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Oncología Médica/historia , Oncología Médica/métodos , Neoplasias/terapia , Sociedades Médicas/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Agencias Internacionales/organización & administración , Oncología Médica/organización & administración , Sociedades Médicas/organización & administraciónRESUMEN
BACKGROUND: Established prognosis-based criteria determine the need for further treatment after primary surgery for breast cancer. Such criteria are lacking after neo-adjuvant chemotherapy. We determine the prognostic value of preoperative [(18)F]-2-fluoro-2-deoxy-D-glucose-positron emission tomography ((18)FDG-PET) after chemotherapy in locally advanced breast cancer (LABC), both as independent indicator and as add-on to postoperative histopathology. PATIENTS AND METHODS: Preoperative PET was carried out in 40 LABC patients. Two expert readers assessed residual (18)FDG uptake in the primary tumor. At histopathological examination of the surgical specimen, chemotherapy response was graded using the Honkoop criteria. Cox proportional hazards analysis was used to determine prognostic relevance of PET and histopathology. RESULTS: Median follow-up was 60 months (range 15-94), during which 13 patients had recurrent disease, eight of whom died. (18)FDG uptake in the primary tumor was inversely related with disease-free survival (DFS) [hazard ratio (HR) 4.09; 95% confidence interval (CI) 1.26-13.31; P = 0.02] and this was superior to histopathology (HR 2.52; 95% CI 0.77-8.23; P = 0.13). Observer agreement of PET was excellent (intraclass correlation coefficient 0.88). Multivariate Cox regression revealed no added value of histopathology versus PET results. CONCLUSION: (18)FDG uptake in the primary tumor at PET was inversely associated with DFS and may help to guide adjuvant therapy.
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Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/patología , Tomografía de Emisión de Positrones , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biopsia con Aguja , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Estudios de Cohortes , Terapia Combinada , Intervalos de Confianza , Supervivencia sin Enfermedad , Femenino , Fluorodesoxiglucosa F18 , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Mastectomía Segmentaria/métodos , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Cuidados Preoperatorios/métodos , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Sensibilidad y Especificidad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The treatment of cancer can have a negative influence on bone metabolism. This can result in the development of early osteoporosis or the aggravation of existing osteoporosis, with an increased risk of fractures. Depending on the duration and type of cancer therapy, prophylactic or therapeutic measures against osteoporosis may become necessary. The risk of osteoporosis may be assessed by screening with osteodensitometry, among other methods. Effective treatment is possible, for example with bisphosphonates.
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Antineoplásicos/efectos adversos , Conservadores de la Densidad Ósea/uso terapéutico , Densidad Ósea/efectos de los fármacos , Difosfonatos/uso terapéutico , Osteoporosis/inducido químicamente , Antineoplásicos/uso terapéutico , Humanos , Neoplasias/terapia , Osteoporosis/prevención & controlRESUMEN
Colorectal cancer (CRC) resistance to fluoropyrimidines and other inhibitors of thymidylate synthase (TS) is a serious clinical problem often associated with increased intracellular levels of TS. Since the tumour suppressor gene p53, which is mutated in 50% of CRC, regulates the expression of several genes, it may modulate TS activity, and changes in the status of p53 might be responsible for chemoresistance. Therefore, this study was aimed to investigate TS levels and sensitivity to TS inhibitors in wild-type (wt) and mutant (mt) p53 CRC cells, Lovo and WiDr, respectively, transfected with mt and wt p53. Lovo 175X2 cells (transfected with mt p53) were more resistant to 5-fluorouracil (5-FU; 2-fold), nolatrexed (3-fold), raltitrexed (3-fold) and pemetrexed (10-fold) in comparison with the wt p53 parental cells Lovo 92. Resistance was associated with an increase in TS protein expression and catalytic activity, which might be caused by the loss of the inhibitory effect on the activity of TS promoter or by the lack of TS mRNA degradation, as suggested by the reversal of TS expression to the levels of Lovo 92 cells by adding actinomycin. In contrast, Lovo li cells, characterized by functionally inactive p53, were 3-13-fold more sensitive to nolatrexed, raltitrexed and pemetrexed, and had a lower TS mRNA, protein expression and catalytic activity than Lovo 92. However, MDM-2 expression was significantly higher in Lovo li, while no significant differences were observed in Lovo 175X2 cells with respect to Lovo 92. Finally, mt p53 WiDr transfected with wt p53 were not significantly different from mt p53 WiDr cells with respect to sensitivity to TS inhibitors or TS levels. Altogether, these results indicate that changes in the status of p53, can differently alter sensitivity to TS inhibitors by affecting TS levels, depending on activity or cell line, and might explain the lack of clear correlation between mutations in p53 and clinical outcome after chemotherapy with TS inhibitors.
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Antineoplásicos/farmacología , Neoplasias Colorrectales/metabolismo , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/farmacología , Timidilato Sintasa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Western Blotting , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Humanos , Mutación , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , ARN Mensajero/análisis , Tetrahidrofolato Deshidrogenasa/metabolismo , Timidilato Sintasa/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Transfección , Proteína p53 Supresora de Tumor/genéticaRESUMEN
In the area of cancer treatment, immunotherapy with vaccines has suffered in the last five years, due to many clinical trial failures. One must keep in mind however, that many of the clinical trials conducted in the past decade were performed without the benefit of sound regulatory guidance or validated and compliant manufacturing processes. This has clearly been the case for patient specific, tumor cell vaccine therapy. The safety concerns that emanated within the regulatory agencies from the Somatic Cell Therapy concepts, translated to active specific immunotherapy with vaccines. Fortunately, in the past five years advances in understanding the immune system, improved design of clinical trials, improvement and compliance of manufacturing processes provided opportunities to significantly improve efficacy and safety. Clearly, the vaccine research establishment has learned the importance of not just selecting antigens but the requirement of tumor associated immunogens that can stimulate a functional immune response. Also, it has become clear that immunotherapy works best in situations of minimal residual disease. Finally, more realistic endpoints in clinical trials have been recognized and accepted by oversight review committees. This commentary describes the "trials and tribulations" of developing a patient specific, autologous tumor cell vaccine for therapy of Stage II colon cancer.
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Vacunas contra el Cáncer/uso terapéutico , Neoplasias del Colon/terapia , Inmunoterapia Activa , Adulto , Anciano , Anciano de 80 o más Años , Vacunas contra el Cáncer/efectos adversos , Neoplasias del Colon/inmunología , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de NeoplasiasRESUMEN
CD13/Aminopeptidase N (CD13) is known to play an important role in tumour cell invasion. We examined whether basic fibroblast growth factor (bFGF) is involved in the regulation of CD13 expression in human melanoma cells. 1F6 human melanoma cells were stably transfected with constructs encoding either the 18 kDa (18 kD) or all (ALL) bFGF isoform proteins. We observed highly increased CD13 mRNA and protein expression in the 1F6 clones regardless of the overexpression of either the 18 kD or all isoform proteins. Neutral aminopeptidase activity was increased five-fold and could be inhibited by bestatin and the CD13-neutralising antibody WM15. The enhanced invasion through Matrigel, but not migration in a wound assay, was efficiently abrogated by both bestatin and WM15. Upregulation of CD13 expression was the result of increased epithelial and myeloid promoter activity up to 4.5-fold in 1F6-18 kD and 1F6-ALL clones. Interestingly, in a panel of human melanoma cell lines, a significant correlation (r(2)=0.883, P<0.05) between bFGF and CD13 mRNA and protein expression was detected. High bFGF and CD13 expression were clearly related with an aggressive phenotype. Taken together, our data indicate that high bFGF expression upregulates CD13 expression in human melanoma cells by activating both the myeloid and the epithelial CD13 promoter. In addition, we show that high bFGF and CD13 expression results in enhanced invasive capacity and metastatic behaviour of human melanoma cells.
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Antígenos CD13/genética , Factor 2 de Crecimiento de Fibroblastos/fisiología , Melanoma/patología , Neoplasias Cutáneas/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Colágeno , Dactinomicina/farmacología , Combinación de Medicamentos , Factor 2 de Crecimiento de Fibroblastos/genética , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Genes Reporteros , Humanos , Laminina , Invasividad Neoplásica , Metástasis de la Neoplasia , Regiones Promotoras Genéticas , Proteoglicanos , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
PURPOSE: To compare the pharmacology of the paclitaxel-cisplatin, gemcitabine-cisplatin and paclitaxel-gemcitabine combinations in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-four chemo-naive patients with advanced NSCLC were randomized to receive one of the three regimens. Plasma pharmacokinetics and pharmacologic parameters in mononuclear cells were compared and related to toxicity and efficacy. RESULTS: Pharmacological parameters of gemcitabine and cisplatin were not influenced by the combination with one of the other agents, while the paclitaxel clearance was significantly lower for the combination with cisplatin as compared to gemcitabine (P=0.024). The percentage decrease in platelets was significantly higher for the gemcitabine combinations (P=0.004) and related to the dFdCTP-Cmax (P=0.030). Pharmacologic parameters were not related to response or survival. CONCLUSIONS: Gemcitabine and cisplatin pharmacology were not influenced by the combination with one of the other agents, while paclitaxel has a lower clearance in combination with cisplatin as compared to gemcitabine.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/farmacocinética , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Interacciones Farmacológicas , Femenino , Semivida , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , GemcitabinaRESUMEN
BACKGROUND: Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are essential enzymes for 5-fluorouracil (5-FU) metabolism. In patients with advanced colorectal cancer (ACRC), retrospective studies have shown that low expression levels of TS and DPD correlated with response to 5-FU. We performed a prospective study in which the choice of first-line chemotherapy with either 5-FU or a non-5-FU containing regimen was based on TS and DPD expression. PATIENTS AND METHODS: Fresh-frozen samples of metastases were obtained from 58 previously untreated patients with ACRC. mRNA expression of TS and DPD was quantified using an RT-PCR assay. Patients with low tumor expression of both TS and DPD received weekly bolus 5-FU/leucovorin (LV) 500 mg/m2 (group A); patients with high TS and/or DPD received 3-weekly oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2 (group B). After progression, cross-over to the alternative regimen was attempted. RESULTS: Of 53 eligible patients, 31 had tumors with both low TS and low DPD, and were treated in group A. A response was observed in 11 patients [35%; 95% confidence interval (CI) 19% to 54%]. Cross-over to second-line oxaliplatin/irinotecan resulted in a partial response in two out of 16 patients (13%; 95% CI 1% to 38%). In group B, four out of 22 patients responded (18%; 95% CI 5% to 40%), while no responses were observed in 12 patients after cross-over to 5-FU/LV (0%; 95% CI 0% to 28%). CONCLUSIONS: Prospective selection of 5-FU/LV chemotherapy based on low TS and DPD expression in patients with ACRC did not confirm the high response rates reported in retrospective studies. The procedure of obtaining metastatic tissue and quantitation of enzymes appeared feasible but cumbersome. Before assessing the clinical utility of a predictive marker in a randomized trial, future studies should focus on prospective validation of the assay in a large and well defined population.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Timidilato Sintasa/metabolismo , Adulto , Anciano , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Dihidrouracilo Deshidrogenasa (NADP)/genética , Femenino , Fluorouracilo/administración & dosificación , Humanos , Irinotecán , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Pronóstico , Estudios Prospectivos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Timidilato Sintasa/genéticaRESUMEN
PURPOSE: To study the effect of autologous tumor cell vaccinations on the presence and numbers of circulating CD8+ T cells specific for tumor-associated antigens (TAA) in metastatic melanoma patients. To investigate the correlation between the presence of tumor-infiltrating lymphocytes (TIL) and circulating TAA-specific CD8+ T cells before and after autologous tumor cell vaccination with overall survival. EXPERIMENTAL DESIGN: Twenty-five stage III and resected stage IV metastatic melanoma patients were adjuvantly treated with a series of intracutaneously injected autologous tumor cell vaccinations, of which the first two contained BCG as an immunostimulatory adjuvant. Tumor samples and blood samples obtained before and after vaccination of these patients were studied for the presence of TAA-specific T cells using HLA-tetramers and results were correlated with survival. RESULTS: In 5 of 17 (29%) melanoma patients, circulating TAA-specific T cells were detectable prior to immunizations. No significant changes in the frequency and specificity were found during the treatment period in all patients. Presence of circulating TAA-specific T cells was not correlated with survival (log rank, P=0.215). Inside melanoma tissue, TAA-specific TIL could be detected in 75% of 16 available tumor samples. In case of detectable TAA-specific TIL, median survival was 22.5 months compared to median survival of 4.5 months in case of absence of TAA-specific T cells (log rank, P=0.0094). In none of the patients, TAA-specific T cells were found both in tumor tissue and blood at the same time. CONCLUSIONS: These data suggest that the presence of TAA-specific TILs forms a prognostic factor, predicting improved survival in advanced-stage melanoma patients. The absence of TAA-specific T cells in the circulation suggests that homing of the tumor-specific T cell population to the tumor site contributes to the effectiveness of antitumor immunity.
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Linfocitos T CD8-positivos , Vacunas contra el Cáncer/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Melanoma/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Adyuvantes Inmunológicos/administración & dosificación , Adulto , Anciano , Formación de Anticuerpos , Antígenos de Neoplasias , Vacuna BCG/administración & dosificación , Vacuna BCG/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Sobrevida , Resultado del Tratamiento , Células Tumorales Cultivadas/inmunologíaRESUMEN
The pharmacokinetics of 5-fluorouracil (5FU) have been related to toxicity and antitumor activity, in particular for continuous infusion schedules, but to a lesser extent for frequently used bolus injections. The use of intensive sampling schedules limits the application of pharmacokinetics to optimize individual dosing or to define the ideal combination with other drugs. We therefore reanalyzed a pharmacokinetic study in order to develop a limited sampling schedule. Patients received escalating doses of 5FU at 500, 600 and 720 mg/m2 as a bolus until toxicity developed. Blood samples were analyzed until 24 h after administration. The area under the concentration time curve from 0-90 min (AUC(0-90)) was strongly correlated with dose and also with toxicity (p = 0.0009). The 5FU concentrations at 30 and 60 min were correlated to the AUC(30-240) and to that of the AUC(0-90) (r2 = 0.970). The use of limited sampling (30, 60, 90 min) in a patient given 353 mg/m2 5FU with severe toxicity at initial dosing at 500 mg/m2 revealed that the AUC(0-90) at 353 mg/m2 was higher than the normal AUC(0-90) for 500 mg/m2. This patient appeared to have an 8-fold lower activity of the 5FU degradation enzyme dihydropyrimidine dehydrogenase. Limited sampling will allow us to define potential aberrant kinetics of pharmacokinetic interaction of 5FU with other drugs being developed for treatment of colorectal cancer.
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Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Fluorouracilo/efectos adversos , Fluorouracilo/farmacocinética , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Área Bajo la Curva , Neoplasias Colorrectales/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Femenino , Fluorouracilo/administración & dosificación , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Endostatin is an endogenous collagen XVIII-fragment with anti-angiogenic properties and remarkable antitumor activity in mice. Preclinical data suggest that continuous low dose administration of endostatin is much more potent than intermittent dosing. The feasibility of this approach is tested in a phase I study. PATIENTS AND METHODS: We determined the safety and pharmacokinetic profile of 4-week continuous intravenous infusion of recombinant human (rh)-endostatin, followed after an interval of 1 week by twice daily subcutaneous injections in patients with advanced cancer. Thirty-two patients received rh-endostatin in six dosing cohorts, ranging from 3.75 mg/m(2)/day to 120 mg/m(2)/day. Serum endostatin pharmacokinetics, toxicity and antitumor response were determined. RESULTS: A total of 160 cycles were delivered without significant toxicities. Pharmacokinetic analysis showed a linear increase of steady-state serum endostatin concentrations with dose (i.v. r(2)=0.96; s.c. r(2)=0.99) reaching 300--1,000 ng/ml for the two highest doses, with considerable interpatient variation. The main pharmacokinetic values for both routes of administration were similar. The apparent steady-state concentration and AUC reached at 60--120 mg/m(2)/day were within the range expected to induce anti-angiogenic and antitumor effects based on preclinical tumor models. Although no objective responses were observed, two patients had long-lasting stable disease (defined as a tumor increase<100%). CONCLUSION: rh-endostatin was safely administered both by continuous infusion and by twice daily subcutaneous injections up to 120 mg/m(2)/day. Predictable pK was seen in this dose range and the target endostatin levels were reached from 60 mg/m(2)/day and above.
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Endostatinas/efectos adversos , Endostatinas/farmacocinética , Adulto , Anciano , Área Bajo la Curva , Esquema de Medicación , Endostatinas/administración & dosificación , Endostatinas/uso terapéutico , Femenino , Humanos , Infusiones Intravenosas , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Proteínas Recombinantes , Resultado del TratamientoRESUMEN
We have completed a multicenter, randomized controlled phase III clinical trial in Stages II and III colon cancer patients with active specific immunotherapy (ASI) using autologous tumor cells with an immunomodulating adjuvant bacillus Callmette-Guerin (BCG) vaccine (OncoVAX) in an adjuvant setting. In this study, patients were randomized to receive either OncoVAX therapy or no therapy after surgical resection of the primary tumor and stratified by stage of disease. Since the biologic essence of the effective tumor immunotherapy is the presence in the vaccine of a minimum number of viable, metabolically active, autologous tumor cells, the processing of the vaccine product, occurred within 48 h after surgery. Analysis of prognostic benefit in the pivotal phase III trial, with a 5.8 year median follow-up, showed that a beneficial effect of OncoVAX is statistically significant for all endpoints including recurrence-free interval, overall survival, and recurrence-free survival in Stage II colon cancer patients. Surgery alone cures approximately 65% of Stage II (Dukes B2, B3) colon cancer patients. In the remaining patients, OncoVAX in an adjuvant setting, significantly prolongs recurrence-free interval (57.1% relative risk reduction) and significantly improves 5-year overall survival and recurrence-free survival. No statistically significant prognostic benefits were achieved in Stage III (Duke's C1-C3) patients. A health economics assessment was performed on these results in Stage II colon cancer patients using disease-free survival and overall survival (for the entire intent-to-treat population). Cost-effectiveness, cost-utility and sensitivity analysis were applied with, cost of life years, recurrence-free life years and quality adjusted life years (QALYs) as the primary endpoints to this analysis. The perspective of the economic analysis was the current direct medical cost established by the health care providers. The introduction of new technologies often leads to additional costs. This report verified that the use of OncoVAX for patients with Stage II colon cancer not only has significant prognostic benefit and positive clinical outcomes, but also showed that OncoVAX therapy yields impressive health economics benefits.
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Vacuna BCG/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Neoplasias del Colon/terapia , Adulto , Anciano , Anciano de 80 o más Años , Vacunas contra el Cáncer/economía , Neoplasias del Colon/economía , Neoplasias del Colon/mortalidad , Neoplasias del Colon/cirugía , Terapia Combinada , Análisis Costo-Beneficio , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunoterapia Activa , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
CPT-11 (irinotecan or 7-ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) is an anticancer agent in use for the treatment of colon cancer. In order to be fully active, CPT-11 needs to be converted into SN-38 (7-ethyl-10-hydroxycamptothecin) by the enzyme carboxylesterase (CE). In humans, only a minority of CPT-11 is converted to SN-38. To increase the antitumour effect of CPT-11 by gene-directed enzyme prodrug therapy, we constructed a replication-deficient adenoviral vector Ad.C28-sCE2 containing a fusion gene encoding a secreted form of human liver CE2 targeted to the surface antigen epithelial cell adhesion molecule (EpCAM) that is highly expressed on most colon carcinoma cells. By targeting CE2 to EpCAM, the enzyme should accumulate specifically in tumours and leakage into the circulation should be minimised. Ad.C28-sCE2-transduced colon carcinoma cells expressed and secreted active CE that bound specifically to EpCAM-expressing cells. In sections of three-dimensional colon carcinoma spheroids transduced with Ad.C28-sCE2, it was shown that C28-sCE2 was capable of binding untransduced cells. Most importantly, treatment of these spheroids with nontoxic concentrations of CPT-11 resulted in growth inhibition comparable to treatment with SN-38. Therefore, Ad.C28-sCE2 holds promise in gene therapy approaches for the treatment of colon carcinoma.
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Adenoviridae/genética , Camptotecina/análogos & derivados , Camptotecina/toxicidad , Carboxilesterasa/genética , Antineoplásicos Fitogénicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Vectores Genéticos , Humanos , Irinotecán , Neoplasias OváricasRESUMEN
Conditionally replicating adenoviruses (CRAds) selectively replicate in and thereby kill cancer cells. The CRAd AdDelta24 with pRb-binding-deficient E1A kills cancer cells efficiently. Arming CRAds with genes encoding prodrug-converting enzymes could allow for enhanced anticancer efficacy by the combined effects of oncolytic replication and local prodrug activation. Here, we investigated combination treatment of human colon cancer cell lines with AdDelta24-type CRAds and gene-directed enzyme prodrug therapy (GDEPT) using two different enzyme/prodrug systems, that is, thymidine kinase/ganciclovir (TK/GCV) and carboxylesterase (CE)/CPT-11. On all three cell lines tested, GDEPT with TK/GCV made CRAd treatment less efficacious. In contrast, expression of a secreted form of CE (sCE2) combined with CPT-11 treatment markedly enhanced the efficacy of AdDelta24 virotherapy. Based on this observation, we constructed an AdDelta24 variant expressing sCE2. In the absence of CPT-11, this new CRAd Ad5-Delta24.E3-sCE2 was similarly effective as its parent in killing human colon cancer cells. Low concentrations of CPT-11 inhibited Ad5-Delta24.E3-sCE2 propagation. Nevertheless, CPT-11 specifically augmented the cytotoxicity of Ad5-Delta24.E3-sCE2 against all three-colon cancer cell lines. Hence, the positive contribution of sCE2/CPT-11 GDEPT to colon cancer cytotoxicity outweighed its negative influence on CRAd propagation. Therefore, CRAd-sCE2/CPT-11 combination therapy appears useful for more effective treatment of colon cancer.
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Adenoviridae/genética , Carboxilesterasa/genética , Neoplasias del Colon/terapia , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Profármacos/administración & dosificación , Adenoviridae/fisiología , Antivirales/uso terapéutico , Carboxilesterasa/uso terapéutico , Línea Celular Tumoral , Neoplasias del Colon/virología , Terapia Combinada , Efecto Citopatogénico Viral , Ganciclovir/uso terapéutico , Expresión Génica , Ingeniería Genética , Vectores Genéticos/genética , Humanos , Profármacos/uso terapéutico , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/uso terapéutico , Timidina Quinasa/uso terapéutico , Transducción Genética/métodos , Replicación ViralRESUMEN
Thymidine phosphorylase (TP) catalyzes the phosphorolytic cleavage of thymidine to thymine and deoxyribose-1-phosphate. TP, which is overexpressed in a wide variety of solid tumors, is involved in the activation and inactivation of fluoropyrimidines. TP is known to be regulated by several cytokines and interferons. In our HT29 cell line the TP mRNA and activity expression increased 2-3 fold after treatment with interferon alpha.
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Interferón-alfa/metabolismo , Timidina Fosforilasa/biosíntesis , Regulación hacia Arriba , Uridina/análogos & derivados , Catálisis , Línea Celular Tumoral , Citocinas/metabolismo , Daño del ADN , Células HT29 , Humanos , Interferones/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Uridina/químicaRESUMEN
In a panel of 18 colon cancer cell lines we found that the thymidylate synthase (TS) genotype was related to TS enzyme activity, but not to TS protein and mRNA levels. In addition, no relation with drug sensitivity was observed. TS genotyping of different tissues from 78 colorectal cancer patients revealed a high level of homology in polymorphic status between normal and malignant tissues and the heterozygous genotype to be the most frequent.