[Effectiveness of DNA repair and expression of MLH1, MSH2 and FASR in lymphocytes of patients with chemotherapy-responsive, disseminated cutaneous melanoma].

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.

[Influence of molecular-genetic factors on prognosis in patients with oligodendroglial tumors].

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.

Clinical study of combined use of tomudex (raltitrexed) and xeloda (capecitabine) as first-line treatment for patients with metastasizing colorectal cancer.

We studied the efficiency of combined chemotherapy with tomudex and xeloda preparations in patients with metastasizing colorectal cancer. The treatment (240 courses) was effective in 75% patients. Time median before progression was 6.3 months, mean durations of partial remission and stabilization were 7.8 months, total survival 15.5 months, total survival after effective treatment was 18.2 months. The most prevalent manifestations of III-IV degree toxicity were neutropenia, diarrhea, and asthenia. Other symptoms of toxicity (increased transaminase level, bilirubin, nausea, vomiting) were observed in less than 3% courses. Thus, treatment with tomudex and xeloda are effective and safe for outpatient chemotherapy.

Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 3. Inhibitory effect of SkQ1 on tumor development from p53-deficient cells.

It was proposed that increased level of mitochondrial reactive oxygen species (ROS), mediating execution of the aging program of an organism, could also be critical for neoplastic transformation and tumorigenesis. This proposal was addressed using new mitochondria-targeted antioxidant SkQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) that scavenges ROS in mitochondria at nanomolar concentrations. We found that diet supplementation with SkQ1 (5 nmol/kg per day) suppressed spontaneous development of tumors (predominantly lymphomas) in p53(-/-) mice. The same dose of SkQ1 inhibited the growth of human colon carcinoma HCT116/p53(-/-) xenografts in athymic mice. Growth of tumor xenografts of human HPV-16-associated cervical carcinoma SiHa was affected by SkQ1 only slightly, but survival of tumor-bearing animals was increased. It was also shown that SkQ1 inhibited the tumor cell proliferation, which was demonstrated for HCT116 p53(-/-) and SiHa cells in culture. Moreover, SkQ1 induced differentiation of various tumor cells in vitro. Coordinated SkQ1-initiated changes in cell shape, cytoskeleton organization, and E-cadherin-positive intercellular contacts were observed in epithelial tumor cells. In Ras- and SV40-transformed fibroblasts, SkQ1 was found to initiate reversal of morphological transformation of a malignant type, restoring actin stress fibers and focal adhesion contacts. SkQ1 suppressed angiogenesis in Matrigel implants, indicating that mitochondrial ROS could be important for tumor angiogenesis. This effect, however, was less pronounced in HCT116/p53(-/-) tumor xenografts. We have also shown that SkQ1 and related positively charged antioxidants are substrates of the P-glycoprotein multidrug resistance pump. The lower anti-tumor effect and decreased intracellular accumulation of SkQ1, found in the case of HCT116 xenografts bearing mutant forms of p53, could be related to a higher level of P-glycoprotein. The effects of traditional antioxidant N-acetyl-L-cysteine (NAC) on tumor growth and tumor cell phenotype were similar to the effects of SkQ1 but more than 1,000,000 times higher doses of NAC than those of SkQ1 were required. Extremely high efficiency of SkQ1, related to its accumulation in the mitochondrial membrane, indicates that mitochondrial ROS production is critical for tumorigenesis at least in some animal models.

Variations in the number of regulatory T cells (CD4+CD25+) in patients with breast cancer during herceptin therapy.

We studied the effect of Herceptin therapy on the population composition of lymphocytes and percentage of CD4+CD25+ cells (regulatory T cells) in breast cancer patients. Herceptin treatment decreased the number of "professional" T suppressors (CD4+CD25+ cells and regulatory T cells) in the peripheral blood.

Sensitivity to further endocrine therapy is retained following progression on first-line fulvestrant.

There is a need for new endocrine agents that lack cross-resistance with currently available treatments to extend the endocrine treatment window and delay the need for cytotoxic chemotherapy. This retrospective analysis evaluated the response of postmenopausal patients with previously untreated metastatic/locally advanced breast cancer to further endocrine treatment following progression on first-line fulvestrant or tamoxifen. Patients received fulvestrant 250 mg (intramuscular injection every 28 days) plus matching tamoxifen placebo (once daily), or tamoxifen 20 mg (orally once daily) plus matching fulvestrant placebo (every 28 days) in a double-blind, randomized, phase III trial. Treatment continued until disease progression or withdrawal, when further endocrine therapy was initiated (at the treating physician's discretion). Information regarding subsequent therapies and responses was obtained by follow-up questionnaire. Two-hundred-and-forty-five questionnaires were returned (from 587 patients), 149 of which yielded follow-up data on patients receiving second-line endocrine therapy following fulvestrant (n=83) and tamoxifen (n=66). Second-line therapy produced objective responses (OR) in 6/44 (13.6%) and clinical benefit (CB) in 25/44 (56.8%) patients who had CB with fulvestrant and produced OR in 5/41 (12.2%) patients and CB in 27/41 (65.8%) patients who had CB with first-line tamoxifen. For patients deriving no CB from trial therapy, second-line therapy produced OR in 3/39 (7.7%) and CB in 15/39 (38.5%) patients in the fulvestrant group and OR in 4/25 (16.0%) and CB in 12/25 (48.0%) patients in the tamoxifen group. Results from this questionnaire-based study suggest that postmenopausal women with advanced breast cancer who respond to first-line fulvestrant or tamoxifen retain sensitivity to subsequent endocrine therapy.

Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer.

Bone metastases occur in most women with advanced breast cancer and can lead to considerable morbidity and a rapid deterioration in the patient's quality of life. It was the aim of the present study to assess changes in quality of life and bone pain due to intravenous (i.v.) ibandronate, a potent third-generation bisphosphonate. In a phase III randomised, double-blind, placebo-controlled trial in patients with bone metastases due to breast cancer, 466 women were randomised to receive placebo, 2 mg ibandronate or 6 mg ibandronate for up to 96 weeks. Treatment was administered i.v. at 3- or 4-weekly intervals. Clinical endpoints included the incidence of adverse events, quality of life (assessed using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Scale - Core 30 questionnaire (QLQ-C30)), and bone pain (assessed on a 5-point scale from 0=none to 4=intolerable). Ibandronate was generally well tolerated. Compared with baseline measurements, the bone pain score was increased at the last assessment in both the placebo and 2 mg ibandronate groups, but was significantly reduced in the patients receiving 6 mg ibandronate (-0.28+/-1.11, P < 0.001). A significant improvement in quality of life was demonstrated for patients treated with ibandronate (P < 0.05) for all global health status. Overall, at the last assessment, the 6 mg ibandronate group showed significantly better functioning compared with placebo (P = 0.004), and had significantly better scores on the domains of physical, emotional, and social functioning, and in global health status (P < 0.05). Significant improvements in the symptoms of fatigue and pain were also observed in the 6 mg ibandronate group. I.v. ibandronate treatment leads to significant improvements in quality of life, and is an effective and well-tolerated palliative treatment in patients with bone metastases due to breast cancer.

[Serological study of a repertoire of human cancer antigens and autoantigens]. / Serologicheskie issledovaniia reperatura rakovykh antgenov i autoanigenov cheloveka.

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.

Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases.

BACKGROUND: This phase III study compared the efficacy of the new potent bisphosphonate, ibandronate, with placebo as intravenous (i.v.) therapy in metastatic bone disease due to breast cancer. PATIENTS AND METHODS: A total of 466 patients were randomised to receive placebo (n = 158), or 2 mg (n = 154) or 6 mg (n = 154) ibandronate every 3-4 weeks for up to 2 years. The primary efficacy parameter was the number of 12-week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Bone pain, analgesic use and safety were evaluated monthly. Results SMPR was lower in both ibandronate groups compared with the placebo group; the difference was statistically significant for the ibandronate 6 mg group (P = 0.004 versus placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also experienced decreased bone pain scores and analgesic use. Treatment with ibandronate was well tolerated. CONCLUSIONS: These results indicate that 6 mg i.v. ibandronate is effective and safe in the treatment of bone metastases from breast cancer.

Expression of Flt-1 and Flk-1 receptors for vascular endothelial growth factor on tumor cells as a new prognostic criterion for locally advanced breast cancer.

We studied expression of Flt-1 and Flk-1 receptors on tumor cells obtained from 83 patients with locally advanced breast cancer after neoadjuvant chemotherapy. The mean period of observations was 32.3 months. The median recurrence-free survival periods for Flt-1(+) and Flt-1(-) patients were 55 and 32 months, respectively (p=0.0064). The overall survival periods for Flt-1(-) and Flt-1(+) patients were 45 and 67.6 months, respectively (p=0.014). The mean recurrence-free survival periods for Flk-1(+) and Flk-1(-) patients were 40.8 and 60.9 months, respectively (p=0.035). Expression of VEGF had no prognostic value. Our results show that overexpression of Flk-1 on breast cancer cells in patients receiving neoadjuvant chemotherapy is associated with a poor prognosis. By contrast, overexpression of Flt-1 improves survival.

[Molecular-biological markers as prognostic factors in breast cancer of I-IIA stage]. / Molekuliarno-biologicheskie markery kak faktory prognoza pri rake molochnoi zhelezy I-IIA stadii.

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.

[Prognostic significance of p53, HER-2/neu, Ki-67 and VEGF expression in chondrosarcomas]. / Prognosticheskoe znachenie ékspressii p53, HER2/neu, Ki-67 i VEGF v khondrosarkomakh.

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.

Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia.

Hypercalcaemia is an important cause of morbidity in malignant disease. We studied the efficacy and safety of intravenous ibandronate (a new, potent bisphosphonate) in a multicentre study of 147 patients with severe cancer-associated hypercalcaemia which had been resistant to treatment with rehydration alone. Of 131 randomized patients who were eligible for evaluation, 45 were allocated to receive 2 mg ibandronate, 44 patients to receive 4 mg and 42 patients to receive 6 mg. Serum calcium values fell progressively in each group from day 2, reaching a nadir at day 5, and in some patients normocalcaemia was maintained for up to 36 days after treatment. The 2-mg dose was significantly less effective than the 4-mg or 6-mg dose in correcting hypercalcaemia, as the number of patients who achieved serum calcium values below 2.7 mM after treatment was 50% in the 2-mg group compared with 75.6% in the 4-mg group and 77.4% in the 6-mg group (P < 0.05; 2 mg vs others). In a logistic regression analysis, three factors were found to predict response; ibandronate dose (higher doses were more effective), severity of presenting hypercalcaemia (severe hypercalcaemia was associated with less complete response) and tumour type (patients with breast carcinoma and haematological tumours responded better than those with other tumours). Ibandronate was generally well tolerated and no serious drug-related adverse events were observed. We conclude that ibandronate is a safe, well tolerated and effective treatment for cancer-associated hypercalcaemia, which should prove a useful addition to the current range of therapies available to treat this condition.