PubMed Health⌕ Search

Biomedical subjects

A Ferrario

Publications and source records attributed to A Ferrario.

At least 37 records · Page 2Linked to original sources
PubMed1993

Adriamycin resistance in Chinese hamster fibroblasts following oxidative stress induced by photodynamic therapy.

Photodynamic therapy (PDT) generates reactive oxygen species that are responsible for the initial cytotoxic events produced by this treatment. An extended (16 h) porphyrin incubation prior to light irradiation increased expression of the 75, 78 and 94 kDa glucose-regulated stress proteins (GRP), as well as the cognate form of the 70 kDa heat shock protein. However, these stress proteins were not induced following isoeffective PDT doses using a short (1 h) porphyrin incubation protocol. In the current study, Chinese hamster fibroblasts were used to examine sensitivity to adjunctive PDT and adriamycin as previous reports indicate a correlation between stress protein synthesis and a decrease in adriamycin cytotoxicity. Treatments that either induced GRP (i.e. PDT with an extended porphyrin incubation or exposure to the calcium ionophore A23187) or did not induce GRP (i.e. PDT with a short porphyrin incubation or UV irradiation) were followed at increasing time intervals with a 1 h adriamycin incubation. A time-dependent decrease in adriamycin cytotoxicity was observed when cells were first exposed to either of the PDT protocols or to A23187. Alterations in intracellular drug levels did not account for the change in adriamycin sensitivity. Likewise, intracellular glutathione concentrations and antioxidant enzyme activities were not significantly altered following PDT or A23187. Parameters associated with altered adriamycin sensitivity included a decrease in the percentage of S phase cells following PDT and A23187 as well as a depletion of intracellular ATP after PDT using the extended porphyrin incubation. These results demonstrate that PDT can be added to the growing list of diverse stresses producing transient resistance to adriamycin and that stress protein induction is not universally associated with all oxidative treatments inducing this resistance.

Animals↗
PubMed1992

Metabolic properties and photosensitizing responsiveness of mono-L-aspartyl chlorin e6 in a mouse tumor model.

A mouse mammary tumor model was used to evaluate metabolic properties of the photosensitizer mono-L-aspartyl chlorin e6 (NPe6) and to determine the optimal time interval between drug administration and light treatment for effective photodynamic therapy (PDT). Photosensitizer metabolism was evaluated by comparing tissue distribution patterns of NPe6 having 14C atoms positioned on either the tetrapyrrole ring or on the aspartyl residue. High performance liquid chromatographic analysis of photosensitizer extracted from tumor tissue was also obtained as a function of time after drug administration. NPe6 distribution in tissue samples and pharmacological calculations of area under the curve were similar for both forms of [14]NPe6. Likewise, metabolic contaminants of NPe6 were not detected by high performance liquid chromatographic analysis following extraction of the photosensitizer from tumor tissue. Maximal in vivo PDT effectiveness was achieved when light treatments were started within 2 h of drug injection. PDT effectiveness was decreased by 50% when light treatments were initiated 6 h after drug injection and was abolished with a 12-h interval between NPe6 injection and light exposure. Responsiveness to NPe6-mediated PDT was correlated with photosensitizer levels in the plasma but not in tumor tissue. These results show that NPe6 was not metabolized following in vivo administration and that the responsiveness of NPe6 mediated PDT was associated with vascular clearance of the photosensitizer.

Animals↗
PubMed1992

Establishment of a Chinese hamster ovary cell line that expresses grp78 antisense transcripts and suppresses A23187 induction of both GRP78 and GRP94.

GRP78, a 78,000 dalton protein residing in the endoplasmic reticulum, is postulated to play important roles in protein folding and cell survival during calcium and other physiological stress. Here we describe the construction of an eukaryotic expression vector for the constitutive expression of grp78 antisense RNA and the creation of a CHO cell line, 78WO, which expresses high levels of the grp78 antisense RNA through amplification of the stably transfected antisense vector. We observed that whereas 78WO maintains a basal level of GRP78 similar to that of control cells, GRP78 is no longer inducible by A23187. The 78WO cells have undergone a compensatory increase in grp78 transcription such that the effects of antisense are cancelled out at the protein level under nonstressed conditions. In these same cells, GRP94, a 94,00 dalton ER protein, is also rendered noninducible by A23187. This provides the first evidence that the regulation of two ER proteins might be coupled such that the failure to induce GRP78 results in the down-regulation of GRP94. The 78WO cell line grows with a doubling time of about 26 hr and exhibits decreased tolerance to A23187, suggesting the GRPs contribute to cell viability under calcium stress. The establishment of this cell line, which can be stably maintained, will provide a useful tool for testing whether the induction of the GRPs is important for protein folding or transport and whether their enhanced synthesis is the cause or consequence of a variety of physiological adaptations.

Animals↗
PubMed1991

Glucose regulated protein induction and cellular resistance to oxidative stress mediated by porphyrin photosensitization.

Photodynamic therapy (PDT) utilizes a tumor localizing porphyrin photosensitizer in the clinical treatment of cancer. At a mechanistic level, porphyrin photosensitization generates reactive oxygen species which initiate oxidative damage to a wide spectrum of biomolecules. Cellular stress proteins are also increased following oxidative stress treatments. In the current study, we examined porphyrin photosensitizing parameters associated with induction of the glucose regulated family of stress proteins. Elevated levels of mRNA encoding glucose regulated proteins (GRPs) as well as increases in GRP protein synthesis were observed for mouse radiation induced fibrosarcoma cells exposed to an extended (16-h) porphyrin incubation prior to light exposure. However, a short (1-h) porphyrin incubation prior to light treatment (designed to produce comparable phototoxicity as PDT using the 16-h porphyrin incubation protocol) was associated with only minimal increases in GRP mRNA levels or GRP protein synthesis. The relationship between GRP levels and PDT sensitivity was examined in radiation induced fibrosarcoma cells pretreated with the calcium ionophore A-23187 in order to overexpress GRPs prior to photosensitization. Resistance to PDT was observed in cells overexpressing GRPs only under photosensitizing conditions associated with the extended porphyrin incubation protocol, and this response was not due to changes in cellular porphyrin uptake. In separate experiments, a transient elevation of GRP mRNA levels was observed in transplanted mouse mammary carcinomas following in vivo PDT treatments. Our results indicate that specific targets of oxidative damage (modulated by porphyrin incubation conditions) instead of generalized cellular exposure to reactive oxygen species are correlated with PDT mediated GRP induction. In this regard, GRP induction may be a useful in vivo biochemical marker of PDT mediated injury. These results also support the hypothesis that GRPs may play a role in modulating sensitivity to cellular stresses including certain types of oxidative injury.

Animals↗
PubMed1991

[Clinical course of refractory anemia. Study of a case series of 56 patients].

We analysed the course and clinical features of a series of refractory anaemias (RA, RAEB, RAEBt). We could not find evidence to support the hypothesis that these three MDS classes are inevitably subsequent events of a single disease. Therefore aggressive treatment of RA, aimed at avoiding its evolution to RAEB or RAEBt, does not seem justified.

Adult↗
PubMed1991

Direct comparison of in-vitro and in-vivo Photofrin-II mediated photosensitization using a pulsed KTP pumped dye laser and a continuous wave argon ion pumped dye laser.

A pulsed KTP pumped dye laser (25 kHz repetition rate and 470 nsec pulse width) has been compared to a continuous wave argon ion pumped dye laser as the source of 630 nm light during in-vitro and in-vivo Photofrin-II mediated photosensitization studies. Individual experiments documented the effectiveness of each laser system on a) photosensitizer induced cytotoxicity and induction of stress protein synthesis using Chinese hamster fibroblasts; b) photobleaching of Photofrin-II in aqueous solution; c) Photofrin II mediated photosensitization of normal mouse skin; d) Photofrin II mediated photodynamic therapy of a mouse mammary carcinoma; and e) tumor temperature levels generated during laser exposure. Comparable results were obtained for both laser systems in all experiments.

Animals↗
PubMed1991

Increased transcription and translation of heme oxygenase in Chinese hamster fibroblasts following photodynamic stress or Photofrin II incubation.

Porphyrin mediated photosensitization can enhance the transcription and translation of several oxidative stress genes. In this study, we report on the enhanced expression of the gene encoding for heme oxygenase in Chinese hamster fibroblasts by; (1) incubation in Photofrin II; (2) Photofrin II mediated photosensitization; and (3) photosensitization induced by Rose Bengal. Increased expression of heme oxygenase mRNA was accompanied by a concomitant increase in the synthesis of the 34 kDa heme oxygenase protein. Western blot analysis using antibody to heme oxygenase confirmed the immunoreactivity of the 34 kDa protein induced by Photofrin II and PDT. These results demonstrate that heme oxygenase can be activated by non-metalloporphyrins as well as by photosensitization associated with singlet oxygen mediated subcellular injury.

Animals↗
PubMed1991

Lithotripsy with a Q-switched alexandrite laser system. Preliminary in vivo and in vitro results.

An alexandrite laser system which emits a wavelength of 750 nm, has recently been proposed as a substitute for the pulsed-dye laser (504 nm) for laser lithotripsy. We have carried out in vitro lithotripsy trials in order to evaluate the efficiency of a flashlamp pumped Q-switched alexandrite laser. In the first experiment, we compared the Q-switched alexandrite laser to the pulsed-dye laser with respect to their effectiveness in fragmentizing urinary and model stones (HMT target stones). In the second experiment, we evaluated the effect of Q-switched alexandrite radiation on the urinary wall (bladder, ureter, renal pelvis and liver) of animals (Wistar rats and rabbits) under general anesthesia. In conclusion, the alexandrite laser system is comparable to the pulsed dye laser. The 750-nm wavelength involves minimal risk of damage to the urinary tract and constitutes a safe alternative, especially during blind lithotripsy. It is a compact solid-state system, with no toxic chemical agents as laser material.

Animals↗
PubMed1990

Tissue distribution and photosensitizing properties of mono-L-aspartyl chlorin e6 in a mouse tumor model.

Mono-L-aspartyl chlorin e6 (NPe6) is a photosensitizer that possesses properties such as chemical purity and a major absorption band at 664 nm which are potentially exploitable for photodynamic therapy (PDT). The current investigation examined pharmacological and photosensitizing parameters of NPe6 in tumor and normal tissues in mice. [14C]NPe6 was used to obtain quantitative tissue distributions of the photosensitizer as a function of: (a) time following administration; (b) drug dose; (c) mode of drug administration; and (d) tumor size. The in vivo photosensitizing efficiency of NPe6 was compared directly to Photofrin II in experiments which evaluated tumor responses and induction of normal skin damage. Initial PDT experiments demonstrated that NPe6 was ineffective at inducing tumor cures when a 24-h time interval (between drug administration and light treatment) was used. However, PDT-induced tumor cures were obtained when NPe6 was administered 4-6 h prior to light exposure, and these NPe6-PDT treatment parameters were as effective as standard Photofrin II-mediated PDT. Interestingly, the level of PDT-induced normal skin damage was significantly greater for Photofrin II than for NPe6 at comparable drug and light doses. An analysis of pharmacological data and PDT time interval requirements suggests that plasma concentrations of NPe6 may be a more important predictive factor than tumor tissue levels of the photosensitizer for the production of PDT-mediated tumor cures. The results of this investigation indicate that NPe6 is an effective tumor photosensitizer with in vivo clearance properties that eliminate the side effect of prolonged normal skin photosensitization.

Animals↗
PubMed1990

Systemic toxicity in mice induced by localized porphyrin photodynamic therapy.

An unexpected high level of acute lethality has been documented following Photofrin II-mediated photodynamic therapy (PDT) treatments which were localized to the hind leg of normal and tumor-bearing mice. Doses of PDT which induced lethality (10 mg/kg Photofrin II, 200-500 J/cm2) were in the range of doses required to obtain murine tumor cures. The percentage of lethality was proportional to the total light dose but was inversely proportional to the dose rate of delivered light. Comparable levels of acute toxicity were observed in four pigmented mouse strains (C57BL/6J, C3H/HeJ, DBA/1, and DBA/2) and in two albino mouse strains (BALB/c and Swiss Webster). Decreased sensitivity to PDT-induced lethality was observed in two pigmented mouse strains (B10D2/OSN and B10D2/NSN). The administration of warfarin, aspirin, indomethacin, or antihistamine had significant protective effects in terms of decreasing PDT-induced lethality. However, injection of cobra venom factor (to deplete C3 and C5 of the complement system) did not alter the lethality mediated by PDT. Histological profiles obtained 24 h following PDT demonstrated vascular congestion in the liver, kidney, lung, and spleen. Significant decreases in removable blood volume, core temperature, and spleen weight were also observed within 24 h of localized PDT treatment. These results indicate that PDT-induced lethality is consistent with a traumatic shock syndrome and suggest that endogenous vasoactive mediators of shock such as prostaglandins, thromboxanes, and histamine are associated with the lethality induced by localized PDT in mice.

Animals↗
PubMed1990

[Sodium nitroprusside and inhibition of coronary vasoconstriction in isolated hearts of guinea pigs].

Recent data suggest that nitrate compounds, beside determining vasodilatation by cGMP-mediated Ca++ uptake in the sarcoplasmic reticulum, may also inhibit vasoconstriction by reducing phosphatidyl inositol bisphosphate hydrolysis, a major step in the biochemical pathway responsible for vasoconstriction induced by a variety of agents including angiotensin II (AII). We assessed the inhibitory effects of Na-nitroprusside (NP) on the coronary resistances induced by increasing doses of AII in Krebs perfused (basal pressure: 2.5-3 KPa) Guinea-pig isolated hearts. AII bolus injections (5 to 100 ng) were given before and 10 min after a 7.6.10(-8) to 7.6.10(-6) M infusion of NP for 10 min. AII produced a highly reproducible, linearly dose-related, increase in perfusion pressure (PP) (5 ng: 4.4 +/- 1.16; 10 ng: 8.1 +/- 2.1; 25 ng: 18.7 +/- 3.06; 50 ng: 23.6 +/- 2.31; 100 ng: 30 +/- 1.37 mmHg) that was persistently and dose-dependently inhibited by NP. Well after (greater than 10 min) full recovery from the initial NP-induced vasodilatation and drop in PP its inhibitory effect was observed, varying from 22.1% at the maximal AII and minimal NP does and 90.6% at the minimal AII and maximal NP doses. This study demonstrates that, apart from causing the well-known immediate vasodilatory response by stimulation of cGMP synthesis, NP also causes delayed inhibition of AII-induced coronary vasoconstriction, possibly by preventing phosphatidyl inositol hydrolysis.

Angiotensin II↗
PubMed1989

Properties and applications of photodynamic therapy.

Photodynamic therapy (PDT) is the treatment of malignant lesions with visible light following the systemic administration of a tumor-localizing photosensitizer. Pharmacological and photochemical properties of the photosensitizer are combined with precise delivery of laser-generated light to produce a treatment which can offer selective tumoricidal action. Hematoporphyrin derivative (HD) and a purified component called Photofrin II are currently being used in clinical PDT. Initial patient results have been encouraging, and considerable interest has developed in the synthesis and evaluation of new photosensitizers with improved photochemical and pharmacological characteristics. In addition, there has been a gradual increase in knowledge related to in vitro and in vivo mechanisms of action of PDT. This report provides an overview of the properties and applications of PDT. Information and data related to drug development, photochemistry, subcellular targets, in vivo responses, and clinical trials of PDT are presented.

Clinical Trials as Topic↗
PubMed1988

Molecular, cellular, and tissue responses following photodynamic therapy.

Photodynamic therapy (PDT) is being utilized in the treatment of a wide variety of malignant tumors. Results using PDT have been encouraging, and controlled clinical trials are currently being performed. The procedure exploits both the tumor-localizing and -photosensitizing properties of hematoporphyrin derivative or its purified component, Photofrin II. When this porphyrin mixture is administered systemically, it is retained preferentially in tumor tissue as compared to surrounding normal tissue. Localized tumor destruction induced by PDT results from the photochemical generation of cytotoxic oxygen species within the tumor. This review will provide a summary of historical and current research pertaining to molecular, cellular, and tissue responses induced by PDT. Emphasis is placed on information related to the chemistry of current photosensitizers, subcellular targets, preclinical treatment parameters, and clinical responses following PDT.

Animals↗
PubMed1988

[Computed arthrotomographic evaluation of chronic lesions of the cruciate ligaments].

The high incidence of cruciate ligament injuries as a result of acute knee trauma with hemarthrosis and abuse of diagnostic arthroscopies call for a suitable radiological imaging of the central pivot. Computed Arthrotomography (CAT) was used to examine the knee joint in 20 cases of clinically suspected chronic cruciate ligament injury. The images were correlated with arthroscopic and/or arthrotomic findings. Thirteen lesions of the anterior cruciate ligament (ACL) (65%) were found, plus 1 lesion of the posterior cruciate ligament (PCL) (5%), 2 associated lesions of ACL + PCL (10%), and 4 normal cases. Confirmation of pathology was available in all cases but one by arthroscopy and/or surgery. The central pivot diseases were classified as follows: absence, detachment, partial or complete tear. CAT findings of cruciate ligament injuries are emphasized and the role of the technique as compared to arthroscopy is discussed. CAT is useful in 3-D evaluation of central pivot and detection of different cruciate ligament injuries, with high sensitivity-specificity for ACL and high specificity-moderate sensitivity for PCL. In the evaluation of the chronic unstable knee, CAT is highly accurate and gives the surgeon useful information towards the planning of therapeutic procedures. CAT is almost non-invasive, well tolerated and easy to perform in out-patients, which make it a first-choice procedure in the screening of chronic ligament injuries.

Accidents, Traffic↗
PubMed1987

The effect of localized porphyrin photodynamic therapy on the induction of tumour metastasis.

Studies were performed to determine whether localized treatment of subcutaneously growing Lewis Lung Carcinoma (LLC) in C57BL/6 mice with porphyrin photodynamic therapy (PDT) affects the formation of distant metastases. Treatments consisted of a 10 mg kg-1 dose of dihematoporphyrin-ether (Photofrin II) followed 24 h later by local tumour irradiation with 630 nm red light. Total doses of light ranged from 0-500 J cm-2 and the irradiance of delivered light was 150 mW cm-2. Primary LLC tumours were treated at a volume of 25-30 mm3, and lung metastases were determined 21 days following transplantation. Mice exposed to PDT treatment which produced either partial or complete local tumoricidal responses had significantly decreased numbers of metastatic lung colonies compared to controls. In addition, PDT treated mice had equal or less metastatic lung colonies than comparable mice treated with local surgical excision of the primary LLC lesion. These results indicate that local PDT does not enhance metastatic spread of LLC following either curative or noncurative treatments.

Animals↗
PubMed1987

Photodynamic therapy in vitro and in vivo with hematoporphyrin derivative and laser light.

Photodynamic therapy is currently under investigation as a new form of treatment for solid malignant tumors in animals and in humans. The method involves photosensitization of drugs and fluorescent dyes, such as hematoporphyrin derivative (Hpd), after preferential incorporation by neoplastic cells. In in vitro experiments laser light activation completely destroys Hpd-pretreated EL4 cells. Mice bearing MS-2 fibrosarcoma treated with Hpd and laser light survived indefinitely, in comparison with control animals that were untreated or treated only with Hpd or laser light. In mice bearing the highly metastatic tumors B16 melanoma and Lewis lung carcinoma (LLC) treated with Hpd and laser light delivered through a quartz fiber optic significantly prolonged the median survival time. This therapy was compared with surgical excision of primary tumors and, for superficial nonmetastatic neoplasma MS-2, the photodynamic therapy was more effective than surgery, while for metastatic tumors B16 and LLC, there was no significant difference between the two methodologies. However, phototherapy is much less traumatic to the animals.

Animals↗
PubMed1986

Expression of potentially lethal damage in Chinese hamster cells exposed to hematoporphyrin derivative photodynamic therapy.

Experiments were performed to determine whether the expression and/or repair of potentially lethal damage could be observed in mammalian cells exposed to hemataporphyrin derivative (HPD) photodynamic therapy (PDT). Photodynamic therapy was combined with posttreatment protocols known to inhibit the repair of potentially lethal damage in cells treated with X-rays, ultraviolet radiation, or alkylating agents. Potentiation of lethal damage from photodynamic therapy was induced by hypothermia (4 degrees C) following short (1 h) or extended (16 h) HPD incubation conditions. Caffeine potentiated the lethal effects of PDT only when cells were incubated with HPD for extended time periods. However, 3-aminobenzamide had no effect on the cytotoxic actions of PDT following either short or extended HPD incubations. Recovery from potentially lethal damage expressed by posttreatment hypothermia was complete within 1 h, while recovery from potentially lethal damage expressed by posttreatment caffeine required time periods of up to 24 h. The lack of effect of 3-aminobenzamide on expression of potentially lethal damage following photodynamic therapy may be related to direct inhibition of adenosine diphosphoribose transferase by photodynamic therapy. These results indicate that the expression and repair of potentially lethal damage can be observed in cells treated with PDT and will vary as a function of porphyrin incubation conditions.

Animals↗