Biomedical subjects
G Savi
Publications and source records attributed to G Savi.
[Propolis: its use in technology and research].
Analytical procedure more advanced allowed to identify, to isolate, and assay the compounds present in propoli which is is developed to be a valuable biological product as food resource as medical resource. Analytical procedure more and more sophisticated allowed (us) to assay the propoli composition without operate the derivatization of phenolic constituents making use the capacity of different detector used. These phenolic contents were analysed by capillary gas chromatography using an electron-capture detector. This detector shown a good electron capture response of these compounds, which belong to the so-called "conjugated electrophores".
Interleukin 2 enhances the efficiency of immunotoxins in the treatment of mice with ascitic tumors.
Two multivalent immunotoxins (ITs) with cytotoxic potential against Thy 1.2-expressing tumor cells were used in association with mouse interleukin 2 (IL2) for treatment of mice bearing ascitic EL4 lymphomas. The combined treatment, ITs + IL2, induced an enhanced antitumor effect revealed by a significant prolongation of the survival time of mice as compared to the simple treatment with ITs or IL2 alone. According to the survival of mice treated by combined therapy, the proportion of killed tumor cells rose up to 94% as resulted from the dose-dependent curve of the survival of nontreated mice versus the number of tumor cells inoculated.
Effect of amrinone on anthracycline-induced lethal and cardiac toxicity in mice and rats.
The protective role of amrinone against toxicity of anthracyclines was examined in both mice and rats. These two anthracyclines were selected since they are characterized by different patterns of toxicity. In contrast to doxorubicin, the 4'-deoxy derivative did not cause delayed mortality. The results of this investigation indicate that amrinone is an effective protective agent against acute lethal events induced by both anthracyclines. However, the inotropic agent did not reduce the delayed mortality produced by doxorubicin. This parallels the apparent lack of prevention of doxorubicin-induced myocardial toxicity in CD rats, as determined by ECG changes and by morphologic alterations following multiple drug administrations. The administration of amrinone did not interfere with the antitumor activity of 4'-deoxy-doxorubicin against C-26 colon tumor.
Treatment of murine EL4 leukemia in ascitic form with anti-Thy 1.2 specific immunotoxins.
C57BL/6 mice with EL4 leukemia cells in ascitic form were intraperitoneally treated with ricin A chain-multivalent antibody immunotoxins. The immunotoxins containing rabbit IgG anti-Thy 1.2 antibodies complemented by protein A of Staphylococcus aureus were able to interact specifically with the target cells and to induce an antitumor effect as revealed by an increase in survival time of the mice. No apparent secondary effects consecutive to a cytotoxic action on the normal Thy 1.2 antigen bearing cells were observed with the immunotoxin doses used.
Effects of tauromustine, a water-soluble nitrosourea compound on NMU-1 murine lung tumor.
This study assessed the antitumor activity of 1-(2-chloroethyl)-3-/2-(dimethylaminosulfonyl)ethyl-1-nitrosourea (TCNU), a newly soluble nitrosourea, on NMU-1 lung tumor, a transplantable murine model poorly sensitive to BCNU. TCNU delivered orally was more effective after weekly than after biweekly treatments. When TCNU was given weekly intravenously, its therapeutic index was higher than after oral treatment. Compared with BCNU, TCNU showed superior antitumor effects on NMU-1 murine lung tumor. In this experimental model, TCNU activity was comparable to that of drugs active on human lung cancer.
Influence of tumor growth kinetics on response to doxorubicin treatment of C3H mammary carcinoma.
The influence of tumor growth kinetics on response to doxorubicin treatment of C3H mammary carcinoma was investigated. Gompertzian growth curves were obtained for the tumor mass of each mouse by a computerized best fit program. The response was assessed by evaluating: a) the total clonogenic cell reduction as a fraction of the initial tumor volume or the tumor volume that should result at the end of treatment in a free growth condition, and b) the partial clonogenic cell reduction at each drug administration, assuming a first order cell kill hypothesis. Slowly growing tumors at each dose level showed a significantly poorer response than rapidly growing tumors. Each response index exhibited a linear correlation with the specific instantaneous growth rate at the time of treatment. Data also suggested a dose-response dependence.
Topical administration of tetrasodium-meso-tetraphenyl-porphinesulfonate (TPPS): correlation between drug penetration and depth of necrosis in skin of nude mice following red light irradiation.
The main side effect in photodynamic therapy is photosensitization of the patient's skin following systemic administration of the photosensitizing agent. In the case of superficial lesions, this problem can be avoided by topically applying the drug: in this way a local treatment can be performed. We tested the photosensitizing properties of a 2% solution of TPPS (tetrasodium-tetraphenylporphinesulfonate) in a vehicle containing a penetration enhancer, Azone, on skin of nude mice. An aliquot of 0.1 ml/cm2 of the solution was painted on the skin overlying an s.c. implanted NMU-1 tumor. Subsequently, animals were sacrificed at different times after application. Fluorescence microscopy revealed that TPPS penetration depth was related to time elapsed after application and to painting modalities. Solution penetration was enhanced by wiping with ether immediately before painting. Irradiation at 80 mW/cm2 for 20 min with a dye laser emitting at 640 nm, 4 h after TPPS application, produced necrosis of the upper skin layers, up to 0.2 mm in depth. These findings suggest that topical TPPS administration, followed by laser irradiation, may be a suitable treatment modality for skin lesions involving epithelial layers, even though several aspects of this metodology need further investigation.
A study on the possible involvement of nonlinear mechanism of light absorption by HpD with Nd:YAG laser.
The purpose of this study was to investigate whether excitation of porphyrin could be related to nonlinear mechanisms of absorption of porphyrin itself or of the medium in which porphyrin is embedded. This possibility was proposed as an explanation for results of previous experiments where a Nd:YAG laser was used. An MS-2 sarcoma transplanted into the hind pad of BALB/c mice was used as the experimental tumor model. Mice were given HpD i.v. (25 mg/kg) 24 h before exposure to light delivered from an IR laser (1,060 nm). Since at dose-rates ranging between 600 and 1,200 mW/cm2 the thermal effect tended to mask the nonlinear effect, the temperature of the limb of mice was kept cold by running water. Irradiation performed under cooling conditions did not show any tumor growth inhibition. Experiments in vitro performed on HT-29 cells by a continuous wave (CW) or pulsed (Q-switch) Nd:YAG laser indicated no appreciable difference in DNA synthesis between irradiated and nonirradiated cells. Our results did not evidence nonlinear mechanisms of absorption by HpD with Nd:YAG laser both in CW and pulsed (nanosecond range) modes. Whether this effect should occur, in any case it is unlikely to be suitable to induce a photodynamic effect due to its low efficiency. Nd:YAG laser could induce a heating related effect, which can improve the therapeutic efficacy of PDT.
Synthesis and antitumor activity of a platinum (II)-doxorubicin complex.
A mixed platinum (II) complex with tert-butylamine and doxorubicin (coordinated via the amino-group) has been synthesized and tested for antitumor activity. The results indicate that the complex was active against doxorubicin-resistant P388 and cisplatin-resistant L1210 leukemias, while maintaining antitumor activity against sensitive parent lines.
Analysis of free growth and post-treatment regrowth of C3H mammary carcinoma in individual mice.
Free growth and post-Doxorubicin treatment regrowth of the C3H mammary carcinoma were analysed in individual mice. In both cases, the Gompertzian function provided a better fit than the exponential function, and the difference was statistically significant (P less than 0.001, chi 2 test). No comprehensive Gompertzian function was found, and each individual tumour growth or regrowth was described by a specific curve. Nevertheless, although both individually measured alpha 0 and beta, Gompertzian parameters varied from one animal to another, in both free-growing and post-treatment regrowing tumours a strong linear correlation between alpha 0 and beta was found. A parallelism test was performed to verify if there exists any treatment-induced alteration. The two regression lines appeared to be identical, however.
Poly-L-aspartic acid as a carrier for doxorubicin: a comparative in vivo study of free and polymer-bound drug.
The synthetic polypeptide, poly-L-aspartic acid (PAA, mol. wt = 20,000) has been used as a macromolecular carrier for doxorubicin. The drug may be released in vivo through hydrolysis of the ester linkage formed between the carboxyl groups of the polymer and the drug side chain. PAA has been found to be a suitable carrier since it is a soluble, biodegradable, multivalent and nontoxic polymer. The toxicity and the therapeutic efficacy of free and polymer-linked doxorubicin have been evaluated in normal and tumour-bearing mice, using a variety of experimental tumour systems. In studies on single and multiple drug administration, the results indicated that the polymeric derivative of doxorubicin had approximately 3-fold lower toxicity than did free drug. In addition, the severity of specific toxic effects, including cardio- and vesicant toxicity, were appreciably reduced following conjugation to PAA. The doxorubicin-PAA conjugate gave similar or rather greater therapeutic effects than free drug at less toxic doses. This effect, more evident in the highly sensitive tumours, suggests an improvement of the therapeutic index of the polymer-linked drug.
Hyperthermal effects in phototherapy with hematoporphyrin derivative sensitization.
Although the photochemical reaction of hematoporphyrin derivative (HpD) appears to play a major role in cytotoxic activity, the hyperthermal contribution to tumor destruction has not yet been clarified. We investigated its role in the effectiveness of laser photoradiation therapy using MS-2 sarcoma transplanted into the hind pad of BALB/c mice as the experimental model. Mice received HpD i.v., 25 mg/kg - 24 h before exposure to light delivered from a dye laser or Nd-YAG laser, or before warming in a thermostated bath. Since our aim was not to cure the tumor, the treatment response was evaluated only as inhibition of tumor growth at different days after treatment. Our results support the view that in laser photochemotherapy the hyperthermia produced by irradiation and the photodynamic effect mediated by HpD could contribute to tumor destruction. Moreover, a synergistic interaction between the photodynamic effect and heat was observed in this experimental model.
Comparison of antitumor effects of daunorubicin covalently linked to poly-L-amino acid carriers.
Daunorubicin was covalently linked to poly-L-aspartic and poly-L-lysine of different molecular weights via the methylketone side-chain of the drug by the use of a method that employs the 14-bromo derivative of the antibiotic. During reaction ester and C-N linkages were formed with poly-L-aspartic acid and poly-L-lysine respectively. Whereas a reduction of drug toxicity was observed with both types of conjugate, only the linking to the anionic polymer produced an enhancement of drug activity. In contrast, when drug was covalently attached to poly-L-lysine, cytotoxic activity and in vivo potency and efficacy were markedly reduced. The different therapeutic properties of these conjugates can be explained in terms of the different nature and stability of chemical bonds formed between the drug and the amino groups and carboxyl functions of the polyamino acid carrier.
A comparison of efficacy of photoradiation therapy and other conventional treatment modalities on experimental MS-2 sarcoma.
The therapeutic efficacy of photoradiation therapy (PRT) following hematoporphyrin derivative (HpD) administration was compared in the experimental MS-2 tumour model to that of conventional treatment methods for local control of neoplastic diseases. The therapeutic effects of PRT and surgical removal of primary tumour were comparable in these experiments. However, optimal effects were critically dependent on the stage of tumour development. In addition, the therapeutic advantage of PRT over radiotherapy suggest an interesting role of a new approach in tumours resistant to this conventional treatment.
Effectiveness of laser photoradiation therapy following hematoporphyrin derivative administration in the experimental MS-2 tumor model.
The effectiveness of laser photoradiation therapy with hematoporphyrin derivative sensitization was tested in the MS-2 sarcoma. This solid tumor, transplanted into the pad of the hind leg of BALB/c mice, was found to be a sensitive experimental model for a quantitative evaluation of response to phototherapy and for determination of critical parameters in laser phototherapy treatment. Under our experimental conditions, optimal therapeutic effects appeared to be critically dependent on drug dose, number of treatments, light intensity, and irradiation of the peripheral border of the tumor.
Protective effect of reduced glutathione against cis-dichlorodiammine platinum (II)-induced nephrotoxicity and lethal toxicity.
Pretreatment of Swiss mice and Sprague-Dawley rats with glutathione (GSH) reduced the acute lethal toxicity of cis-dichlorodiammine platinum (II) (cis-DDP) in a dose-dependent manner. The protection was accompanied by reduction of both body weight loss and by reduction of nephrotoxicity, as measured by a rise in serum blood urea nitrogen (BUN), creatinine levels and by histopathologic changes, which occurred 4 days following cis-DDP treatment. The antitumor effects of cis-DDP on experimental tumor models (P388 and Gross leukemia) were not significantly altered by GSH treatment. It is suggested that the partial protection by GSH from acute toxicity of the antitumor drug is directly related to protection of renal function.
Antitumor activity in mice of 4'-deoxydoxorubicin in comparison with doxorubicin.
4'-Deoxydoxorubicin has been compared with doxorubicin as regards potency, antitumor activity and toxicity in tumored and non-tumored mice treated i.v. according to different schedules. 4'-Deoxydoxorubicin was 1.5-3 times more toxic and more potent than doxorubicin. At equitoxic doses, 4'-deoxydoxorubicin was: as active as doxorubicin against Gross leukemia, mammary carcinoma and MS-2 sarcoma; slightly less active than doxorubicin against B16 melanoma; more active than doxorubicin against colon 38 adenocarcinoma. The best schedule of administration of 4'-deoxydoxorubicin in mice was the weekly treatment. The strong effectiveness against colon 38 adenocarcinoma makes 4'-deoxydoxorubicin a particularly interesting new anthracycline derivative that deserves clinical trials.