Biomedical subjects

R R Weichselbaum

Publications and source records attributed to R R Weichselbaum.

At least 253 records · Page 14Linked to original sources

PubMed1985

Treatment of perineural metastasis from squamous carcinoma of the skin with aggressive combination chemotherapy and irradiation.

Perineural metastasis from squamous cell carcinoma is quite rare. The treatment of such metastasis in the head and neck region is difficult due to base of skull or intracranial involvement by tumor. Surgery and radiotherapy may provide local control, but patients often fail distantly. We present a patient with squamous cell carcinoma presenting with perineural metastasis who was successfully treated with combination chemotherapy and definitive radiation therapy. Suggestions of therapeutic management are made of this uncommon clinical problem.

Aged↗

PubMed1985

Similar sensitivity of human lymphoblast cells proficient or deficient in nucleotide biosynthesis to the cytotoxic and cell cycle effects of 3-aminobenzamide.

3-Aminobenzamide (3AB), a potent inhibitor of poly(ADP-ribose) polymerase, induces cytotoxicity and cell cycle delays in exposed cells. 3AB has been reported to inhibit de novo nucleotide synthesis in human lymphoblasts. To determine if the 3AB-mediated effects are related to this inhibition of DNA synthesis, cytotoxicity and cell cycle progression in human lymphoblastoid cell lines, proficient or deficient in salvage nucleotide synthesis pathways, were determined after exposures to 3AB. In addition, changes in cell cycle progression were followed after treatment with 3-aminobenzoic acid (ABA), a nonactive analog of 3AB, and 5-methylnicotinamide (5MN), a less potent inhibitor of poly(ADP-ribose) synthesis. All three lines responded similarly to the different treatments. Cells deficient in salvage nucleotide synthesis pathways were no more sensitive to the cytotoxic or cell cycle effects of 3AB, ABA or 5MN. Thus, effects on nucleotide synthesis are not responsible for either cytotoxicity or the retarded cell growth found in human lymphoblastoid cells exposed to inhibitors of poly(ADP-ribose) synthesis.

Aminobenzoates↗

PubMed1985

Treatment complications after sequential combination chemotherapy and radiotherapy with or without surgery in previously untreated squamous cell carcinoma of the head and neck.

One hundred consecutive patients with previously untreated advanced squamous cell carcinoma of the head and neck were treated with induction combination chemotherapy followed by definitive surgery and/or radiotherapy, and were evaluated for radiotherapy related toxicity. The induction regimen consisted of cisplatin, bleomycin and methotrexate/leucovorin. Acute toxicity consisted predominantly of mucositis and weight loss, and was mild or moderate by degree in 94% of patients. Six percent of patients experienced severe or life threatening acute toxicities. Two acute toxic deaths were noted in this series, one from a combination of mucositis, weight loss and infection and one from hypoglycemia of unknown origin. Thirty-five percent of patients had radiation treatment interrupted briefly because of acute toxicity. Toxicity was greatest in patients who were nonresponders to induction chemotherapy and such may have been related to the continued presence of advanced tumor. Radiotherapy dose, surgical intervention and age did not have an impact on the presence or degree of acute toxicity. Late toxicities included: hypothyroidism in 32% of patients tested: osteoradionecrosis in 5% of patients, associated primarily with a composite resection (4 of 5 cases); and soft tissue ulcerations in 3%. Taken together, these data indicate that induction combination chemotherapy did not significantly increase the toxicity of subsequent radiotherapy with or without surgery.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1985

Inherently radioresistant cells exist in some human tumors.

We investigated the survival of 29 human tumor cell lines after treatment with ionizing radiation during exponential growth. The radiosensitivity of 20 tumor cell lines was within the range of normal fibroblasts. However, 9 cell lines derived from radio-incurable tumors appeared inherently radioresistant. When the ability to repair potentially lethal x-ray damage was studied in plateau phase cultures, some tumor cell lines derived from radio-incurable tumors were more efficient in this process. These results indicate that the presence of radioresistant and/or repair-proficient cells, which exist in some human tumors, may be responsible for failure to obtain local control following therapeutic x-ray treatment.

Cell Line↗

PubMed1985

Differing patterns of cytotoxicity of the phorbol ester 12-O-tetradecanoylphorbol 13-acetate in various human cell strains.

Inhibition of colony formation by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) over a wide range of concentrations (10(-4)-10(2) ng/ml) was examined in two normal human diploid fibroblast strains and eight cell lines derived from various human tumors. Three dose-response patterns were observed: (i) no killing at any dose, which is characteristic of rodent cells; (ii) increasing cytotoxicity with TPA doses of 0.1 ng/ml or greater; and (iii) a biphasic response with maximal cytotoxicity at 1.0 ng/ml, and minimal effects at much lower or higher concentrations. The latter response group included both normal and tumor cell strains. When normal cells were incubated concurrently with superoxide dismutase or CuDIPS, survival was enhanced in a dose-dependent manner. Specific binding of [3H]PDBu to cells from each of the three response categories was studied to determine whether the cells might contain two classes of specific phorbol ester receptors. Scatchard plots yielded straight lines, consistent with one class of binding sites. The possible significance of this cytotoxic effect of TPA in human cells at dose levels usually considered typical for specific phorbol ester responses is discussed.

Breast Neoplasms↗

PubMed1985

Different efficiencies of interaction between 3-aminobenzamide and various monofunctional alkylating agents in the induction of sister chromatid exchanges.

3-Aminobenzamide (3AB), an inhibitor of poly(ADP-ribose) polymerase, interacts synergistically with certain monofunctional alkylating agents to increase the frequency of sister chromatid exchanges (SCEs) in Chinese hamster ovary cells (CHO). Not all alkylating agents interact with 3AB to the same extent. Because 3AB has been reported to inhibit DNA strand break rejoining, experiments were carried out to determine if 3AB interacts preferentially with alkylation-induced DNA strand breaks or some other alkylated DNA lesion in the induction of SCEs. SCE frequency was determined in CHO cells that were pretreated with methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), ethylnitrosourea (ENU) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 2 h before being incubated with 3AB, and compared to the frequency of DNA strand breaks, as measured by alkaline elution, induced by these treatments. MNNG was by far the most potent DNA strand-breaking and SCE-inducing agent, followed in order of reactivity by MMS, EMS and ENU. The 3AB-enhanced SCE frequency was greatest, however, after MMS treatment. Thus the magnitude of the 3AB-mediated potentiation of SCE induction is not directly related to either the number of DNA strand breaks produced by the alkylating agent or the alkylation-induced SCE frequency. Furthermore, when MMS-treated cells were held in a non-cycling state for 2 days before release and treatment with 3AB, a procedure that results in a 60% reduction in MMS-induced SCE frequency, no synergism between MMS and 3AB in SCE induction was detected. These results suggest that 3AB does not interact with alkylation-induced DNA lesions in the induction of SCEs.

Alkylating Agents↗

PubMed1985

Repair of potentially lethal X-ray damage in fibroblasts derived from patients with hereditary and D-deletion retinoblastoma.

We examined X-ray induced potentially lethal damage repair (PLDR) in density inhibited plateau phase cultures of six fibroblast strains derived from patients with hereditary retinoblastoma and two patients with D-deletion retinoblastoma and compared them to three normal controls. PLD was measured in hereditary retinoblastoma (7 Gy exposure) and normal cells (7 and 9 Gy exposure) after 24 h repair time. PLD survival curves were performed at 2-9 Gy on six retinoblastoma and three normal control cell strains. Thus, PLDR was compared at equitoxic survival levels as well as after exposure to equal doses of radiation. Some retinoblastoma strains showed normal PLDR whereas others were possibly deficient. Implications of PLDR for susceptibility to radiation-induced and spontaneous tumours in hereditary retinoblastoma patients are discussed.

Adolescent↗

PubMed1985

Multidisciplinary treatment of advanced squamous carcinoma of the head and neck.

Advanced squamous carcinoma of the upper aerodigestive tract continues to be a therapeutic challenge. With recent advances in chemotherapy, systemic treatment has been used in an attempt to improve treatment results produced by radiation therapy and/or surgery. Such multidisciplinary experimental approaches have given new hope for cure in stage III and stage IV disease, but have reopened old questions as to the natural history and underlying biology of this disease. Multidisciplinary treatment, whether synchronous or sequential, appears to improve survival for stage III and stage IV patients achieving a complete response to chemotherapy plus irradiation. The role of surgery or radiotherapy for control of primary or nodal disease remains unchanged and is an essential component of all curative treatment plans.

Carcinoma, Squamous Cell↗

PubMed1985

Comutagenic effects of 3-aminobenzamide in Chinese hamster ovary cells.

Inhibition of poly (ADP-ribose) synthesis by agents such as 3-aminobenzamide (3-AB) potentiates the cytotoxic, carcinogenic, and clastogenic effects of certain DNA-damaging agents. Experiments were carried out in Chinese hamster ovary cells to compare chromosome aberration production and cytotoxicity with the induction of somatic mutations at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and sodium-potassium ATPase loci after treatment with 3-AB in combination with certain monofunctional alkylating agents. On its own, 1 to 10 mM concentrations of 3-AB were not mutagenic, reduced plating efficiencies only slightly, and produced a small elevation in the frequency of chromatid aberrations. In combination with ethyl methanesulfonate (EMS), 3-AB increased cytotoxicity and the frequency of alkylation-induced chromatid aberrations. 3-AB also increased the frequency of EMS and N-methyl-N'-nitro-N-nitrosoguanidine-induced 6-thioguanine-resistant cells (a marker for the HGPRT- phenotype). It had no effect on the frequency of EMS-induced ouabain-resistant cells (a marker for ATPase mutations). All the effects were dose dependent. Larger absolute increases were found with 10 mM 3-AB as compared with 1 mM 3-AB and with 2 mM EMS as compared to 1 mM EMS. The 3-AB-mediated increases in 6-thioguanine-resistant cells, which are often deletion mutations, and the lack of any increase in the frequency of ouabain-resistant cells, which can only arise through point mutation induction, along with the increases in chromosome aberration frequency, suggests that 3-AB increases the frequency of deletion mutations by increasing the frequency and duration of DNA strand breaks.

Animals↗

PubMed1984

Advanced squamous carcinoma of the head and neck. A preliminary report of neoadjuvant chemotherapy with cisplatin, bleomycin, and methotrexate.

Between Oct 1, 1979 and Aug 1, 1982, 93 patients with advanced squamous carcinoma of the head and neck were given neoadjuvant treatment with cisplatin, bleomycin sulfate, and methotrexate before standard local treatment. Ninety-three patients were evaluable for response. The response rates were as follows: complete response, 24%; partial response, 64%; and no response, 12%. Differences in primary tumor site, performance status at presentation, histologic grade, and tumor size did not correlate with response to this chemotherapy. For patients achieving notable tumor reduction to 2 cm or less, standard local treatment with either surgery plus radiotherapy or high-dose radiotherapy alone was effective in controlling local disease. For patients with larger tumor masses following neoadjuvant chemotherapy, surgical resectability appeared to improve local control rates. In our series, patients not receiving maximal standard local treatment often had relapse of local disease despite favorable responses to chemotherapy.

Adolescent↗

PubMed1984

The role of post-operative radiation therapy in the treatment of malignant tumors of the parotid gland.

Twenty-nine patients treated with postoperative radiotherapy for malignant tumors of the parotid gland were reviewed at the Joint Center for Radiation Therapy. Most patients were treated between 5,000 and 6,500 rad. All were treated because of microscopic residual disease, extra capsular extension, or tumor close to the facial nerve. The overall results showed one in-field failure, two marginal recurrences, and eight patients failed distantly. Poor prognostic factors included high-grade, extracapsular extension, and nodal involvement. We conclude that patients with malignant tumors of the parotid should be treated with postoperative radiation therapy if any of the bad prognostic signs are present. This may enable the surgeon to spare the facial nerve and obtain local control results equal to or better than more radical surgical procedures.

Adolescent↗

PubMed1984

The mechanism of 3-aminobenzamide-mediated increases in spontaneous and induced SCEs.

Cells exposed to the poly-(ADP-ribose)-polymerase inhibitor, 3-aminobenzamide (3AMB), have increased levels of sister chromatid exchanges (SCEs). In addition, cells exposed to certain monofunctional alkylating agents in combination with 3AMB have frequencies of SCEs much greater than expected if the 2 agents acted independently. Because poly-(ADP-ribose)-polymerase is stimulated by the production of DNA strand breaks, and 3AMB is said to inhibit strand-break rejoining, we determined the relationship between DNA strand breakage and SCE formation. Alkylating agents and the incorporation of bromodeoxyuridine (BrdUrd) into DNA led to the production of DNA strand breaks and the most potent SCE-inducing agents were also the most efficient DNA strand-breaking agents. In increasing SCE frequency, 3AMB interacted most strongly with those agents that produced the greatest number of DNA strand breaks. 3AMB also increased the frequency of strand breaks by delaying strand-break rejoining and introducing new strand breaks. The protease inhibitor, antipain, inhibited the formation of 3AMB-induced strand breaks in BrdUrd-containing cells and reduced by half the 3AMB-mediated increase in SCE frequency, suggesting that one mechanism for SCE induction involves the introduction of breaks into DNA possibly in response to changes in chromatin structure. We conclude that the primary lesion responsible for SCE induction after exposure to alkylating agents or incorporation of BrdUrd into DNA is either a DNA strand break or a lesion that can result in a strand break. 3AMB increases SCE frequency in combination with these agents by introducing new breaks and possibly delaying strand-break rejoining.

Alkylating Agents↗

PubMed1984

Effects of estradiol concentration on levels of nuclear estrogen receptors in MCF-7 breast tumor cells.

We have measured the time-course of estrogen receptor levels in nuclei of the estrogen-responsive breast tumor cell line MCF-7 during 90-120 min exposure of the cells to estradiol at physiologic (10(-10)M), pharmacologic (10(-6)M), and an intermediate (10(-8)M) concentration. Cells were preincubated for one week in a serum-free defined medium resembling that of Barnes and Sato, and then incubated in estradiol-containing medium. Nuclei were isolated at various times during the incubation, and filled and unfilled nuclear estrogen receptor levels were assayed. Increasing the concentration of estradiol in the incubation medium from 10(-10)M to 10(-8)M yielded increasing levels of filled nuclear receptor at all times studied, while further increase of the estradiol concentration of 10(-6)M decreased filled receptor levels from 10(-8)M values. Unfilled receptor levels dropped rapidly to zero under 10(-6)M and 10(-8)M estradiol incubation, but remained unchanged under 10(-10)M estradiol incubation. Together these results suggest that high-concentration estradiol may lead to "down-regulation" of filled nuclear receptors, which may be a contributing factor in inhibition of tumor growth. On the other hand, the continued presence of unfilled receptors only under physiological concentrations of estradiol may suggest a role for these receptors in sustaining tumor growth.

Breast Neoplasms↗

PubMed1984

The role of DNA repair processes in the response of human tumors to fractionated radiotherapy.

The relationship of inherent radiosensitivity, sublethal and potentially lethal damage repair to radiation therapy is not yet fully explained. I will examine how these various repair processes might be relevant to radiotherapy, based on laboratory investigation of human tumor cells in vitro. Although radiocurability is a complex function, recovery processes manifested in the post-radiation period may be a determinant of radiocurability.

Ataxia Telangiectasia↗

PubMed1984

Modification by dexamethasone of radiation response of in vitro cultured cells.

Because of the potential clinical significance of the report that dexamethasone is a radioprotector of Chinese hamster V-79 cells, the effect of dexamethasone treatment on the radiosensitivity of five other cultured mammalian cell lines (including two human cell lines) was tested and preliminary investigations into the mechanism of protection of V-79 cells were undertaken. In agreement with the published results of others, we found that treatment of V-79 cells with dexamethasone results in a 1.3-fold increase in D0. Conversely, dexamethasone had no effect on the radiosensitivity of Chinese hamster ovary cells, murine fibrosarcoma, rat glioma cells, human diploid fibroblasts, or human mammary carcinoma cells. To study the mechanism of the radioprotective effect of dexamethasone on V-79 cells, the cell cycle was examined. Dexamethasone treatment causes a change in cell cycle distribution in V-79 cells, resulting in a dose-dependent reduced fraction of S-phase and an increased fraction of G1- and G2 + M-phase cells. However, these kinetic changes cannot explain the observed radioprotection of asynchronous populations, since purified G1 cells are more radiosensitive. Furthermore, cells synchronized in G1 by centrifugal elutriation were shown to be protected by dexamethasone to the same extent as was the unsorted population, thereby ruling out the mechanism of protection being a redistribution in the cell cycle.

Animals↗

PubMed1984

Quantitation of the response of human tumor spheroids to daily radiation exposures.

Two human tumor lines, NB-100 neuroblastoma and C-32 melanoma, were grown as multicellular tumor spheroids (MTS) and exposed to daily doses of gamma rays, 5 days per week. It required daily doses of 200 rad to arrest the growth of the NB-100 MTS, while 350 rad per day was required to arrest the growth of the C-32 MTS. Calculation of the delay in time to grow 200 um beyond the original size yielded similar differences in radiation resistance. When the volume of the treated MTS was expressed as a fraction of their potential volume and plotted as a function of cumulative dose, there appeared to be little fraction size dependence over the range studied. This prediction was tested experimentally and confirmed: daily administration of two 100 rad doses separated by 4 hours to NB-100 MTS was only marginally less effective than a daily single dose of 200 rad. These data suggest that MTS may prove to be valuable tools in studying the response of human tumors to clinical exposure protocols, including hyperfractionation.

Cell Line↗

PubMed1984

Development of additional primary tumors after 62 years in the first patient with retinoblastoma cured by radiation therapy.

In the first well-documented case of bilateral retinoblastoma to be cured by X-irradiation of the nonenucleated eye, a basal cell carcinoma and then a squamous cell carcinoma of the eyelids developed 60 years after the original treatment. The patient, a 66-year-old man, had been treated by Verhoeff between 1917 and 1919. These new tumors may have been examples of second primary tumors, found in about 0.5% to 2.5% of patients with bilateral retinoblastoma, or they may have been coincidental. Because of the 60-year period between the patient's original treatment and the development of these tumors, it seems unlikely that they were the result of the irradiation.

Basal Cell Carcinoma↗

PubMed1984

Potentially lethal damage repair as a possible determinant of human tumour radiosensitivity.

In this paper we review the current data on the role of potentially lethal damage (PLD) recovery in human tumour cell lines, both in vitro and in vivo. In the case of cell lines studied in vitro, the mean recovery ratios found were higher for cells derived from tumours of low curability (glioblastoma, hypernephroma, osteosarcoma, melanoma) than for cells derived from tumours of high curability (breast carcinoma, neuroblastoma). Experiments were performed in vivo only with tumours of low and intermediate curability (melanoma, adenocarcinoma of the colon, pancreatic tumour). Although fragmentary and obtained only with established cell lines, these results argue in favour of the occurrence of PLD repair in human tumour, the amplitude of this repair being, in certain cases, sufficient to explain the incurability of a tumour by radiation therapy.

Animals↗