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Patients with advanced malignant melanoma have poor prognosis as conventional chemotherapy induces complete response in a very small fraction (not more than 20%). One of research strategies aimed at raising its efficiency is the search for markers predicting individual response to chemotherapy. Our study was concerned with evaluation of the potential of DNA damage, repair (BER, MMR), expression of proteins MLH1, MSH2 and FasR as prognosticators of chemotherapy. These parameters were assessed in lymphocytes sampled from the blood of patients with metastatic cutaneous melanoma before and after one cycle of chemotherapy with lomustine, dacarbazine, cisplatin and interferon-gamma (LDCI). Clinical response was evaluated after a full course of therapy. We established that the major DNA damage induced by chemotherapy occurred on the levels of AP sites and single strand (SS) breaks. Despite the individual variations in BER efficacy, complete repair of SS breaks was reported in lymphocytes of all patients 30 days after the first cycle of chemotherapy. As a consequence, this type of damage and relevant BER efficacy did not correlate with clinical response. Conversely, the number of DNA double strand breaks detected in lymphocytes after the first cycle of chemotherapy was in good correlation with positive clinical response (p < 0.001). This parameter does not fully represent MMR function and, if coupled with cytotoxic effect of chemotherapy on lymphocytes, may be used as a predictive marker for clinical response to LDCI chemotherapy regimens for melanoma.

Previous studies demonstrated that patients with oligodendroglial tumors (OT) have longer overall and recurrence free survival than patients with other glial tumors of the same grade. Recent investigations showed high influence of genetic alterations on patients' outcome: overall and recurrence free survival increased in the case of presence 1p19q deletion and decreased in the presence of 9p or 10q deletion and/or EGFR amplification. In the series of 241 cases (107 male, 134 female patients, median age -- 38 years, (16-73)) we analyzed the impact of histology, tumor grade and genetic alterations on time to tumor progression (TTP). All patients underwent surgical resection of tumor or biopsy from 2000 to 2005. 70 patterns (oligodendroglioma (O) -- 13 cases, oligoastrocytoma (OA) -- 13, anaplastic oligodendroglioma (AO) -- 30, anaplastic oligoastrocytoma (AOA) -- 14) were assessed by fluorescent in situ hybridization. Median follow up was 24 months. The type of tumor (pure or mixed) didn't influence survival. TTP of patients with grade II and grade III tumors was 37.7 and 48.2 months, respectively (p = 0.035). Deletion 1p19q was noted in 34 (49%) cases. In pure O codeletion 1p19q was detected more frequently (in O -- 75%, in AO -- 56%) than in mixed tumors (in OA -- 31%, in AOA -- 35%). Deletions 9p, 10q and EGFR amplification were noted in 5, 6 and 4 cases, respectively. None of the tumors with 1pl9q deletion had other genetic alterations. Thus, we generated three prognostic groups: A -- deletion 1p19q; B -- balanced chromosomal profile; C -- deletion 9p. Median TTP in groups A, B and C was 46.6, 25.3 and 6.4 months, respectively (p < 0.001). The percentage of OT with 1p19q codeletion was lower than in previous studies. Pure O more frequently had 1p19q deletion than mixed tumors. Genetic alterations predict outcome stronger than histological criteria.

The spectrum of human antigens allows a monitoring of various pathological processes such as autoimmune disorders and tumorigenesis. Serological analysis of cDNA expression libraries (SEREX) is now used to search for new cancer-associated antigens, which are potential diagnostic markers or targets for immunotherapy of cancer. The results obtained for several solid tumors are reviewed. Groups of antigens detectable by SEREX, causes of immunogenicity of autoantigens, and prospective implication of antigens in diagnostics and monitoring of cancer are discussed.

The study of molecular-biological markers for prediction of recurrence-free survival in breast cancer stage I-IIA demonstrates that high expression of thymidilate synthetase and high maximal density of microvessels are prognostically effective and that the prognosis is influenced by expression of both Bcl-2 and Bax. Low recurrence-free survival was observed in Bcl-2-/Bax patients (31%, median 44 months) while such survival was high in Bcl-2+/Bax patients (86%, median was not reached). The findings can be used for prognostication of a breast cancer clinical course.

Expression of the mutant protein-suppressor of tumor growth p53 and the receptor of epidermal growth factor of type II--HER-2/neu may serve as prognostic factors for patients with chondrosarcoma of malignancy grade II. Combined expression of these proteins in the tumor tissue correlates with shorter 5-year survival of recurrence-free patients. The data obtained may be used for prognosis of chondrosarcoma course and choice of adequate therapy.

Clinical trials of bleomycetin and platidiam combination were carried out in 13 patients with disseminated melanoma of the skin. Two regimens of the treatment were used. Regimen I included intravenous administration of platidiam in a dose of 20 mg/m2 with a water load on days 2, 3, 4, 5 and 6 of the treatment course and intravenous administration of bleomycetin in a dose of 30 mg/m2 on days 1 and 7. The intervals between the courses consisted of 4 weeks. Regimen II included the use of platidiam in a dose of 20 mg/m2 administered as 6-hour intravenous infusions in 1.2 1 of isotonic sodium chloride solution daily for 5 days. On the first day of this cycle bleomycetin was administered intravenously in a dose of 30 mg/m2. The cycles were performed during the 1st and the 3rd weeks of the treatment course. During the 2nd and the 4th weeks platidiam was administered in a dose of 40 mg/m2 once a week and bleomycetin was administered intramuscularly in a dose of 6 mg/m2 daily for 5 days. A more than 50 per cent decrease in the tumor formation was observed in 38 per cent of the patients. The combination had no toxic effect on hemopoiesis and may be used in new programs on chemotherapy of disseminated melanoma of the skin.

Roentgenography of the cranium, ribs, vertebral column, pelvis and scintigraphy of the skeleton were performed every 3-4 mos in 39 patients with breast cancer metastases to the bones. Criteria of therapeutic efficacy were the following: a complete therapeutic effect, a partial therapeutic effect, stabilization and progression. In osteolytic metastases a complete therapeutic effect was obtained in 72% of the cases. Sixteen patients have been in remission during 16-36 mos.

Different schemes of prospidin administration to 54 patients were evaluated. Stage IV paresthesia or renal derangements are limitations of prospidin treatment due to its toxicity. Rheovasographic studies established that disorders in vascular tension are responsible for paresthesia development. The best results were obtained with the administration of 300-400 mg every other day for 2-3 weeks. Schemes of combined administration of prospidin and cyclophosphamide and bleomycin were worked out (58 cases). Therapeutic effect was recorded in the treatment of melanoma, carcinoma of the lip, tongue, nasopharynx, salivary gland and skin. Prospidin, cyclophosphamide and radiation therapy were successfully used in the management of small cell carcinoma of the lung.

Oral administration of deoxycytidine simultaneously with intraperitoneal injections of toxic doses of cytosine arabinosidetomice with advanced L1210 leukemia diminished the toxic effects preventing drug death of these mice. They developed a marked antitumor effect. The mean survival time of these mice was considerably extended as compared to that of untreated animals or those given one of these drugs alone. At the optimum schedule of treatment about 23% of the mice survived over 60 days. Deoxycytidine protection reduced the antileukemic effect of cytosine arabinoside administered in nontoxic doses. The deoxycytidine plus cytosine arabinose combination was ineffective in the treatment of transplantable myeloid leukemia in mice.

57 patients with disseminated tumors of various sites received 10 daily doses of 600 mg/m2 leakadin intravenously. The immunostimulating effect was observed (OKT4/OKT8 normalization). The data on leakadin pharmacokinetics are discussed.

The treatment schedule for disseminated breast carcinoma has been developed. It includes the use of adriamycin (30 mg/m2, days 1, 8, 15), methotrexate (30 mg/m2, day 1), 5-FU (600 mg/m2, day 8), and cyclophosphamide (400 mg/m2, day 15 i. v. by jet injection). A complete response was obtained in 50 to 56% of the patients, with remissions lasting for an appreciable period of time. The use of chemotherapy according to the described schedule combined with radiation of the bones of the pelvis and lumbar part of the spine brought about complete or partial reparation of the osteolytic, osteoblastic and mixed metastatic foci in 76.2% of the patients.

The efficacy of the chemotherapy of 16 patients with metastases of malignant tumors of the testicle was studied. The chemotherapy included vinblastine, platidiam and bleomycetin. The latter was used in a dose of 10 mg daily intramuscularly or as long-term intravenous infusions. As a result of the treatment complete and partial regression of the tumors was observed in 5 (31 per cent) and 4 (25 per cent) patients, respectively. Leukopenia was the main side effect. By present the total doses of bleomycetin had amounted to 250 mg for 4 patients and to 300-350 mg for 7 patients. No signs of pulmonary toxicity were observed with the use of these doses. The problem of clinical studies of bleomycin analogs is discussed.

LD50 of karminomycin, rubomycin and adriamycin were determined after their single administration or 3-, 5-, 10- and 15-fold administration once a day to 540 hybrid male mice F1(C57B1 X CBA). Comparison of the cumulative indices for these antibiotics showed that after injections they were close. After 5 injections the cumulative properties were more pronounced for adriamycin. After 10 or 15 injections the cumulative properties were less pronounced for karminomycin.

During the 1st stage of the clinical trials of karminomycin 92 patients with leukemia, solid tumors and lymphoma were treated with karminomycin. Two schemes for the antibiotic use were developed. The 1st scheme was a prolonged one with single doses of 10-15 mg (7.5 mg/m2) administered intravenously twice a week for 3 weeks, the course dose being 60-75 mg (34-45 mg/m2) with 4-week intervals between the courses. The course dose for the patients previously subjected to intensive chemotherapy did not exceed 50 mg (30 mg/m2). The 2nd scheme was a short one with single doses of 8-10 mg (5.5 mg/m2) administered intravenously every day for 5 days, the course dose being 40-50 mg (23-30 mg/m2) with 3-week intervals between the courses. Karminomycin induced in a number of patients a direct side effect, such as nausea, vomiting, asthenia, tachycardia, pain in the heart. In some patients leucopenia, thrombocitopenia, rare stomatitis, alopecia, lowered T peak in the chest curves of the cardiograms were observed after using the course dose.

Methodologic principles of evaluation of newly-developed antitumor drugs for solid tumors are discussed.

A total of 39 patients with sarcoma of the soft tissues were treated with carminomycin administered intravenously in doses of 10-15 mg twice a week, the total dose being 60-70 mg. The intervals between the courses were 1 month. The objective effect was observed in 17 out of 39 patients, i. e. 43.6%. The tumor decrease was registered in 6 out of 15 patients with leuomyosarcoma, in 3 out of 6 patients with synovial sarcoma, in 2 out of 4 patients with robdomyosarcoma, in 1 out of 4 patients with angiosarcoma, in 1 out of 3 patients with fibrosarcoma, in 1 patient with liposarcoma and in 3 out of 5 patients with stromal sarcoma of the uterus. A necessity for repeated treatment courses in spite of a positive effect or absence of the disease progress is underlined.

Thirteen patients with neglected mammary cancer were treated with karminomycin in combination with hexamethylmelamine. Twelve out of the 13 patients were previously subjected many times to cytostatic and hormonal therapy. A significant therapeutic effect was registered in 5 out the 13 patients (38 per cent), the total rate of the objective effect being 54 per cent. The remission period with a significant effect was 6 to 9 months. Fifteen patients with sarcoma metastases in the soft tissue were treated with karminomycin in combnation with methotrexate and cyclophosphane. A significant therapeutic effect was observed in 45 per cent of the cases with synovial sarcoma, hemangyopericitoma and leuomyosarcoma, the remission period being 4 to 12 months. The side effects of the above combinations were determined.

In 7 oncological institutions of the Soviet Union a correlation was made between the efficacy of fluorofur, hexamethylmelanin and their combination for advanced cancer of the mammary gland in 136 patients. The therapeutic effect was estimated in 104 patients. Fluorofur yielded a considerable tumor regression (more than 50%) in 14 of 36 patients (40%), the duration of the remission in effectively treated patients was 2--5 months. Hexamethylmelanin induced a therapeutic effect in 18 of 37 patients (48%), the regression being complete in 6 patients (16%), its duration was 2--7 months. The combination of these drugs proved to be of an insignificant effect, the therapeutic effect was obtained in 5 of 31 patients (16%), the remission lasted for 1.5--5 months. The fluorofur therapy is rarely accompanied with adverse side effects (leucopenia--in 17%), while with hexamethylmelanin the incidence of leucopenia was 46%, a combination of the drugs reducing it up to 17%. Hexamethylmelanin combined with fluorofur was tolerated much more poorly (vomiting). Fluorofur and hexamethylmelanin are effective drugs for treatment of patients with advanced breast cancer.

Administration of orimeten (aminoglutethimide), for disseminated breast cancer in 38 postmenopausal females, in whom other treatment modalities had failed, proved effective in 39%. Patients who had failed on tamoxifen responded to orimeten. Such side-effects as skin rash, drowsiness and cardiovascular disturbances were not pronounced. Limiting toxicity was 6%.

Side reactions and therapeutic effect of carminomycin were studied in 21 children with various malignant tumors. Carminomycin was administered intravenously in doses of 0.15-0.2 mg/kg twice a week for 2-3 weeks. The treatment courses were repeated in a month. The drug was better tolerated by children than by adults. After the treatment course leucopenia may develop. When used alone or in combination with vincristin or cyclophosphan carminomycin proved to be effective in treatment of sarcoma of the soft tissues (liposarcoma, synovial sarcoma), chondrosarcoma and reticulosarcoma.

The experience gained in the treatment of 111 cases of testicular tumor is summarized in the paper. Methods of management of testicular cancer in the eighties differ significantly from those employed in the seventies. A set of drugs used is different. The share of cases of monochemotherapy has decreased markedly. PVB and VAB-6 schemes are highly effective inducing complete or partial remission in 80-90% of cases. Issues of treatment of patients with massive metastases in retroperitoneal lymph nodes and lungs remain unresolved. Timely diagnosis of dissemination will improve chemotherapy results.

The pharmacokinetics of reumycin, an antitumor antibiotic, was studied with high performance liquid chromatography in patients with tumors of the brain and kidneys. The drug was injected intravenously in single doses of 30-300 mg. It was shown that the pharmacokinetics of reumycin was nonlinear and within every dose could be depicted by a three- or two-compartmental model. Its nonlinearity was due to saturation of the antibiotic binding to blood plasma proteins. 20-40 per cent of the intact antibiotic was excreted with the urine unchanged, which indicated a significant role of extrarenal excretion of the antibiotic. The dose dependence of the pharmacokinetic parameters and in the particular of the area under the reumycin blood concentration on the time curve and cumulative renal excretion varied with patients. Distribution of patients by these parameters was bimodal. This factor and the differences in renal excretion caused significant variability in the reumycin pharmacokinetics, which required individualization and control of the antibiotic use in patients. The reumycin half-life in man predicted with the use of the Dedrick pharmacokinetic time scale by the data of experiments on rats appeared close to that established in patients (41 and 33.5 hours, respectively).

The in vitro experiments on CaOv cells demonstrated that ribamidyl (ribavirine) (Rb) enhances the intracellular pool of pyrimidine precursors of DNA. This was the basis for studies of its modifying effect on the antitumour activity of antimetabolites. In experiments with intact hybrid mice F1 (CBA+C57B1) the five times administration of ribavirine increase sharply the toxicity of 5-FU. The data should be taken into consideration when combining Rb with antimetabolites in clinical practice.

The results of utilization of different variants of the complex therapy in 416 patients with inoperable lung cancer are reported. 5-fluoruracil, cyclophosphan, methotrexate, chrysomallin were employed as antitumor drugs. Radiotherapy was carried out on a distance gamma machine. The best immediate and early results were gained in patients treated by distance gammatherapy against the background of cyclophosphan injections. The results proved to be most favourable within the terms of 3 years and longer in case of gammatherapy associated with 5-fluoruracil. Application of a fractionated radiation course rendered no positive effect on the results of treatment.

Karminomycin was used for the treatment of cases with disseminated cancer of the mammary gland in doses of 5 mg/m2 of the body surface intravenously every day for 5 days (15 patients) or 6 mg/m2 twice a week for 2-3 weeks (30 patients). Partial remission or diminution of the tumor size at least by 50 per cent was observed in 26 and 17 per cent of the patients respectively. The remission duration was from 2 to 6 months. With the use of the shortperiod scheme the frequency of the direct side reactions increased. Leucopenia as a side effect was registered in 100 and 40 per cent of the patients and thrombocytopenia was registered in 18 and 3 per cent of the cases respectively.