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Interaction of solid malignant tumours with optical beams
Abstracts / Cancer Genetics and Cytogenetics 203 (2010) 66e99
INTERACTION OF SOLID MALIGNANT TUMOURS WITH OPTICAL BEAMS M.L. Pascu2, R. Fumarel1, M. Gherghe1 1. “Professor Doctor Alexandru Trestioreanu” Institute of Oncology, Sos. Fundeni 252, Sector 3, Bucharest, Romania 2. National Institute for Laser, Plasma and Radiation Physics, 409 Atomistilor Street, Magurele, 077125, Bucharest, Romania
In photodynamic therapy (PDT), optical radiation is used to treat solid malignant tumours by using phototoxic agents, which may produce singlet oxygen after interaction with light photons. Recent experiments have shown that, besides the phototoxic agents used in PDT, other cytostatics currently used in cancer therapy may generate singlet oxygen or free radicals following interaction with light beams. Based on this approach, we report data obtained from common cytostatics used in conjunction with optical radiation for the treatment of the malignant tumours. The aim of this study is to get better insight into the interaction of cytostatics with malignant cells and to obtain better therapeutic options as compared to conventional chemotherapy. In relation to photostimulated chemotherapy, we here report, first, the action of the cisplatin on eye metastases when submitted to both cytostatics and uncoherent optical radiation. The possibility to increase the therapeutic index of cisplatin on metastases from a mammary neoplasm within the eye, when exposing the tumour eye zone to visibleeinfrared optical radiation, was studied. Two main lines of research were developed: (i) assess the physiological effect of uncoherent optical radiation on eye tissues “in vivo” and (ii) follow the evolution of the ocular metastases generated by a primary malignant breast lesion after applying a photo-chemotherapeutical treatment protocol that uses cisplatin in conjunction with exposure to optical beams of the tumour zone. Second, The action of methotrexate (MTX) as a photosensitizer in conjunction with optical irradiation of solid malignant tumours was studied. This requires knowledge on the intra-tumour retention time of the cytotoxic agent. This retention time can be measured by sequential scintigraphy and implies radioactive labelling with isotope 99mTc. Radioactive chromatography (RC) and ultravioletevisible absorption spectroscopy was used to confirm the possibility of synthesizing a radiopharmaceuticum (2,4 diamino 6-pertechnetate pterine) that pursues the biodistribution of MTX. Sequential scintigraphy showed that the intra-tumoural retention time of MTX lasts approximately one hour from the systemic administration in bolus.
77
GROWTH FACTOR RECEPTOR 1 AND 2 (HER1 AND HER2) GENE AND PROTEIN ASSESSMENT AND EVALUATION OF LAPATINIB PLASMA CONCENTRATIONS (PCS) IN BREAST CANCER PATIENTS Radek Trojanec1, Magdalena Cizkova1,3, Katerina Bouchalova1, David Friedecky2, Adriana Polynkova2, Anna Janostakova1, Marta Dziechciarkova1, Lenka Radova1, Marian Hajduch1, Bohuslav Melichar3, Karel Cwiertka3, Zdenek Kolar4 1. Laboratory of Experimental Medicine, Department of Paediatrics, Faculty of Medicine and Dentistry, Palacky University and Faculty Hospital Olomouc, Czech Republic 2. Laboratory for Inherited Metabolic Disorders, Department of Clinical Biochemistry, Faculty of Medicine and Dentistry, Palacky University and Faculty Hospital Olomouc, Czech Republic 3. Oncology Clinic, Faculty of Medicine and Dentistry, Palacky University and Faculty Hospital Olomouc, Czech Republic 4. Laboratory of Molecular Pathology, Department of Pathology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
Trastuzumab is a monoclonal antibody targeting HER2. Lapatinib, a tyrosine kinase inhibitor, targets HER2 and HER1 (also EGFR), but the HER1 status is not assessed in clinical practice. Drug plasma concentrations (PCs) may influence the treatment outcome. This study focuses on HER1 status, lapatinib PCs, and lapatinib treatment response. Retrospective tumor and blood samples from 28 lapatinib plus capecitabine treated patients (Pts) were used. HER1 gene, chromosome 7 (Ch7), and protein status were assessed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in archival tumors. Lapatinib PCs were evaluated by ultra performance liquid chromatographye tandem mass spectrometry. Blood samples were taken in 16 to 30 hours after lapatinib administration. The data were evaluated by standard statistical methods. Pts were treated with lapatinib plus capecitabine for advanced disease. Most tumors were invasive ductal carcinomas 82% (23/28); 43% (12/28) displayed hormonal receptor positivity. Lapatinib treatment lasted from 1.2 to 15.6 months. Twenty Pts ended lapatinib due to progression, 6 owing to toxicity. Ch7 polysomy was found in 30% (6/20) of Pts. HER1 amplification was not observed. HER1 membrane expression was found in 22% (5/23). Median of lapatinib PCs was 5.09 g/ml, with small interindividual variations. The exception was 1 patient (11.25 g/ml) with hepatotoxicity. HER1 IHC membrane positivity correlated negatively with disease-free survival (DFS) (p ! 0.014) and cytoplasmic positivity correlated negatively with DFS (p ! 0.017) and overall survival (OS) (p ! 0.035). Longer trastuzumab to lapatinib intervals correlated with longer OS (p ! 0.008). Intercalation of 5-FU based regimens between trastuzumab and lapatinib influenced negatively survival on lapatinib plus capacitabine (p ! 0.02). Intercalation of chemotherapy based on 5-FU before lapatinib plus capecitabine regimen reduces the treatment effect and suggests preselection of resistant cells before lapatinib plus capecitabine administration. Lapatinib PCs were higher in one patient who developed liver toxicity. Thus, measurement of PCs may be a way of identifying hepatotoxicity high risk patients and titering their lapatinib doses to avoid side effects. Supported by internal grant of the Faculty of Medicine and Dentistry, Palacky University, no. 91110301 and MSM 6198959216.
INTERACTION OF SOLID MALIGNANT TUMOURS WITH OPTICAL BEAMS M.L. Pascu2, R. Fumarel1, M. Gherghe1 1. “Professor Doctor Alexandru Trestioreanu” Institute of Oncology, Sos. Fundeni 252, Sector 3, Bucharest, Romania 2. National Institute for Laser, Plasma and Radiation Physics, 409 Atomistilor Street, Magurele, 077125, Bucharest, Romania
In photodynamic therapy (PDT), optical radiation is used to treat solid malignant tumours by using phototoxic agents, which may produce singlet oxygen after interaction with light photons. Recent experiments have shown that, besides the phototoxic agents used in PDT, other cytostatics currently used in cancer therapy may generate singlet oxygen or free radicals following interaction with light beams. Based on this approach, we report data obtained from common cytostatics used in conjunction with optical radiation for the treatment of the malignant tumours. The aim of this study is to get better insight into the interaction of cytostatics with malignant cells and to obtain better therapeutic options as compared to conventional chemotherapy. In relation to photostimulated chemotherapy, we here report, first, the action of the cisplatin on eye metastases when submitted to both cytostatics and uncoherent optical radiation. The possibility to increase the therapeutic index of cisplatin on metastases from a mammary neoplasm within the eye, when exposing the tumour eye zone to visibleeinfrared optical radiation, was studied. Two main lines of research were developed: (i) assess the physiological effect of uncoherent optical radiation on eye tissues “in vivo” and (ii) follow the evolution of the ocular metastases generated by a primary malignant breast lesion after applying a photo-chemotherapeutical treatment protocol that uses cisplatin in conjunction with exposure to optical beams of the tumour zone. Second, The action of methotrexate (MTX) as a photosensitizer in conjunction with optical irradiation of solid malignant tumours was studied. This requires knowledge on the intra-tumour retention time of the cytotoxic agent. This retention time can be measured by sequential scintigraphy and implies radioactive labelling with isotope 99mTc. Radioactive chromatography (RC) and ultravioletevisible absorption spectroscopy was used to confirm the possibility of synthesizing a radiopharmaceuticum (2,4 diamino 6-pertechnetate pterine) that pursues the biodistribution of MTX. Sequential scintigraphy showed that the intra-tumoural retention time of MTX lasts approximately one hour from the systemic administration in bolus.
77
GROWTH FACTOR RECEPTOR 1 AND 2 (HER1 AND HER2) GENE AND PROTEIN ASSESSMENT AND EVALUATION OF LAPATINIB PLASMA CONCENTRATIONS (PCS) IN BREAST CANCER PATIENTS Radek Trojanec1, Magdalena Cizkova1,3, Katerina Bouchalova1, David Friedecky2, Adriana Polynkova2, Anna Janostakova1, Marta Dziechciarkova1, Lenka Radova1, Marian Hajduch1, Bohuslav Melichar3, Karel Cwiertka3, Zdenek Kolar4 1. Laboratory of Experimental Medicine, Department of Paediatrics, Faculty of Medicine and Dentistry, Palacky University and Faculty Hospital Olomouc, Czech Republic 2. Laboratory for Inherited Metabolic Disorders, Department of Clinical Biochemistry, Faculty of Medicine and Dentistry, Palacky University and Faculty Hospital Olomouc, Czech Republic 3. Oncology Clinic, Faculty of Medicine and Dentistry, Palacky University and Faculty Hospital Olomouc, Czech Republic 4. Laboratory of Molecular Pathology, Department of Pathology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
Trastuzumab is a monoclonal antibody targeting HER2. Lapatinib, a tyrosine kinase inhibitor, targets HER2 and HER1 (also EGFR), but the HER1 status is not assessed in clinical practice. Drug plasma concentrations (PCs) may influence the treatment outcome. This study focuses on HER1 status, lapatinib PCs, and lapatinib treatment response. Retrospective tumor and blood samples from 28 lapatinib plus capecitabine treated patients (Pts) were used. HER1 gene, chromosome 7 (Ch7), and protein status were assessed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in archival tumors. Lapatinib PCs were evaluated by ultra performance liquid chromatographye tandem mass spectrometry. Blood samples were taken in 16 to 30 hours after lapatinib administration. The data were evaluated by standard statistical methods. Pts were treated with lapatinib plus capecitabine for advanced disease. Most tumors were invasive ductal carcinomas 82% (23/28); 43% (12/28) displayed hormonal receptor positivity. Lapatinib treatment lasted from 1.2 to 15.6 months. Twenty Pts ended lapatinib due to progression, 6 owing to toxicity. Ch7 polysomy was found in 30% (6/20) of Pts. HER1 amplification was not observed. HER1 membrane expression was found in 22% (5/23). Median of lapatinib PCs was 5.09 g/ml, with small interindividual variations. The exception was 1 patient (11.25 g/ml) with hepatotoxicity. HER1 IHC membrane positivity correlated negatively with disease-free survival (DFS) (p ! 0.014) and cytoplasmic positivity correlated negatively with DFS (p ! 0.017) and overall survival (OS) (p ! 0.035). Longer trastuzumab to lapatinib intervals correlated with longer OS (p ! 0.008). Intercalation of 5-FU based regimens between trastuzumab and lapatinib influenced negatively survival on lapatinib plus capacitabine (p ! 0.02). Intercalation of chemotherapy based on 5-FU before lapatinib plus capecitabine regimen reduces the treatment effect and suggests preselection of resistant cells before lapatinib plus capecitabine administration. Lapatinib PCs were higher in one patient who developed liver toxicity. Thus, measurement of PCs may be a way of identifying hepatotoxicity high risk patients and titering their lapatinib doses to avoid side effects. Supported by internal grant of the Faculty of Medicine and Dentistry, Palacky University, no. 91110301 and MSM 6198959216.