Biological effect of doxorubycin in standard (10(-3) mol/l) and ultra low doses (10(-5)-10(-20) mol/l) against some "signal" animal tumor systems--Lewis lung carcinoma, 755 adenocarcinoma, B-16 melanoma, Ehrlich carcinoma and L1210 leukemia was studied. The all models were very sensitive to the action of the drug in standard dose. Solid tumors' growth inhibition by 80-95% as well as increasing in life span of mice with L1210 leukemia by 86% in comparison with control and surviving of animals with Ehrlich carcinoma had been revealed. It had been shown that the drug in the area of ultra low doses occurred the following effects: inhibition of Lewis lung carcinoma growth by 80-95% compared to control after administration of the all tested ultra low doses; increasing of the life span of the animals with Ehrlich carcinoma and L1210 leukemia by 86-123% and 6-23%, correspondingly, upon the action of all tested ultra low doses; inhibition of B-16 melanoma growth by 50 and 70% after administration of the drug in doses 10(-20) mol/l and 10(-5) mol/l, correspondingly as well as deceleration of 755 carcinoma growth by 40% compared to control after action of the drug in the dose 10(-20) mol/l; stimulation of the B-16 melanoma growth by 20% relative to control after 10(-10) mol/l dose injection and enhancement of tumors sizes by 20-60% above control levels as a result of treatment of mice with 755 carcinoma by the drug in such ultra low doses as 10(-5) and 10(-15) mol/l. So, it was found that all tested tumor systems revealed certain sensitivity to the some ultra low doses of the drug. At the same time it was shown that doxorubycin in ultra low doses displayed alternative character of its biological effect, directivity of which varied according with the dose level and tumor strain.

To investigate the influence of pulse-therapy on anticoagulant system of the endothelium in patients with nonspecific aortoarteritis.

The antiestrogen drug tamoxifen, which is widely used in adjuvant hormone therapy of breast cancer, presents certain risk of causing hyperplasia and endometrial carcinoma. Our clinical data on 1,969 breast cancer patients (stage I-III) (tamoxifen--947; control--1,022) showed a double rise in endometrial carcinoma risk in cases receiving hormone therapy. Endometrial carcinoma incidence in tamoxifen-treated patients was 3% while in the untreated ones--1.6% (p < 0.05). According to the endometrial tissue study in 439 breast cancer patients, proliferative effect of tamoxifen in the form of endometrial hyperplasia was 5--6 times in tamoxifen users. Meanwhile, endometrial carcinoma and hyperplasia risk increased during a much longer exposure to tamoxifen and in combination with such factors as obesity, diabetes mellitus, uterine myoma and estrogen-type colpocytological response. Hence, breast cancer patients need to undergo dynamic follow-up of the endometrium including ultrasonic examination of the small-pelvis organs and cytological study of ecto- and endocervical smears and endometrial aspirates.

The effectiveness and tolerability of xeloda (capecitabine), a tumor-reactivated oral fluoropyrimidine, alone were investigated in 19 patients, aged 39-79, with relapsing and cisplatin-resistant ovarian tumors. Unfavorable prognosis of chemotherapy was in 11 cases (57.8%): cisplatin-resistant tumors (7) and early relapse--before month 6 (4). Xeloda was administered orally, 1,250 mg/m2, twice a day, for two weeks at an interval of one week. A total of 68 cycles (an average of 3.6 cycles) were evaluated. Complete response was registered in 1, partial--4, and stabilization--4 cases. Total response was in 26.3%, clinically significant effect--47.3% (9 out of 19). Toxic side-effects generally persisted with in stage I-II (palm-and-sole syndrome, leukopenia, neutropenia, sickness, vomiting, diarrhea) without interfering with the treatment.

The investigation has established a potential of low-dosage chemotherapy with cytostatics when used in combination with nitric oxide (NO) donor. Such regimen resulted in more animals being cured of leukemias P388 and L1210 and longer survival. Similar effect was reported with transplantable intracerebral leukemia P388 in which case mean survival after cyclophosphamide plus NO-donor was three times as high as that after cyclophosphamide alone. Combination therapy also promoted animetastatic effect: melanoma B16 inhibition by cyclophosphamide alone was 50% vs. 80% after cyclophosphamide plus NO-donor. NO-donor inhibited development of drug resistance to cyclophosphamide.

The authors have analyzed 48 cases of breast cancer detected among more than 16,000 patients with thyroid pathology including thyroid carcinoma. It was established that breast cancer associated with thyroid pathology (thyroid cancer included) had specific features of the clinical course. Relative risk of breast carcinoma in thyroid cancer patients was not higher than the incidence in female population. Possible etiologic and pathogenic factors of the relationship between thyroid pathology and breast tumors are discussed. It is supposed that hypersecretion of prolactin and gonadotropins might play some role in such association. Radiotherapy and chemotherapy for breast carcinoma also can be predisposing factors to the development of subsequent thyroid pathology.

Two methods of obtaining of 3 alpha-betulinic acid and related compounds from their 3 beta-epimers were studied: the reaction of bimolecular substitution and the stereoselective reduction of 3-ketoderivatives. The substitution of acyloxy by formyloxy group in 3-O-tosyllupeol or of the betulin hydroxyl by benzoyloxy group resulted only in delta 2, 3-elimination products, with none of the expected products of bimolecular substitution being found. The catalytic hydrogenation of betulonic acid over Raney nickel resulted only in reduction of the isopropenyl double bond, whereas the use of 5% Ru/C gave a 60:40 mixture of epimers of dihydrobetulinic acid. Practically the same mixture of betulinic acid epimers was obtained when reducing betulonic acid with L-Selectride. The cytotoxic activity of 3 alpha-betulinic acid increased toward melanoma Bro cells and decreased toward melanoma MS cells.

1-(2,3,5-Tri-O-acetyl)-beta-D-ribofuranosyl indole, the key compound in the synthesis of glycosides with the bis(indole) aglycone, was obtained for the first time by the indoline-indole method. There were synthesized 3-(1-methylindol-3-yl)-4-(1-glycosylindol-3-yl)furan(or pyrrole)-2,5-diones containing the residue of beta-D-ribofuranose or 2-deoxy-beta-D-ribofuranose and analogous glycosides of indolo[2,3-a]furano(or pyrrolo)[3,4-c]carbazol-5,7-diones, which are structurally relative to the antitumor antibiotic rebeccamycin. Their cytotoxicities toward a number of human tumor cell lines were studied in vitro, and the carbazole N-glycosides were shown to be more active than the bis-(indole) glycosides. At the same time, the ribofuranosides were found to be less active than the corresponding ribopyranosides synthesized previously.

A significant number of patients with colorectal cancer have metastases (MTS) to the liver. Cytoreductive surgery (CRS) and new antitumor drugs provide promising results. The aim of the study was to evaluate clinical results of CRS in combination with modern antitumor drug irinotekan (kampto). Forty-seven patients suffering from colorectal cancer with MTS to the liver were treated. Primary focus was resected. All the patients were divided into 4 groups depending on combination of surgical treatment and chemotherapy: with liver resection and complete removal (or devitalization) of metastatic lesions in combination with postoperative intravenous (group 1) or intraarterial regional (group 2) injection of Irinotekan and without resection of the liver with implantation of a catheter to the hepatic artery with postoperative intraarterial (group 3) or systemic intravenous (group 4) therapy with Irinotekan. Mean dose of kampto was 350 mg per 1 m2 of body surface. It was demonstrated that intraarterial infusion was highly effective. The follow-up in group 1 was 9.5 +/- 3.75 months, in group 2--11.3 +/- 4.2, in group 3--6.5 +/- 5.3, in group 4--4.6 +/- 2.3 months. It is concluded that cytoreduction of the the liver with intraarterial intrahepatic regional chemotherapy is an effective method of treatment of patients with metastatic colorectal cancer of the liver.

It was shown that hen egg-white lysozyme (LM) in the dose 100 mg/kg under the daily intragastral use slightly inhibited tumor grown or did not influence significantly upon it and did not change antitumor activity of cyclophosphamide. When used at mice C57Bl/6J with the transplanted ascitic or solid T-cell lymphoma EL4 (syngeneic system). On model of the same tumors in ascitic form at mice-hybrids (C57Bl/6J x DBA2)F1 (semisingeneic system) LM significantly potentiates antitumor activity of cyclophosphamide, though it had no effect on the rate of tumor growth. Potentiation of the effect of cyclophosphamide revealed itself in more slow development of ascite, increased mean life-span and the overall survival, appearance of completely cured animals. Our clinic-laboratory studies have revealed a sharp deficit of endogenic lysozyme in the blood serum of leukemic patients and extremely low lysozyme content in lavage liquid, from leukemic patients, with pneumonia. These data suggest that LM can be useful as a food additive in the complex treatment of oncological patients for enhancing antineoplastic chemotherapy efficacy.

The antiproliferative, differentiating and apoptogenic effects of purinic (cytidine and thymidine) and pyrimidinic (guanosine) nucleosides on K562 cells were investigated. Induction of erythroid differentiation (haemoglobin synthesis) in cancer cells was observed after 2 and 4 days incubation with 2 mM thymidine and 1 mM guanosine. Increase of haemoglobin synthesis in K 562 cells incubated with 2 mM cytidine was detected at 4 day. Analysis of the DNA-degrading effect (induction of apoptosis) of the reagents used on K 562 cells by fluorescent dyes and modulation activity of caspase 9 and also caspases 3,7,10 is induced with thymidine and guanosine but not with cytidine.

Elderly patients as a rule have modifications related to age (physiologic changes) and to other concomitant diseases (comorbidity). The glomerular filtration rate decreases with age. Before any chemotherapy is started creatinine clearance should be performed, and the doses of cytotoxic agents with active renal excretion should be modified according to creatinine clearance. Decreased liver blood flow may influence drug disposition. Some changes in liver function do occur with advanced age and may form the basis of some drug toxicities. The lean body mass in elderly people is characterized by an increase in fat, with a decrease in intracellular water, and this change, along with a decrease in serum albumin, can considerably modify drug pharmacokinetics. Decreasing in bone marrow reserve related to age increases the risk of myelotoxicity after cytotoxic therapy. Nevertheless chemotherapy may be tolerable and successful in elderly patients carefully selected. This article contains information about elderly cancer patients treated with cisplatin-based combinations (cisplatin + Vepesid + Nitrullyn, cisplatin + taxotere). There were no serious side effects.

We studied the effect of oxidative stress induced by hyperoxia, hydrogen peroxide, or menadione on mouse leukemia P388 cells at early (4 days) and late (7 days) stages of tumor growth. Oxidative stress proved to inhibit cell division and to induce apoptosis. Seven-day leukemia cells feature lower proliferative potential and higher sensitivity to oxidative stress and platidiam.

Cytotoxic activity of dammarane triterpenoids isolated from beach leaves was studied. These substances differ from the native ginseng genin (20(S)-protopanaxadiol) by the number, location, or configuration of OH-groups. Using fertilized egg cells of sea urchin Stronglyocentrotus intermedius we demonstrate that the orientation of C-3 OH-group has no effect on cytotoxic activity of triterpenoids as well as a higher activity of a triterpenoid with 3 alpha,12 beta-OH as compared to a C-3 ketone but lower activity as compared to a triterpenoid with 3 alpha,17 alpha-OH. Depending on the number of OH-groups the cytotoxic activity of triterpenoids decreases in the row: tetraol > pentaol > triol. Dammar-24-ene-3 alpha 2 beta,17 alpha,20(S)-tetraol (compound IV) is cytotoxic for the Ehrlich ascite carcinoma cells and this effect is additive to cytotoxic activity of anthracycline antibiotic carminomycin in vitro. Compound IV changes the permeability and microviscosity of the tumor cell membranes.

Evaluation of benzylpenicillin (penicillin G) effect for infection prophylaxis at the oncological patients with severe postcytostatic neutropenia was performed. All the patients with neutrophils levels lower than 0.5 x 10(9)/L were recommended to use antibiotics for infection prophylaxis. Test-group (n = 40) used ciprofloxacin (0.5 g twice daily, per os) combined with benzylpenicillin (1.0 g four times daily, i/v); control group was treated by ciprofloxacin in the same dose only. Combination with benzylpenicillin resulted in statistically significant reduction of infections frequency among oncological patients.

Functional activity of multidrug resistance (MDR) markers (total activity of ABC-transporters, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) activities) in human colon adenocarcinoma and normal mucosa was examined. Functional activity of ABC-transporters was revealed in all colon tumors and in 70% of normal mucosa samples investigated. Expression of Pgp and MRP functional activity was determined in about 50% and 70% of colon tumors respectively. Pgp+MRP+ phenotype was determined in 36% of normal mucosa and adenocarcinoma samples. Expression of Pgp+MRP- phenotype was practically the same in normal mucosa and tumors (in 10 and 18% of samples respectively). Pgp-MRP+ phenotype was revealed two times more often in tumors than in mucosa--in 36 and 18% respectively. On the contrary, Pgp-MRP- phenotype was detected more rarely in tumors than in mucosa (in 10 and 36% of samples respectively). Transporters different from Pgp and MRP were also determined in some tumors and normal mucosa. At the patients with expression of Pgp function in normal mucosa the activity of the transporter was revealed in 25% of tumor samples only. On the contrary, at the patients with expression of MRP function in normal mucosa the activity of the transporter was revealed in 70% of tumor samples. At the patients with no expression of Pgp or MRP activity in normal mucosa the function of the transporters in tumors was determined in 60% and 70% of samples respectively. It is concluded that functional activity of various ABC-transporters (Pgp, MRP and other different from Pgp and MRP) is expressed in human colon adenocarcinoma; expression of ABC-transporters functional activity in normal mucosa does not predict MDR phenotype of the tumor.

Sensitivity of 293 human epithelial kidney cells transfected by human cytochrome CYP450 gene to cyclophosphamide was investigated. Transfection was carried out by plasmid DNA containing CYP2B6 gene complexed with cationic liposomes. Liposomes were prepared from mixture of cationic lipids and cholesterol at different molar ratios. Experimental protocol included the following steps: transfection of epithelial kidney cells by complexes of plasmid DNA-cationic liposomes, clone selection in the medium with antibiotic Geneticin G418, selected clone harvesting and their treatment by cyclophosphamide as following cytotoxicity evaluation. It was shown that addition of 0.25 mM of cyclophosphamide resulted in death of 40-45% transfected cell population.

The biochemical and morphological study of the cytoskeleton and extracellular matrix of rat heart was carried out after single injection of adriamycin (2.2 or 0.44 mg/kg). Hearts were taken for the study after 2 hours and 3 weeks after injection. The light and electronic microscopy, immunohistochemical determination of type I, III and IV collagens and fibronectin using specific antibodies were implied for morphological study; electrophoresis and immunoblotting were implied for the determination of the content of some proteins of cardiomyocytes (KRP or telokin, desmin, tubulin and vinculin), and extracellular matrix (fibronectin) and vascular smooth muscle cells (MLCK, myosin light chain kinase). Adriamycin injection in the dose 2.2 mg/kg which is close to therapeutic and known to alter intracellular membranes approximately in the half of cardiomyocytes, did not influence the relative volume and structure of collagen network but distinctly reduced the density of fibronectin-distribution. The content of tubulin, fibronectin, MLCK and KRP was significantly decreased by 18-24%, while contents of desmin and vinculin were changed insignificantly. After 3 weeks, an increased density and extension of collagen network indicating the development of diffuse fibrosis were observed. Contents of tubulin and KRP were increased above control level by 50 and 20%, respectively. Similar hyperrestitution of tubulin, fibronectin and KRP content by 15-25% was determined after smaller dose of adriamycin (0.44 mg/kg). Only content of MLCK out of proteins studied remained at lower level in both groups by 25-34%. Isolated chick embryo cardiomyocytes subjected to adriamycin responded by increased level of KRP expression by 20% in 4 days while the level of tubulin expression remained unchanged. Results showed that damage of cardiomyocytes and extracellular matrix after single injection of adriamycin in the dose close to therapeutic was followed by increased expression of some proteins of cytoskeleton and extracellular matrix. KRP seems to play active role in this reparative response while the steadily reduced level of MLCK expression may disturb the control of coronary vessels.

The role of high-dose chemotherapy; with subsequent autologous bone marrow rescue (AutoBMR) for high risk or recurrence of advanced solid tumor was evaluated in 16 children (August 1998-March 2001). At present, 11 (69%) patients are still alive, showing no evidence of the disease, 11-31 mo after therapy (median follow-up of 17 mo). Tumor progression was reported in 5 (31%) at months 5, 6, 8, 9 and 11 (after AutoBMR rhabdosarcoma--3; Ewing's sarcoma--2). Overall and recurrence-free survival among all patients was 74 and 66%, respectively.