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Biomedical subjects

A Russo

Publications and source records attributed to A Russo.

At least 577 records · Page 32Linked to original sources
PubMed1986

The enigma of testicular leukemia: a critical review.

Isolated testicular relapse (T.R.) in acute lymphoblastic leukemia (ALL) has an overall incidence of 10% and affects mainly patients off therapy. Multivariate analysis of pretreatment characteristics has shown that lymphadenopathy and splenomegaly are independently associated with increased risk of T.R. during maintenance and off therapy, respectively. Sequential biopsy studies have demonstrated that testicular biopsies are unable to detect scanty infiltrates and have no practical utility. Prophylactic gonadal irradiation produced equivocal results and should not be used because of its sterilizing effect. Intensive multi-drug regimens or prolonged maintenance were unable to substantially reduce T.R. rate. On the contrary, intermediate-dose methotrexate (IDM) early in remission has almost abolished T.R. These findings strongly support the hypothesis that testicular interstitium is a very peculiar site where blasts are partially protected from the drug action; high drug concentrations are required for the optimal cytocidal effect. There are sufficient clues of a link between the excess of late marrow relapse in male sex and the capacity of testes of harboring blasts. Therefore IDM early in remission should be routinely adopted for prevention of testicular leukemia and its potential of late spread.

Animals↗
PubMed1986

Surveillance of birth defects: the Multicommunity Sets Technique tested by computer simulation.

Using a computer simulation for a series of births subject to various congenital malformations, the surveillance performance of the Multicommunity Sets Technique (MST) was compared to that of the Cumulative Sum Technique (CUSUM). Increases in malformation frequencies were simulated in (i) 6 out of 6 centres and (ii) only 3 out of 6 centres. MST was neither more sensitive nor more specific than CUSUM, and signalled increases with greater delay. One type of CUSUM procedure showed to accumulate more false alarms than MST in long periods of surveillance at the baseline malformation rate. The advantage of CUSUM was also shown for a single malformation with a very low baseline incidence, which according to Chen et al. (1983) should have been particularly suitable for MST surveillance.

Computer Simulation↗
PubMed1986

The roles of intracellular glutathione in antineoplastic chemotherapy.

Glutathione is a sulfhydryl containing tripeptide that participates in detoxification of xenobiotic compounds, including the alkylating agents melphalan, cyclophosphamide, and BCNU. The role of glutathione in the detoxification of these compounds, both in terms of initial tumor response, and drug-induced resistance to these alkylating agents is examined. Since glutathione disulfide and glutathione are a pivotal redox pair, the modulation of intracellular glutathione levels is shown to change the cytotoxicity of drugs dependent on the redox cycle, such as adriamycin and bleomycin, as well as the oxygen dependent drug neocarzinostatin. Areas of further research are discussed.

Animals↗
PubMed1986

Potentiation of chemotherapy cytotoxicity following iododeoxyuridine incorporation in Chinese hamster cells.

This study reports on the potentiation of selected chemotherapy drugs following halogenated pyrimidine incorporation into cellular DNA. Exponentially growing cultures of Chinese hamster V79 cells were exposed to 10(-5) M IdUrd or BrdUrd for 17 hr (approximately 2 cell doublings). This exposure resulted in approximately 16% replacement of thymidine by IdUrd or BrdUrd in the cellular DNA. Following the IdUrd exposure, dose response curves were determined for a 1 hr exposure to the various drugs. IdUrd pre-treatment was shown to enhance the cytotoxicity of melphalan, adriamycin, cisplatin, and neocarzinostatin with enhancement ratios at 1% survival of 1.5, 1.8, 1.5, and 1.4 respectively. BrdUrd pre-treatment also enhanced cisplatin cytotoxicity. A combination of BrdUrd pretreatment, cisplatin, and X rays was shown to yield additive survival effects. These findings are discussed in the context of possible clinical application of local drug perfusion of tumor-containing organs.

Animals↗
PubMed1986

The use of non-hypoxic cell sensitizers in radiobiology and radiotherapy.

Many different non-hypoxic cell radiosensitizers have been identified over the years. Radiosensitization by these agents is mediated through a variety of mechanisms, including inhibition of repair (both enzymatic and chemical), modification in the DNA molecule, and perturbation and redistribution in the cell cycle. Recent clinical interest in the use of halogenated pyrimidines as radiosensitizers has prompted a number of questions requiring both laboratory and clinical research to maximize this therapeutic approach. Other radiosensitizers that alter cellular redox processes in different ways are discussed in the context of better understanding the cellular biochemical systems that are affected in aerobic radiosensitization. Advancement in the use of non-hypoxic cell sensitizers in radiation cancer treatment will most likely depend on a knowledge of the detailed biochemical mechanisms of these agents and how they might be used to exploit any subtle biochemical differences between tumor and normal tissue.

Animals↗
PubMed1986

Modulation of X ray DNA damage by SR-2508 +/- buthionine sulfoximine.

It has been demonstrated that glutathione (GSH) depletion with buthionine sulfoximine (BSO) potentiates SR-2508 radiosensitization in hypoxic cells. We have measured the effect of SR-2508 alone, BSO alone, and combined treatment on radiation-induced DNA strand breaks in hypoxic V79 cells using alkaline and neutral elution. DNA base damage recognized by a damage specific endonuclease from M. luteus was also studied. Hypoxic irradiation markedly reduces the efficiency of single-strand (SSB) and double-strand breaks (DSB) to 10-20% compared to oxic irradiation. Hypoxia had less effect on the efficiency of base damage (ESS). BSO treatment alone, resulting in GSH depletion to less than 5% of controls, had little effect of hypoxic-SSB, DSB, and ESS. SR-2508 (5 mM) treatment alone in hypoxic cells increased the number of SSB, DSB and ESS to approximately half of that resulting from oxic irradiation. However, the combination of BSO and SR-2508 in hypoxic cells resulted in SSB and DSB comparable to oxic irradiation. This combined treatment resulted in less effect on ESS. We conclude that the observed hypoxic radiosensitization, using clonogenic survival assays with combined BSO-SR-2508, correlates with our results assessing DNA strand breaks and base damage.

Animals↗
PubMed1986

The relationship of SR-2508 sensitizer enhancement ratio to cellular glutathione levels in human tumor cell lines.

We have recently demonstrated that intracellular elevation of glutathione (GSH) by oxothiazolidine 4-carboxylate lessens SR-2508 hypoxic cell radiosensitization in Chinese hamster cells. This observation, coupled with the fact that GSH depletion potentiates SR-2508 hypoxic radiosensitization, prompted a study of human tumor cell lines whose inherent GSH levels are high compared to normal human cell lines or rodent cell lines. Sensitizer enhancement ratios (SER) for a range of SR-2508 concentrations were determined for human tumor cell lines varying in inherent GSH levels. The SER (at the 1% survival level) for 1 mM SR-2508 was found to decrease as the inherent intracellular GSH level increased, particularly for clinically relevant SR-2508 concentrations. All human tumor cell lines studied yielded lower SER values than Chinese hamster V79 cells over the SR-2508 concentrations studied. GSH depletion by buthionine sulfoximine (BSO) of a human tumor line (A549) particularly high in GSH resulted in potentiation of SR-2508 effects. Maximal sensitization occurred when extremely low GSH levels were attained; however, enhancement was observed for a drop of only 30% in GSH levels. Should these high GSH levels seen in human tumor cell lines also apply to clonogenic or potentially clonogenic cells in human tumors in vivo, these findings might explain, in part, the negative results of some human nitroimidazole clinical trials.

Cell Line↗
PubMed1986

In vivo modulation of glutathione by buthionine sulfoximine: effect on marrow response to melphalan.

The effect of giving buthionine sulfoximine (BSO), 0.0265 g/mouse (6 mM), at 12 and 6 hr before treatment with melphalan--0.0 mg, 3 mg, 6 mg, and 9 mg/kg, was studied in C3H mice, and was compared with control groups that received normal saline 12 and 6 hr before identical melphalan treatment. BSO treatment resulted in depletion of GSH levels in bone marrow, liver, and muscle to 65, 13, and 41% of control levels, respectively. Hematological toxicity was assessed by measurement of CFU-S survival and peripheral white cell counts. CFU-S survival decreased with increasing doses of melphalan, but no difference was observed with BSO pre-treatment. Likewise, WBC counts following melphalan 9 mg/kg, were similar irrespective of BSO pre-treatment. These data suggest that the marrow toxicity seen with melphalan is not worsened by pre-treatment with BSO and that if tumors can be pre-sensitized with BSO, there may be a clinical role for melphalan/BSO drug combination.

Animals↗
PubMed1986

Inhibition of the protective effect of cyclophosphamide by pre-treatment with buthionine sulfoximine.

Low dose cyclophosphamide (CTX) is protective against a subsequent challenge with a lethal dose of the same drug administered 5 days later. At the time of maximal protection, elevation of glutathione (GSH) and glutathione transferase (GST) levels are detectable in the bone marrow of pre-treated animals. Elevation of GSH levels in the bone marrow was inhibited with the use of D,L-buthionine-S,R-sulfoximine (BSO), and this resulted in loss of the protective effect of CTX pre-treatment. In contrast, the overshoot in GST levels observed in these animals was not affected by BSO therapy. Bone marrow GSH levels in animals treated with BSO alone were minimally depleted (68% of control); whereas, animals pre-treated with CTX followed by BSO exhibited a greater reduction in GSH levels (47% of control). These results suggest that GSH is important in the protective effect afforded by low dose CTX pre-treatment and that the elevation of GSH levels observed is the result of a rebound synthetic process. In CTX pre-treated animals, BSO treatment resulted in greater than predicted depletion in GSH levels, and, therefore, caution is recommended with the potential use of combinations of BSO and cytotoxic drugs in the presence of a regenerating bone marrow.

Animals↗
PubMed1986

Variation in sensitizing efficiency for SR 2508 in human cells dependent on glutathione content.

The observation by several authors and ourselves that manipulation of glutathione (GSH) levels in cultured cells would change the relative sensitization of hypoxic cells by nitroimidazole sensitizers led to the hypothesis that natural variation in GSH level could influence the sensitizer enhancement ratio (SER). Since many human tumor cell lines have shown high GSH levels, the A549 lung line, the HeLa line and a skin fibroblast line, the AG1522, were studied in monolayer culture in glass flasks. The GSH levels (nmol/mg protein) measured were 324 for A549, 103 for HeLa, and 32 for 1522 cells. For V-79 cells the level was 25 nmol/mg. In control experiments there was no effect of up to 10 mM SR 2508 in air but BSO (D,L-buthionine-S-R-sulfoximine) treatment modestly sensitized the A549 in air and nitrogen. Calculation of SER values at 1% survival revealed very little sensitization at 0.1, 0.5, and 1.0 mM SR 2508 for A549 cells (SER not significantly different than 1). At 5 mM the SER was 1.5 and at 10 mM 1.65. In contrast, the SER for fibroblasts was 1.65 at 0.5 mM and 2.2 at 1.0 mM SR 2508. The results for HeLa were intermediate, 1.25 and 1.45 at the same concentrations. Thus, the SER relates to the GSH levels in the cells. Treatment with BSO increased the sensitization of A549 to a level similar to that seen for AG1522 at 0.5 and 1.0 mM. These findings could explain the negative results of some sensitizer clinical trials.

Cell Line↗
PubMed1986

Photodynamic therapy of ascites tumours within the peritoneal cavity.

A murine ascites tumour was treated with intraperitoneal haematoporphyrin derivative (HPD) and laser light (10mW, 514nm, Argon laser). HPD was given intraperitoneally 2 hours before 16 minute laser treatment. Uptake studies 2 hours after HPD injection showed 5-12 fold greater concentration of HPD in tumour cells than in 4 different normal tissues. A total of four HPD/laser treatments, given at 2 day intervals, resulted in 100% complete response; the cure rate was 85%. This study illustrates the effective use of intraperitoneal photodynamic therapy and opens the possibility of exploring different sensitizers, excitation wavelengths, and delivery systems in the treatment of human ascites tumours.

Animals↗
PubMed1986

On the spin trapping and ESR detection of oxygen-derived radicals generated inside cells.

Recently several attempts to identify oxygen-derived radicals in whole cells by spin trapping and electron spin resonance have been reported by using 5,5-dimethyl-1-pyrroline-N-oxide as the spin trap. In the present study, the feasibility of this method is examined. Chinese hamster V79 cells and human erythrocytes served as the test systems, while OH radicals were generated by gamma radiolysis. Several spin traps were used to scavange the radicals and a distinction between exo- and endocellular ESR observable species was achieved using tri(oxalato) chromiate(III) as a line broadening agent. To distinguish between exo- and endocellular sites of radical formation, we studied the effects of high molecular weight scavengers (polyethylene glycols), which do not enter the cell. Various possible obstacles associated with trapping and detecting the radicals inside the cells were examined. The results indicate that the primary radicals react with the spin traps. However, these spin adducts decayed within the cells. Cellularly induced decay of 2-hydroxy-5,5-dimethyl-1-pyrrolidinyloxyl radical presented the major difficulty in detecting the endogenous radicals, and potential experimental approaches to overcome this difficulty are discussed.

Animals↗
PubMed1986

Population structure of eastern Sicily.

A sample of 465 persons from Eastern Sicily was studied for 11 red-cell enzymes, namely GLO, GPT, EsD, PGP, PGD, Dia, AcP, PGM, SOD, CAI and CAII. The allele frequencies were compared with those of other Italian populations and showed that the island is homogeneous with the mainland for these systems. The rate of heterozygosity was studied as a function of interparental distance; although high (0.77) the correlation did not reach significance.

Acid Phosphatase↗
PubMed1986

Selective modulation of glutathione levels in human normal versus tumor cells and subsequent differential response to chemotherapy drugs.

Cellular glutathione (GSH) levels were found to be 7-fold higher in a human lung adenocarcinoma cell line (A549) than in a normal human lung fibroblast line (CCL-210). Differential modulation of cellular GSH was explored in these cell lines by (a) stimulation of GSH synthesis by oxothiazolidine-4-carboxylate (OTZ) and (b) inhibition of GSH synthesis by buthionine sulfoximine (BSO). In the tumor cell line, OTZ treatment had no effect; however, GSH levels of 140-170% of control were achieved in the normal fibroblast line. With BSO, the normal cell line was depleted of GSH at a faster relative rate than with the tumor line. Within 7 h, 5% GSH remained in the CCL-210 line while approximately 40% GSH remained in the A549 line. Survival response of normal versus tumor cell lines to selected chemotherapy drugs was compared following modulation of GSH levels. OTZ pretreatment of the A549 line provided no protection to a 1-h exposure to melphalan, cisplatin, or bleomycin; however, OTZ pretreatment of CCL-210 elevated GSH and provided protection to melphalan, cisplatin, and bleomycin (protection ratios at 5% survival of 1.2, 1.4, and 1.4, respectively). Neocarzinostatin toxicity in the normal CCL-210 line pretreated with BSO was greatly reduced (protection ratio at 50% survival = 5.0). The same BSO treatment to A549 cells (40% GSH remaining) yielded a similar survival curve to control cells. These studies demonstrate that selective differential chemotherapy responses of normal versus tumor cells is possible by manipulating the GSH synthetic cycle. Should basic phenotypic differences with regard to reductive capacity exist in vivo, such manipulation in GSH levels might yield a therapeutic gain for carefully selected chemotherapy drugs.

Antineoplastic Agents↗