RESUMEN
BACKGROUND: Vascular endothelial growth factor (VEGF) is a hypoxia-induced endothelial cell-specific mitogen, which is angiogenic in vivo and up-regulated in several malignancies. VEGF can be used as a prognostic marker, but the effect of surgical trauma on serum VEGF (S-VEGF) concentrations is unknown and might reduce the value of VEGF as a serum marker. METHODS: We monitored S-VEGF levels by enzyme-linked immunosorbent assay in patients undergoing surgery. RESULTS: Eighteen patients with major surgery had slightly elevated S-VEGF compared with the preoperative level (median 9.5 pg/mL) on the first (median 35 pg/mL; P = 0.0002) and third (median 19 pg/mL; P = 0.004) postoperative day, but not in later samples. The levels measured in 8 patients after minor surgery did not differ from the preoperative levels (P = 0.14). CONCLUSIONS: Even major surgery is associated only with a slight and transient increase in S-VEGF levels, and, therefore, is unlikely to interfere markedly with the use of VEGF as a prognostic marker.
Asunto(s)
Factores de Crecimiento Endotelial/sangre , Linfocinas/sangre , Procedimientos Quirúrgicos Operativos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Isoformas de Proteínas/sangre , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
The growth of solid tumors is dependent on angiogenesis, the formation of new blood vessels. Vascular endothelial growth factor (VEGF) is a secreted endothelial-cell-specific mitogen. We have recently characterized two novel endothelial growth factors with structural homology to VEGF and named them VEGF-B and VEGF-C. To further define the roles of VEGF-B and VEGF-C, we have studied their expression in a variety of human tumors, both malignant and benign. VEGF-B mRNA was detected in most of the tumor samples studied, and the mRNA and the protein product were localized to tumor cells. Endothelial cells of tumor vessels were also immunoreactive for VEGF-B, probably representing the binding sites of the VEGF-B polypeptide secreted by adjacent tumor cells. VEGF-C mRNA was detected in approximately one-half of the cancers analyzed. Via in situ hybridization, VEGF-C mRNA was also localized to tumor cells. All lymphomas studied contained low levels of VEGF-C mRNA, possibly reflecting the cell-specific pattern of expression of the VEGF-C gene in the corresponding normal cells. The expression of VEGF-C is associated with the development of lymphatic vessels, and VEGF-C could be an important factor regulating the mutual paracrine relationships between tumor cells and lymphatic endothelial cells. Furthermore, VEGF-C and VEGF-B can, similarly to VEGF, be involved in tumor angiogenesis.
Asunto(s)
Factores de Crecimiento Endotelial/metabolismo , Neoplasias/metabolismo , Adenocarcinoma/metabolismo , Northern Blotting , Neoplasias de la Mama/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Técnicas para Inmunoenzimas , Hibridación in Situ , Linfoma no Hodgkin/metabolismo , Melanoma/metabolismo , ARN Mensajero/análisis , Sarcoma/metabolismo , Factor B de Crecimiento Endotelial Vascular , Factor C de Crecimiento Endotelial VascularRESUMEN
PURPOSE: To investigate the cytotoxicity of bleomycin (BLM), two Auger-emitting bleomycin complexes (indium-111 ((111)In)-BLMC) and (111)InCl3 in three squamous cell cancer (SCC) cell lines. MATERIAL AND METHODS: Three recently established SCC cell lines were investigated using the 96-well clonogenic assay. Concentrations causing 50% inhibition in cell survival (IC50) were calculated for BLM and two specific activities of (111)In-BLMC (40 MBq/mg BLM (low) and 195 MBq/mg BLM (high)). RESULTS: (111)In-BLMC (low) was the most toxic to the SCC cell lines. (111)In-BLMC containing 4.9-fold more activity of (111)In (195 MBq/mg BLM) was more effective than BLM (p=0.0029), but not as toxic as (111)In-BLMC (low) (p=0.0023). UT-SCC-19A had a IC50 value for BLM as low as 4.1 nM, whereas IC50 values for (111)In-BLMC (low) and (111)In-BLMC (high) were 2.0 nM and 2.6 nM, respectively. The most chemoresistant cell line UT-SCC-12A had a IC50 value for BLM of 18.8 nM, for (111)In-BLMC (low) 10.7 nM and for (111)In-BLMC (high) 12.7 nM. (111)InCl3 had no cell killing effect. CONCLUSIONS: This study shows that (111)In-BLMC is superior in SCC cell killing compared with BLM. These data provide the basis for further clinical investigations of (111)In-BLMC.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Bleomicina/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Radioisótopos de Indio/farmacología , Terapia Combinada , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indio/administración & dosificación , Indio/farmacología , Marcaje Isotópico , Células Tumorales Cultivadas/efectos de la radiaciónRESUMEN
Bleomycin (BLM) has been used successfully for treatment of head and neck cancer. Combining radionuclide therapy with chemotherapy is a fascinating possibility. We have studied the biokinetics of BLM labeled with indium-111 (In-111). A complex formed at low pH had an activity of 100 MBq/mg BLM. This substance was intravenously injected into 10 head and neck cancer patients in escalating doses of 75, 175, and 375 MBq. Scintigraphic data from these patients were compared with tissue samples obtained at surgery. The activity distribution and penetration into tumor tissue was not affected by increasing the injected activity. In-111-BLMC uptake was directly proportional to Ki-67/MIB-1 activity and number of mitoses in tumor tissue. Based on the biokinetics, dosimetric calculations for In-111 and In-114m have been performed. S values for realistic geometry (a phantom designed from Patient CT) have been calculated. In-114m could deliver a 4-fold absorbed radiation dose into the tumor compared with In-111. We think that In-111-BLMC could be used for radiochemotherapy in head and neck cancer or adjuvant Auger-electron therapy using In-114m combined with BLM. Further studies on cellular dosimetry should be undertaken.
Asunto(s)
Antineoplásicos/farmacocinética , Bleomicina/análogos & derivados , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Radioisótopos de Indio/farmacocinética , Compuestos Organometálicos/farmacocinética , Adulto , Anciano , Antineoplásicos/uso terapéutico , Bleomicina/farmacocinética , Bleomicina/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , División Celular/efectos de los fármacos , División Celular/efectos de la radiación , Terapia Combinada , Femenino , Semivida , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Radioisótopos de Indio/uso terapéutico , Riñón/metabolismo , Masculino , Persona de Mediana Edad , Método de Montecarlo , Compuestos Organometálicos/uso terapéuticoRESUMEN
Bleomycin (BLM) is a natural antibiotic, toxic to dividing cells (G2/M-phase), also proven effective in squamous cell carcinomas (SCC). We have clinically shown that a short-range beta-emitting radionuclide combined to bleomycin (In-111-BLMC) is a tumor-targeting agent in SCCs. With higher radionuclide activities it may be possible to develop a more effective agent, to be tested in animal studies. Using a 96-well clonogenic assay we investigated three SCC cell lines, grown in our own laboratory. IC20, IC50 and IC90 values for BLM were determined. The UT-SCC-12A and UT-SCC-12B cells were originated from a primary tumor and a metastasis of the same patient. UT-SCC-12A cells were also inoculated subcutaneously into nude mice and the tumor growth was analysed. The IC50 value for UT-SCC-19A cell line was 4.0 +/- 1.3 nM. UT-SCC-12A and UT-SCC-12B were both more resistant to BLM; IC50 values were 14.2 +/- 2.8 nM and 13.0 +/- 1.1 nM, respectively. Within 35 days the weight of nude mice increased 2.8 +/- 0.6g. At 25 and 35 days after tumor inoculations the tumor volumes were 111 +/- 51 mm3 and 874 +/- 577 mm3, respectively. The calculated doubling time was 3.86 +/- 0.76 days. SCC cell lines demonstrate different sensitivity to BLM. Our SCC tumor xenograft model showed a rapid growth proper for radiochemotherapeutic studies using In-111-BLMC. The uptake of In-111-BLMC in vivo has been directly proportional to proliferation activity, and the tumors with high binding capacity could be predicted from animal model dose calculations.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Bleomicina/análogos & derivados , Carcinoma de Células Escamosas/tratamiento farmacológico , Radioisótopos de Indio/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Animales , Bleomicina/uso terapéutico , Carcinoma de Células Escamosas/radioterapia , Terapia Combinada/métodos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
Bleomycin (BLM) is used for the treatment of head and neck cancer. In order to improve the effectiveness of this chemotherapeutic drug, BLM was combined with indium-111. A complex of these agents (111In-BLMC), formed at low pH, was injected intravenously into ten head and neck cancer patients in escalating activities of 75, 175 and 375 MBq. The internally delivered dose to the tumours varied from 0.20 to 2.73 mGy at 75 MBq, from 0.33 to 2.51 mGy at 175 MBq, and from 0.87 to 31.3 mGy at the 375 MBq activity level. Uptake of radioactivity was 0.45+/-0.24x10(-3)% ID/g in primary tumours and 0. 52+/-0.20x10(-3)% ID/g in metastases (at 48 h). Tumour volumes varied from 0.51 to 49.0 cm3. The radioactivity half-lives in the tumours were 30+/-7 h. The activity distribution and penetration into tumour tissue were not affected by increasing the injected activity. There was a positive correlation between BLMC uptake and Ki-67/Mib activity as well as number of mitoses in tumour tissue. These data indicate that 111In-BLMC has potential as a radiochemotherapeutic agent in head and neck cancer and that adjuvant Auger-electron therapy is possible using 114mIn-labelled BLMC.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Bleomicina/análogos & derivados , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Radioisótopos de Indio/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Adulto , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Bleomicina/administración & dosificación , Bleomicina/farmacocinética , Bleomicina/uso terapéutico , Carcinoma de Células Escamosas/diagnóstico por imagen , Terapia Combinada/métodos , Femenino , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Humanos , Radioisótopos de Indio/administración & dosificación , Radioisótopos de Indio/farmacocinética , Masculino , Persona de Mediana Edad , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/farmacocinética , Cintigrafía , Distribución TisularRESUMEN
Bleomycin, a natural antibiotic toxic to dividing cells, has been successfully used in combinations for treatment of recurrent head and neck cancer. In this study, we investigated five recently established head and neck squamous cell cancer lines (UT-SCC-2, UT-SCC-8, UT-SCC-9, UT-SCC-12A, UT-SCC-19A) in terms of response to bleomycin and radiation treatment. Experiments were carried out using the 96-well plate clonogenic assay for concentration determinations causing 20% (IC20), 50% (IC50), and 90% (IC90) inhibition of clonogenic survival and dose-response calculations for bleomycin. Survival fraction after a radiation dose of 2 Gy (SF2) was used as a measure for radiation sensitivity. The sensitivity for bleomycin was in good accordance with radiation sensitivity except for cell line UT-SCC-9. This was the cell line most sensitive to radiation (SF2 = 0.25 +/- 0.03) but was fairly resistant to chemotherapy (IC50 = 11.5M). Sensitivity patterns may suggest partly different mechanisms of action.