The effect of cisplatin and the new drug cycloplatam (amine (cyclopentylamine)-S-(-)-malatoplatinum (II)) on protein kinase C (PKC) activity and Ca(2+)-dependent binding of PKC to T lymphocytes membranes was studied in vivo and in vitro. At first, the effect of the drugs on PKC activity of intact and activated lymphocytes was studied in vivo. In 48 hours after intraperitoneal injection of mice with therapeutic doses of the drugs, PKC activity of intact lymphocytes was differentially affected. Cisplatin did not practically alter the enzyme activity, whereas cycloplatam inhibited the PKC activity by 37% versus control. In lymphocytes activated by mouse P-388 leukemia cells in vivo, the drugs caused almost complete suppression of PKC activity and Ca(2+)-dependent binding of the enzyme to the membranes. The drugs were effective in intact cells. After incubation of intact lymphocytes in vitro for 24 hours with cisplatin or cycloplatam (10(-5)M), PKC activity was increased 1.62- and 1.35-fold, respectively, versus control. Ca(2+)-dependent binding of the enzyme to the membranes was also increased 1.61- and 1.36-fold by cisplatin and cycloplatam, respectively. On the contrary, at 10(-4) M concentration under similar conditions, the drugs did not affect the PKC activity of the lymphocytes. Furthermore, cycloplatam, unlike cisplatin, reduced the PKC binding to cellular membranes by 31%. The mechanisms of the drugs effects on PKC activity are suggested. The data indicate that increase or decrease of PKC activity induced by the drugs cause stimulation or depression of functional activity of T lymphocytes, respectively. Thus, the membrane-bound PKC can play the key role in initiation and development of immunomodulatory effects of cisplatin and cycloplatam.

Experiments on Wistar rats studied the state of the posterity born as a result of mating of intact females with males, who were injected with the antitumor drug platidiam one month before mating (once, intravenously, maximal tolerance dose). The pre- and postimplantation death rate did not grow in female rats mated with test males. However, the fetuses showed visceral anomalies and delayed development of skeleton. A decrease in the muscle tone, as well as ability for the training and extrapolation behavior, were observed in some newborn rat pups.

Plasmapheresis had a marked therapeutic effect in 14 cancer patients with grave myelotoxic complications of antitumor therapy: 13 of these patients survived, felt better, isosensitization to drugs and blood preparations was eliminated, the efficacy of common detoxifying and blood-substituting therapy improved. The therapeutic effect of the procedure was obvious even in the patient who died: the anuretic stage of acute renal failure changed for the polyuretic one. Plasmapheresis caused the most pronounced shifts in the system of homeostasis maintenance. The activation of the organism's autocleansing was attended by positive laboratory and clinical shifts.

A 22% response rate was achieved in clinical trials of Russian drug cycloplatam in disseminated and hormone-resistant cancer of the prostate. In 80% of cases the drug has improved quality of life of patients with prostatic cancer stage III and IV. Antitumor effect and low toxicity make cycloplatam applicable in combined therapy of prostatic cancer.

DNA damage of the tumor cells was studied by the method of alkali elution from filters after introduction of 1-methyl-1-nitrosourea (MNU) and 1,3-dimethyl-1-nitrosourea (DMNU) to mice with Ehrlich ascites carcinoma or after treatment of the cultivated cells with these drugs. DNA was essay fluorometrically using DAPI. The degree of DNA damage was characterized by the constant of the alkali elution rate (Kae), which was estimated according to the anamorphism of the kinetic curves of elution. It was shown that in the case of MNU application the tumor cell DNA was damaged to a greater extent than in the case of DMNU application. Kae increased with the concentration of drugs. A correlation was established between the antitumor activity of the drug (kappa), K(ae), and the number of chromosome defects per cell (gaps, deletions, microfragments, ring chromosomes, and translocations). This suggests that kappa is due both to DNA damage and chromosome defects.

N-alkyl-N-nitrosoureas exhibit a wide spectrum of antitumor activity. They react as alkylating agents at nucleophilic sites in purine and pyrimidine moieties of DNA. The predominant site of this alkylation is N7 of guanine, which is followed by the site N3 of adenine and 06 of guanine. The formation and persistence of 0(6)-alkylguanine (0(6)-AG) may be of primary importance in cytotoxicity of the nitrosoureas. 0(6)-AG adducts of DNA of the tumor cells are repaired by protein 0(6)-alkylguanine-DNA transferase (0(6)-AGT) which transfers the alkyl group to internal cysteine residue being the acceptor protein for the alkyl group in an irreversible transfer reaction. 0(6)-AGT can protect the tumor cells against 0(6)-AG adducts by the way of inhibiting the formation of the DNA interstrand cross-links 0(6)-AGT plays an important role in the drug resistance because it repairs the DNA alkyl adducts at the 0(6) position of guanine. The 0(6)-AGT activity inversely correlates with the cytotoxic effect of the nitrosoureas. The agents like 0(6)-methylguanosine, 0(6)-methyl-2'-deoxyguanosine, and some 0(6)-benzylated guanine derivatives are effective inactivators of 0(6)-AGT, and thus can be used to enhance the cytotoxicity of N-nitrosoureas. The activation of 0(6)-AGT and other repairing enzymes such as alpha and beta DNA-polymerases as well as an increase in the level of reduced glutathione may be used in developing the resistance to the nitrosoureas.

The experiments performed on Wistar rats showed morphological damages of the rat testis over a one-month period after platidiam administration (4 mg/kg, one-time intravenous injection), namely a decrease in the index of spermatogenesis, in the number of normal spermatogonia, Leydig cells, and testis tubes at the 12th stage of meiosis and an increase in the number of testis tubes squamous epithelium. In the remote period (3 and 6 month after platidiam administration) the recovery of morphological and functional state of the rat testis was observed.

Mutagenic (Ames tests) and genotoxic (SOS chromotest) activities of highly-efficient natural anthracycline monosaccharides possessing antitumor activity-daunorubicin (also known as daunomycin or rubomycin), doxorubicin (adriamycin), and carminomycin-were studied. At the same time, the hypothesis was tested that intercalation of the antibiotic moiety into the helix of cell DNA, which was mediated by the saccharide amino group, played a crucial role in genotoxicity of these anthracyclines. The hydrolysis products of these antibiotics (the corresponding aglycones) and aclacynomycin A (an anthracycline trisaccharide), as well as aclavinone (its derivative aglycone), were studied. All these compounds lacked the saccharide amino group necessary for intercalation. It was found that all anthracycline monosaccharides studied had a strong mutagenic effect on strain TA98 and a moderate effect on strain TA100 of Salmonella typhimurium. Aclacynomycin A was found to have no mutagenic effect on any strain. Lack of the glycoside amino group did not necessarily result in loss of mutagenic activity in the derivative aglycones of anthracycline monosaccharides: they exhibited moderate mutagenic activity in strain TA98 and low but significant activity in strain TA100. The S9 microsomal fraction did not alter the mutagenic activity of either anthracycline monosaccharides or their aglycones; however, it dramatically increased the mutagenic activity of aclavinone: correspondence between positive responses in Ames tests and the SOS chromotest was found. Apparently, the mutagenic activity of the substances studied in bacterial cells was mediated by inducing the SOS-repair process. If the compound contained the amino glycoside moiety, functional and structural precursors of the SOS response were formed via intercalation of the reagents into the DNA duplex; if the substance did not contain this moiety, the precursors were formed via ionic interaction.

The efficiency of site-specific interaction of target DNA with bleomycin derivatives of short nucleotides can be significantly increased using flanking effector oligonucleotides. The cleavage of a 20-mer single-stranded target DNA by a tetranucleotide containing a bleomycin A5 residue at the 5'-end was studied in the presence of effector oligonucleotides bearing phenazine residues at the 5'- and 3'-ends. In the presence of two effectors, the extent of the target DNA modification at 37 degrees C increased from 20 to 70%. Site-specific cleavage occurs, by up to 90%, at a single site of the target DNA. The melting temperature of the complementary complex formed by the bleomycin A5-modified tetranucleotide and target DNA in the presence of two effectors was 45 degrees C, whereas in the absence of the effectors, below 7 degrees C.

In the course of treatment for tumors and recurrences, 86 children, aged 4-16 years, received polychemotherapy which induced excessive vomiting. Navoban (tropisetron) was administered to control vomiting. Total or partial control of nausea and vomiting was observed in 94.1%. No side-effects were registered.

The results of clinical trials of Makmiror-Complex for treatment of infectious vulvovaginitis of mixed etiology are discussed. The study group included 15 patients, aged 18-50, who contracted infectious vulvovaginitis of mixed etiology in the course or shortly after radiation and/or chemotherapy for tumors. The drug proved highly effective.

A third series of randomized evaluation of postoperative (adjuvant) hormone therapy (tamoxifen, sinestrol and orimeten) was carried out in breast cancer patients. The study group involved 1.332 reproductive and postmenopausal females with stage I-III tumors. The investigation established quite a range of 10-year survival evidence versus stage and reproductive status; however, no significant differences were recorded in either of the groups. Untoward side-effects were more frequent when treating with diethyl-stilbestrol (over 30%) than with tamoxifen (3.5%). No significant differences were registered in five-year total and recurrence-free survival in the treatment with orimeten or tamoxifen.

The increasing doses of 2.4-3.5 g/m2 ifosfamide, i/v, dropwise, were administered for 40 min, on days 1-5 each week, for 3 weeks, in 4 courses. Simultaneously, MESNA was given in a dose two-thirds of that of ifosfamide. The maximum single tolerable dose of ifosfamide was 3.2 g/m2. The dose of 3.5 g/m2 proved neurotoxic causing encephalopathy. The other toxic effects were stage III-IV neutropenia (47%), nausea and vomiting (91%) and weakness (33%). No clinical evidence of renal failure was attributed to the high dosage of the drug in the course of assays of biochemical components of the blood, blood- and urine-beta-2-microglobulins, N-acetyl-D-hexoaminidase (NAG) level in urine, creatinine clearance and complex renoscintigraphy data. On days 3-5, ifosfamide treatment was followed by increase in NAG and beta-2-microglobulin levels in urine which pointed to the toxic effect exerted on the epithelium of renal tubules. The antitumor effect was apparent in 5 (29%) patients for 6 months, which testifies to the high effectiveness of ifosfamide treatment for soft-tissue sarcoma.

Toremifene (Fareston)-a novel antiestrogenic drug with a triphenylethylene structure-has been effective in the treatment of postmenopausal breast cancer patients. It is safely administered even in high doses up to 300 mg/day. The purpose of the study was to investigate the effect and tolerability of high dose toremifene in the treatment of patients with advanced renal cell carcinoma (RCC). Thirty six patients started the treatment with toremifene 300 mg/day. There were 26 males and 10 females. Mean age was 56.0 years, range 35-75 years. Nineteen patients were nephrectomized. One patient was not evaluable for response because of too short treatment time. The response rate was 17.1%, including 1 CR (2.9%) lasting for 121 + weeks and 5 PR (14.3%) with the mean duration of 39.8 + weeks. Ten cases of NC (28.6%) had the mean duration of 23.7 weeks. There were no significant differences in response rate when patients with lung metastases only were compared to patients with metastases of other sites with or without lung metastases. Total pain control was achieved in 45% and partial control in 20% of those patients who had pains in the beginning of the treatment. Ten patients (27.8%) had adverse reactions which led to discontinuation of the treatment in one case. It can be concluded that high-dose toremifene is an effective and safe means of palliative treatment in advanced RCC.

The endonuclease activity of two drug-sensitive and drug-resistant mouse myeloma cell lines during cytotoxic drug-induced apoptosis was studied. It was shown that internucleosomal fragmentation of DNA in drug-sensitive line sp2/0, undergoing apoptosis in the presence of adriamycin and colchicine, was not dependent on intracellular calcium content and was associated with activation of both Ca(2+)-Mg(2+)-dependent and acidic cation-independent endonucleases. In contrast, in multidrug resistant spEBR-5 cells, treated with the same drugs, only Ca(2+)-Mg(2+)-dependent endonuclease activity was detected. These data suggest that the differences in the pattern of endonuclease activity revealed in these cells are linked to drug-resistant phenotype and do not depend on the apoptosis-inducing agent used.