Biomedical subjects
Publications and source records attributed to D W Newling.
Twenty-one patients with advanced metastatic carcinoma of the prostate, no longer responsive to conventional therapy, were treated with weekly low-dose doxorubicin (Adriamycin). Twelve had an impressive subjective response in terms of pain relief and improved performance status and in nine this was maintained for 3 or more months.
A successful pregnancy in a patient who presented with renal failure secondary to pelvi-ureteric obstruction is described. Haemodialysis was instituted during the pregnancy. An Anderson-Hynes pyeloplasty was performed, probably preventing deterioration of remaining renal function. Metabolic acidosis was managed using additional bicarbonate in the dialysate. An active, multidisciplinary approach is recommended in the management of such patients.
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Efforts continue to improve the outlook for patients with all stages of prostate cancer. The addition of adjuvant or neo-adjuvant hormone therapy to radical prostatectomy may improve the curability of advanced localized disease. Various novel forms of maximal androgen blockade continue to be explored, including the reintroduction of safer forms of estrogen therapy. Chemotherapy remains largely experimental but its earlier introduction, when the patient's general condition remains good, may lead to improvement in the quantity and quality of life of patients with advanced disease.
BACKGROUND: A combination of local irradiation and systemic cytotoxic treatment could improve therapeutic efficacy in metastatic prostate cancer. Radiosensitization can augment the treatment response to standard doses of radiation or enable lower treatment doses to be given; thus decreasing possible side effects. Intracellular glutathione has been implicated in the mechanism of such radio- sensitizing effects. MATERIALS AND METHODS: In the present study, R3327-MATLyLu prostate tumor cells were treated with cisplatin (0.0325 microM, 0.1625 microM, 0.325 microM and control "0 microM") in combination with irradiation (2, 4, 6, 8 Gy and control "0 Gy"). The survival of clonogenic tumor cells in agar was determined. In another experiment the irradiation was carried out after a 3 hours pretreatment with cisplatin concentrations (1.63 microM, 3.25 microM, 6.5 microM and control "0 microM") both in the presence and absence of Glutathione. RESULTS: In both experimental conditions the combination of cisplatin with irradiation yielded significant supra-additive treatment effects. CONCLUSIONS: The analysis of combination treatment effects, using two different methods confirmed the existence of synergism. The presence of a high level of extracellular glutathione did not alter the radiosensitization effects observed without glutathione, suggesting that the presence of glutathione may not be a major limiting factor in the radiosensitization effects observed in these investigations.
OBJECTIVES: We evaluated the effects of irradiation, doxorubicin and dexamethasone on human PC-3 prostate cancer cells, investigating whether dexamethasone and doxorubicin can alter the irradiation cytotoxicity of PC-3 cells. METHODS: We used the human PC-3 prostate cancer cells, analyzing cell growth with trypan blue exclusion, indices of the cell cycle with flow cytometry and apoptosis with flow cytometry and analysis of DNA fragmentation on simple agarose gel. RESULTS: Doxorubicin (100 nM) arrested cell cycle at the G2/M phase, decreased cell growth and produced apoptosis of PC-3 cells in a time-dependent manner. Dexamethasone (100 nM) increased the distribution of PC-3 cells at G0/G1 phase in the cell cycle, exerting an inhibitory effect on the proliferation of PC-3 cells after 48 and 72 hr, but it did not produce apoptosis. Irradiation (4 Gy) initially arrested cells at the G2/M phase in the cell cycle (24 hr) which was gradually overcome and the PC-3 cells were shifted into G0/G1 phase or apoptosis after 48 and 72 hr. Irradiation decreased the PC-3 cell growth by 40-50% after 48 and 72 hr, respectively. Treatment with doxorubicin (100 nM) for 24, 48, and 72 hr after irradiation potentiated irradiation cytotoxicity of PC-3 cells. Dexamethasone treatment 24 hr before and 24, 48 and 72 hr after irradiation increased the number of surviving PC-3 cells and partially neutralized the irradiation effects on cell cycle. CONCLUSION: Doxorubicin potentiated while dexamethasone partially reversed the irradiation cytotoxicity of PC-3 cells. These data may be of clinical importance for the treatment of hormone refractory prostate cancer.
Over 80% of clinically manifested prostate cancers respond to androgen withdrawal. Several alternatives to castration have been explored. Since a growth promoting role for androstenedione has been suggested, we investigated the effect of inhibition of 3 beta-hydroxy-steroid-dehydrogenase (3 beta-HSD), a key enzyme involved in the biosynthesis of practically all steroids. In a previous study a reduced proliferation rate of androgen responsive R3327-H tumor was demonstrated after in vivo treatment with 17 beta-N,N-diethylcarbamoyl-4-aza-5 alpha-androstan-3-one (4MA) - a putative 5 alpha-reductase inhibitor. In the present investigation 3 beta-HSD enzyme activity derived from human placenta, testis and ovarian cancer cell line and from rat testis was determined using radiolabeled dehydroepiandrosterone (DHEA) or pregnenolone. Among different synthetic compounds known to interfere with steroidogenesis, only 4MA was shown to potently inhibit in vitro 3 beta-HSD activity from all tissue sources. 4MA was administered to male Copenhagen rats bearing R3327-H androgen dependent prostate tumors and levels of different androgens in serum and prostate tumor were measured using reversed phase HPLC and radioimmunoassay. The decreased content of androstenedione in serum and tumor tissue with DHEA accumulation in prostate tumor tissue showed an effective 3 beta-HSD inhibition by 4MA occurring in vivo as well. These observations unequivocally demonstrate a 3 beta-HSD inhibiting effect of 4MA in vitro as well as in vivo and point to a role for androstenedione in the promotion of cell proliferation in androgen sensitive tumors. 3 beta-HSD dependent androstenedione production could thus constitute a proper target -eventually combined with other endocrine treatment - for the treatment of hormone dependent prostate cancer.