ABSTRACT
In order to provoke an immune response, a tumor vaccine should not only maximize antigen-specific signals, but should also provide the necessary "co-stimulatory" environment. One approach is to genetically manipulate tumor cells to either secrete lymphokines (GM-CSF, IL-12, IL-15) or express membrane bound molecules (CD80, CD86). Furthermore, patient dendritic cells can be loaded with tumor-associated antigens or peptides derived from them and used for immunotherapy. Genetic modification of dendritic cells can also lead to presentation of tumor-associated antigens. Transfection of dendritic cells with DNA encoding for such antigens can be done in vitro, but transfection efficiency has been uniformly low. Alternatively, dendritic cells can also be modulated directly in vivo either by "naked" DNA immunization or by injecting replication-deficient viral vectors that carry the tumor specific DNA. Naked DNA immunization offers several potential advantages over viral mediated transduction. Among these are the inexpensive production and the inherent safety of plasmid vectors, as well as the lack of immune responses against the carrier. The use of viral vectors enhances the immunogenicity of the vaccine due to the adjuvant properties of some of the viral products. Recent studies have suggested that the best strategy for achieving an intense immune response may be priming with naked DNA followed by boosting with a viral vector. We have successfully completed a phase I and phase II clinical trials on immunotherapy of prostate cancer using naked DNA and adenoviral immunizations against the prostate-specific membrane antigen (PSMA) and phase I clinical trial on colorectal cancer using naked DNA immunization against the carcinoembryonic antigen (CEA). The vaccination was tolerated well and no side effects have been observed so far. The therapy has proven to be effective in a number of patients treated solely by immunizations. The success of the treatment clearly depends on the stage of the disease proving to be most efficient in patients with minimal disease or no metastases. A panel of changes in the phenotype of peripheral blood lymphocytes and the expression of intra-T-cell lymphokines seems to correlate with clinical improvement.
Subject(s)
Antigens, Neoplasm/genetics , Cancer Vaccines/administration & dosage , Colorectal Neoplasms/therapy , Prostatic Neoplasms/therapy , Adenoviridae/genetics , DNA, Viral/genetics , Dendritic Cells/metabolism , Genetic Vectors , Humans , Interferon-gamma/metabolism , Interleukin-4/metabolism , Leukocytes, Mononuclear , Lymphocyte Subsets , Male , Transfection , Treatment Outcome , Vaccines, DNA/administration & dosageABSTRACT
The effect of vitamins A, C and E, butylated hydroxytoluene (BHT) and glutathione (GSH) on gastric carcinogenesis induced by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) was investigated. Male and female BD-VI rats 2-3 months old received a single oral application of MNNG dissolved in corn oil. The male rats were divided into four groups: Group-I: MNNG 250 mg/kg by intubation; Group-II: MNNG + vitamin C daily in the drinking water (400 mg/l); Group-III: MNNG + vitamin C (400 mg/l) + 100 g of milk broth (for each of 10 rats) containing vitamin A (40,000 IU), vitamin E (0.5 g) and BHT (0.1 g) three times a week. The treatment with antioxidants started 7 days before the MNNG administration and continued until the end of experiment. Group-IV rats received MNNG + oxyferriscorbone, i.p. as a single dose of 1.0 mg/kg, daily during the week before and the week after MNNG exposure and than 3 times a week till the end of the experiment. Female rats were divided into two groups: Group-I: MNNG 333 mg/kg by intubation; Group-II: MNNG + GSH orally at a dose of 100 mg/rat 1 h before and 5, 24, 48, and 72 h after MNNG intubation. The incidence of gastric tumors after 15 months of treatment was as follows: male rats, 82.4% in Group-I, 40.0% in Group-II, 40.7% in Group-III, and 50.0% in Group-IV; female rats; 72.7% in Group-I, and 36.0% in Group-II.
Subject(s)
Antioxidants/pharmacology , Methylnitronitrosoguanidine , Stomach Neoplasms/chemically induced , Animals , Ascorbic Acid/pharmacology , Butylated Hydroxytoluene/pharmacology , Drug Interactions , Female , Glutathione/pharmacology , Male , Rats , Vitamin A/pharmacology , Vitamin E/pharmacologySubject(s)
Enbucrilate/toxicity , Neoplasms, Experimental/chemically induced , Tissue Adhesives/toxicity , Abnormalities, Drug-Induced/etiology , Animals , Bulgaria , Cricetinae , Female , Kidney/drug effects , Male , Mesocricetus , Mice , Mutagenicity Tests , Pregnancy , Rats , Rats, Inbred Strains , Skin/drug effectsABSTRACT
In villages with endemic nephropathy (EN) high incidence and mortality rates of some urinary system tumors are reported. Age-adjusted incidences of renal pelvic and ureteral neoplasms were 46/10(5) in females and 27/10(5) in males; for urinary bladder tumors these figures were 16/10(5) and 35/10(5). The frequency of parenchymal kidney tumors was similar to that reported for the country as a whole. An increased relative risk of developing urinary system tumors was observed in patients with EN and with advancing age (only in women). Smoking did not relate to the occurrence of these neoplasms. No tumors of the urinary system were found in the investigated farm and domestic animals from the endemic region.
