Smoking, hormonal factors and molecular markers in female lung cancer.

There has been substantial argumentation about differences in lung cancer occurrence and characteristics between men and women. Lung cancer incidence suggests that gender-related factors may influence lung cancer risk. The carcinogenic effect of tobacco smoke and the use of hormone replacement therapy could result in susceptibility to lung cancer among women. Mutations in EGFR and HER-2/neu genes, and ROS1 gene fusions may also play a role in gender-based survival rate differences. This review summarizes the latest data of disease markers and its usefulness in female lung cancer.

The value of MMP-9 for breast and non-small cell lung cancer patients' survival.

PURPOSE: Matrix metalloproteinases (MMPs) are implicated in cancer cells invasion and metastasis processes and have been investigated as potential cancer biomarkers. In this study MMP-9 gene expression and MMP-9 -1562 C/T polymorphism in breast and non-small cell lung cancer patients' blood and tumor samples and its correlation with clinicopathological parameters were investigated. MATERIAL/METHODS: MMP-9 gene expression was assessed by reverse transcription - polymerase chain reaction method in 108 cancer patients' blood and tumor samples. MMP-9 -1562 C/T polymorphism was determined by the polymerase chain reaction - based restriction fragment length polymorphism method. RESULTS: Significant relationship of MMP-9 gene expression and tumor differentiation grade was found only between groups with G1 and G3 breast tumors. Low survival rates were identified among positive MMP-9 expression in blood and ductal carcinoma of the breast (p=0.01) and negative progesterone receptor reaction (p=0.04). Significant differences in the distribution among genotypes were found between groups with stage I and stages III/IV (p=0.005) as well as between groups with lymph node status N0 and N1 (p<0.001). Breast cancer patients with tumor differentiation grade G3 and identified CC variant had a longer survival time (p=0.014). Shorter survival time was found among positive MMP-9 expression in tumor and stage I non-small cell lung cancer patients with negative lymph node (p=0.012) and squamous cell carcinoma (p=0.019). CONCLUSIONS: Expression of MMP-9 in blood and tumor together indicates worse prognosis for breast cancer patients.

Antioxidative system parameters and level of IL-18 after surgery in patients with renal cell carcinoma according to gender.

Functions of the antioxidative system and cytokines are important factors that can influence the development of cancer. The aim of this study was to determine gender-related differences in the concentration of inflammatory cytokine IL-18 and alterations of antioxidative system parameters after surgical treatment of renal cell carcinoma patients. The study comprised 40 patients (22 women and 18 men). The level of peroxidation product malonodialdehyde (MDA), the status of the antioxidative system and the concentration of interleukin-18 (IL-18) were analyzed. A significant difference in the changes of antioxidative system reflecting parameters was observed according to the gender. In the male group with higher IL-18 concentration after surgery the level of MDA was lower, while in the women group it did not change and the level of catalase activity was higher; superoxide dismutase activity was higher in both groups. It is important to notice that our previous study (where the data were not analyzed in respect of gender) showed that the level of IL-18 was significantly higher after surgical treatment if MDA content was increased. More detailed studies are required to confirm in which cases association between IL-18 concentration and MDA level is related to cancer progression and in which cases - to the better prognosis depending on the patients' gender.

Triple negative breast cancer: adjuvant chemotherapy effect on survival.

PURPOSE: The purpose of this study was to evaluate the overall survival of patients with triple negative breast cancer and the impact of different adjuvant chemotherapy regimens on survival. MATERIAL/METHODS: The study group consisted of 99 breast cancer patients with immunohistochemically confirmed triple negative breast cancer. The impact of various factors as well as the impact of different chemotherapy regimens on survival was evaluated. RESULTS: The overall survival of breast cancer patients was 97.0% (95% CI 90.9-99.0), 84.9% (95% CI 76.1-90.6) and 66.5% (95% CI 55.5-75.3) 10, 30 and 60 months after diagnosis, respectively. Univariate analysis demonstrated that the following were significant risk factors for breast cancer patients survival: patient's age, stage of disease, tumour size, lymph node status, type of surgery and chemotherapy. Better survival was related to younger patients' age, smaller tumour size, lower stage of disease, no lymph nodes involvement. Survival rates were higher among patients who received adjuvant chemotherapy and underwent quadrantectomy. In the multivariate statistical analysis the significant independent prognostic variables influencing survival were lymph node status and adjuvant chemotherapy. Survival rates of the patients, who received adjuvant anthracycline containing chemotherapy were higher, than those in non-anthracycline containing treatment group, but the difference was not statistically significant. CONCLUSION: Patients who had lymph node status N2-3 and those who did not receive adjuvant chemotherapy showed worse prognosis and survival than other patients. The impact of chemotherapy type (anthracycline containing or non-anthracycline containing) on patients survival was not statistically significant.

Evaluation of cytotoxic effect of photodynamic therapy in combination with electroporation in vitro.

Under the influence of electric pulses cells undergo membrane electroporation (EP), which results in increased permeability of the membrane to exogenous compounds. EP is applied in oncology as a method to enhance delivery of anticancer drugs. For that reason it was essential to combine photodynamic tumor therapy (PDT)--the cancer treatment method based on the use of photosensitizers that localize selectively in malignant tumors and become cytotoxic when exposed to light, and EP, with the aim to enhance the delivery of photosensitizers into the tumor and therefore to increase the efficacy of PDT. Thus, the aim of study was to evaluate the cytotoxic effect of PDT in combination with EP. A Chinese hamster lung fibroblast cell line (DC-3F) was used. The cells were affected by photosensitizers chlorin e(6) (C e(6)) at the dose of 10 mug/ml and aluminium phthalocyanine tetrasulfonate (AlPcS4) at the dose of 50 microg/ml. Immediately after adding of photosensitizers the cells were electroporated with 8 electric pulses at 1200 V/cm intensity, 0.1 ms duration, 1 Hz frequency. Then, after 20 min of incubation the cells were irradiated using a light source--a visible light passing through a filter (KC 14, emitted light from 660 nm). The fluence rate at the level of the cells was 3 mW/m(2). Cytotoxic effect on cells viability was evaluated using MTT assay. Our in vitro data showed that the cytotoxicity of PDT in combination with EP increases fourfold on the average. Based on the results we suggest that EP could enhance the effect of PDT.

Schedule-dependent interaction between Doxorubicin and mTHPC-mediated photodynamic therapy in murine hepatoma in vitro and in vivo.

PURPOSE: To evaluate cytotoxic and antitumor effects of a conventional anticancer drug Doxorubicin (Dox) and photodynamic therapy (PDT) mediated by a promising photosensitizer of second generation meta-tetra (3-hydroxyphenyl)-chlorin (mTHPC) in combination. METHODS: Murine hepatoma MH-22A was used for investigation in vitro and in vivo. In vitro, the cells were incubated with 0.15 microg/ml mTHPC for 18 h and exposed to light from LED array (lambda = 660+/-20 nm) at 0.6-2.4 kJ/m2. 0.05-0.2 microg/ml Dox was administered either 24 h prior to or immediately after light exposure (Dox-->PDT or PDT + Dox, respectively). The cytotoxicity was tested by staining with crystal violet. The character of the combined effect was assessed by multiple regression analysis. In vivo, the antitumor activity was estimated by monitoring the tumor volume over time, in mice transplanted subcutaneously with MH-22A and treated with Dox and/or PDT. For PDT, mice were exposed to light from diode laser (lambda = 650+/-2 nm) at 12 kJ/m2 following 24 h after administration of 0.15 mg/kg mTHPC. A 3 mg/kg Dox was administered either within 15 min prior to mTHPC or within 15 min after light exposure (Dox-->PDT or PDT + Dox, respectively). RESULTS: Both in vitro and in vivo, the combination of mTHPC-mediated PDT and Dox was evaluated to be more effective than each treatment alone. In vitro, the difference between cell viability curves after photodynamic treatment as a single modality and after combination of photodynamic treatment with Dox was statistically significant under most of the applied conditions (P < or = 0.02). In the case of PDT + Dox, the combination had an additive character, and the sequence Dox-->PDT caused a sub-additive interaction. In vivo, both regimens of combination were more effective in inhibiting tumor growth than any single treatment (P < 0.09). The antitumor activity of PDT + Dox regimen was more prominent than that of Dox-->PDT; however, significance of the difference was not high (P = 0.08). CONCLUSIONS: These results indicate that Dox potentiates therapeutic efficacy of mTHPC-mediated PDT and vice versa, and the degree of potentiation is influenced by the combination schedule: administration of Dox immediately after light exposure is preferable to administration of Dox at 24 h prior to light exposure.

Electroporation of transplantable tumour for the enhanced accumulation of photosensitizers.

The aim of this study was to verify whether electroporation could increase the accumulation of the hydrophilic photosensitizers: aluminium phthalocyanine tetrasulphonate (AlPcS(4)) and chlorin e(6) (C e(6)) in tumour tissue. The experiment was performed in vivo using hybrid mice (C57Bl/CBA) bearing hepatoma A22 (MH-A22) tumours transplanted in the right haunch. The time dependence of the fluorescence intensity of administered photosensitizers was measured after the ordinary and electrically stimulated delivery. The obtained fluorescence spectroscopy results implied the tumour being affected by an electrical field in a way, which led to a higher accumulation of both photosensitizers (AlPcS(4) and C e(6)) in the periphery of the tumour and it superficial layer. Our pilot study suggests that electroporation could be considered as a useful procedure seeking for the more effective application of photodynamic tumour treatment.

Effects of photodynamic therapy in combination with Adriamycin.

The combination of photodynamic therapy (PDT) and Adriamycin (ADM) was studied in the animal model system. Photohem (PH) was used as a photosensitizer. Mice bearing carcinoma epidermoides LL of the lung received PH once at a dose 10 mg/kg and after 24 h ADM was injected i.p. at a dose 3 mg/kg and tumors were illuminated with laser light after three different time intervals, 15 min, 3 and 24 h. To evaluate the effect of PDT and PDT combined with ADM the intensity of lipid peroxidation in tumor tissue and in blood serum was determined using the thiobarbituric acid assay. PDT induces an increase of malondialdehyde (MDA) concentration in tumor tissue as well as in blood serum. When PDT is combined with ADM, the MDA level in tumor tissue is similar to the level of this product as in the PDT alone. No enhancement of the efficiency of the combined treatment was observed at these experimental conditions. This is also confirmed by the tumor growth dynamics, survival time of animals and flow cytometric DNA analysis of tumor cells. For the successful combination of PDT with chemotherapy it is suggested to apply the drugs at the regimen which will allow to avoid the interaction between two agents since the ground state interaction between PH and ADM is stated spectroscopically. It should lead to the conclusion that the sequence of the combination of two treatment modalities is an important factor for synergistic effect.

Modulation of erythrocyte photohemolysis rate by glutathione reductase inactivating alkylating agents.

In order to determine the role of glutathione reductase (GR) in protection against Alphtalocyanine tetrasulfonate-sensitized human erythrocyte photolysis, we have studied the effects of antitumour alkylating agents that inactivate GR, on photohemolysis rate. The rates of inactivation of reduced GR decreased in order BCNU > pharanox (N-p-[bis-(2-chloroethyl)-amino]-phenylacetic acid N-oxide) > phenalol (N-p-[bis-(2-chloroethyl)-amino]-phenylacetyl-L- phenylalanine) > o-F- and p-F-lophenal (o- and p-isomers of N-p-[bis-(2-chloroethyl)-amino]-phenylacetyl-D,L-fluorophenylalanine) > D,L-melphalan. As supposed, erythrocyte photolysis was accelerated by BCNU and pharanox, however, it was slowed down by phenylalanine mustards. The latter effect was explained by singlet oxygen quenching and/or photooxidation reactions of these compounds. This points out to a possibility of certain phenylalanine derivatives to neutralize the side-effects of photodynamic therapy.

Embryotoxicity and teratogenicity of some derivatives of chloroethylaminophenylacetic acid.

Embryotoxic and teratogenic properties of Lophenal, Phenalon, Pharanox and Pharanoxi selenate were investigated experimentally. All examined antitumour agents showed embryotoxic effects. Lophenal, Phenalon and Pharanox had teratogenic effects. By modifying the structure of Pharanox with selenium a reduction in teratogenic effect was achieved.

Phototransformation of sensitisers: 3. Implications for clinical dosimetry.

Spectroscopic studies of aqueous solutions of haematoporphyrin-type sensitisers reveal that photobleaching during eposure to light is followed by the formation of stable red-absorbing photoproducts. Experiments in model systems (sensitisers bound to human serum albumin or in a suspension of resealed erythrocyte 'ghosts') and in tumour tissue show that similar photomodification takes place in all investigated environments. Loss of total absorption and emission intensities is accompanied by an increase of absorption in the red spectral region (630-650 nm) which is used for the treatment of tumours because of the deeper penetration of light into tissues. This should be taken into account when the duration of illumination is chosen to reach an appropriate photodynamic dose using Hp-type sensitisers in the photodynamic treatment of tumours.

Faranoxi-a new antitumor agent.

The aim of the present study was to evaluate the antitumor activity of faranoxi experimentally and clinically. Faranoxi is a derivative of chloroethylaminophenylacetic acid containing a cytostatic group modified by oxygen in its structure. It has a broad spectrum of antitumor activity in experimental studies. One hundred eighty-eight patients with different types of malignancies were included in clinical studies. At a dosage of 90-120 mg/m2 a day for 12-15 days faranoxi is relatively well tolerated. Clinical studies demonstrate the antitumor activity of faranoxi against melanoma, lymphoma and rectal cancer. It should be noted that primary melanoma was less responsive to faranoxi compared to lymphoid metastases. Using the combination regimen FDV (faranoxi, deticene, vincristine) as treatment of melanoma, partial remission was achieved in up to 50% of the cases. Clinical trials are ongoing.