1.3, D0 = 117 rad[1.17 Gy]), promyelocytic leukemia; K562 (n = 1.4, D0 = 165 rad[1.65 Gy]), erythroleukemia; 45 (n = 1.1, D0 = 147 rad[1.47 Gy]), acute lymphocyte leukemia; and 176 (n = 4.0, D0 = 76 rad[0.76 Gy]), acute monomyelogenous leukemia. More cell lines must be examined before the exact relationship between in vitro radiosensitivity and clinical radiocurability is firmly established.
Improved survival for patients with advanced carcinoma of the head and neck treated with methotrexate-leucovorin prior to definitive radiotherapy or surgery.
Patients presenting with Stage III-IV squamous carcinoma of the head and neck often relapse following aggressive surgery and/or radiotherapy. In an attempt to increase survival in this high risk group of patients, HD-MTX, 3 gm./m2/dose, given weekly, was administered to 21 inoperable patients with Stage III/IV squamous carcinoma of head and neck prior to, and for 1 month after, definitive surgery and/or radiotherapy. Six of 11 patients (55%) who showed a significant response (greater than 50% reduction in tumor volume) to HD-MTX are alive and free of tumor greater than 38 months following treatment (p = 0.6) (Fisher Exact Test). Responder median survival is greater than 38 months while non-responder median survival is 15 months (p = .02) (Log Rank Test). For the entire treatment group, at a mean duration of 44.2 months following initiation of therapy, 7 patients (33%) remain alive and free of tumor. Patients responding to induction MTX-LCV more often become eligible for combined modality approach than did the non-responder group. This "downstaging" of the tumor prior to aggressive surgery or radiotherapy may be responsible for the increased survival rate seen in those patients who responded to MTX-LCV.
Familial retinoblastoma and ataxia telangiectasia: human models for the study of DNA damage and repair.
A variety of genetic diseases are associated with a high incidence of malignant tumors as compared to the general population. Laboratory data are presented that suggest that the increased cancer incidence in ataxia telangiectasia and familial retinoblastoma patients may be related to deficiencies in the normal DNA repair processes in their cells. Finally, we offer a hypothesis regarding the types of possible repair defects involved in these diseases and the biological consequences of such defects.
Lack of selective killing by steroids in normal and malignant cells.
Using a colony formation assay, the cytotoxic effects of steroids and an anti-steroid on an established human breast tumor line and two human diploid fibroblast strains were studied. Experiments involving 17 a-estradiol, 17 beta-estradiol, dexamethasone, cortisone, dihydrotestosterone, and the anti-estrogen Tamoxifen showed no killing at concentrations below 10(-7)M following a 24-hour exposure to these agents. A maximum of 80% killing was observed at 10(-5)M with dexamethasone in one fibroblast strain and at the same dose of 17 beta-estradiol in the breast tumor line. The extent of killing observed is insufficient to account for many of the clinical remissions observed with steroid therapy. The data also suggest that at therapeutic doses, there is no selective killing of malignant cells by these agents.
An in vitro investigation of genetic susceptibility to cancer in diploid fibroblasts from retinoblastoma patients.
Thirty-two diploid fibroblast strains from individuals with the three forms of retinoblastoma were examined with an in vitro clonogenic survival assay to determine their sensitivity to killing by X rays. Strains from sporadic unilateral retinoblastoma patients and normal controls were indistinguishable from one another (group D0's = 147 +/- 15 rads and 146 +/- 5 rads, respectively) while the strains from patients with the hereditary form of the disease were significantly more X-ray sensitive (D0 = 111 +/- 12). Strains derived from individuals with the D-deletion form of the disease resembled the hereditary strains with respect to sensitivity and heterogeneity, suggesting a possible, common etiology for these two forms of the disease. A DNA-repair defect is hypothesized as reflected by the observed hypersensitivity to X-irradiation in these cells. We suggest that this defect may be associated with the enhanced frequency of spontaneous and radiation-induced second tumors seen in some retinoblastoma patients.
Abnormal sensitivity of diploid skin fibroblasts from a family with gardner's syndrome to the lethal effects of X-irradiation, ultraviolet light and mitomycin-C.
Skin fibroblasts isolated from two members of the same family with the cancer-prone disease Gardner' Syndrome (intestinal polyposis, colon cancer, bone and soft tissue tumors) showed enhanced sensitivity to the lethal effects of X-irradiation, ultraviolet light and mitomycin-C. These cells showed no liquid-holding type recovery following UV-irradiation of confluent cultures, but were normal in their capacity for UV-induced unscheduled DNA synthesis. UV survival was not influenced by post-irradaiation incubation with caffeine.
Release of spleen focus-forming virus (SFFV) from differentiation inducible promyelocytic leukemia cell lines transformed in vitro by Friend leukemia virus.
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X-ray sensitivity of human tumor cells in vitro.
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