Targeting the CYP2B 1/cyclophosphamide suicide system to fibroblast growth factor receptors results in a potent antitumoral response in pancreatic cancer models.

The CYP2B1/cyclophosphamide (CPA) suicide gene therapy approach has been shown to be highly promising in clinical trials for the treatment of pancreatic cancer. However, delivering the therapeutic gene to a sufficient number of tumor cells able to trigger a complete response remains a challenge. Target-specific delivery of adenovirus to fibroblast growth factor receptors (FGFRs) has been obtained in a variety of tumor models and has been shown to highly increase transduction efficiency. In the present paper we have tested the therapeutic outcome of retargeting the adenoviral vector, Ad-CYP2B1, to FGFRs, using an FGF2-Fab' conjugate, in pancreatic cancer models. First, we show a heterogeneous subcellular distribution of overexpressed FGFR-1 in pancreatic cancer cells. Higher transduction efficiency was observed in five of the six cell lines studied after FGF2-AdGFPLuc infection. Interestingly, an association between FGFR-1 membrane cell expression and viral entry was found. Moreover, tumors injected with FGF2-AdGFPLuc showed enhanced and persistent transgene expression. Importantly, we demonstrate the relevant enhanced cytotoxic effect of the FGF2-Ad-CYP2B]/CPA system in four of the six cell lines studied. Moreover, retargeting Ad-CYP2B1/CPA to FGFRs resulted in a potent antitumoral effect and in an increased survival rate, in two human pancreatic xenograft models. Thus, our results indicate that redirecting adenoviruses to FGFRs highly increases the potency of the suicide system CYP2B1/CPA. Consequently, it may constitute a promising approach to the treatment of patients with pancreatic tumors, in which a high proportion of FGF receptors precisely localize to the plasma membrane.

[Localization of prostate cancer within the central gland by endorectal MR spectroscopic imaging]. / Localización del cáncer de próstata en la glándula central mediante espectroscopia de resonancia magnética endorectal.

OBJECTIVES: The endorectal MR spectroscopic imaging is a new imaging test which allows more accurate and reliable localization and staging of prostate cancer than simple endorectal MRI. The combination of spectroscopic MR and MRI has recently achieved technical improvements that increased reliability in the detection of prostate cancer. Our group is now working in the detection of prostate cancer with the spectroscopic MR, in co-operation with the Agency for the Evaluation of Technology for Medical Research (Agencia de Evaluación de Tecnología para la Investigación Médica-AATRM); although we are waiting for definitive results, we can advance that this technique may be used as a good alternative for localization of prostate cancer in patients with previous negative biopsies in whom the suspicion of prostate cancer persists. METHODS: We present a series of 5 patients under control for permanent elevation of PSA with previous negative biopsies. We were performing ultrasound guided sextant biopsies every 6 months, after blood test for PSA. Endorectal MRI and spectroscopic MRI were performed to try to localize the prostate cancer so diminishing the number of biopsies. RESULTS: All patients in the series had a low intensity lesion within the normal low intensity of the central gland, with an obvious spectroscopic metabolic abnormality suggesting the existence of prostate cancer, as it was then demonstrated by biopsy. CONCLUSIONS: The endorectal MR spectroscopic imaging is a non invasive method which offers the ability to detect prostate cancer within the central gland with a higher reliability in selected patients. The central gland is an area in which prostate cancer is less commonly localized, but it often shows the same signal intensity than hyperplastic tissue, so that it is difficult to be detected by purely morphological methods. Endorectal MR spectroscopic imaging allows evaluating the metabolic disturbances in the whole gland, increasing the reliability of detection of prostate cancer both in the central and peripherical glands.

Localización del cáncer de próstata en la glándula central mediante espectroscopia de resonancia magnética endorectal / Localization of prostate cancer within the central gland by endorectal MR spectroscopic imaging

OBJETIVO: La espectroscopia de resonanciamagnética endorectal (E-RME) es una nueva técnicade imagen que permite una evaluación más acuraday fiable de la localización y estadiaje del cáncerde próstata (CaP) que la resonancia magnética endorectalsola. La combinación de la RME y la E-RME haconseguido recientemente mejorías técnicas que hanpermitido aumentar la fiabilidad en la detección delCaP. Nuestro grupo está actualmente trabajando con laE-RME en la detección del CaP, en colaboración con laAgencia de Evaluación de Tecnología para laInvestigación Médica (AATRM), y en espera de resultadosdefinitivos podemos avanzar que ésta técnicapuede ser utilizada como una buena alternativa en lalocalización de CaP en pacientes con biopsias previasnegativas pero en quienes persiste la sospecha de CaP.MÉTODOS: Presentamos aquí una serie de 5 casos clínicosde pacientes controlados por elevación persistentedel PSA y biopsias previas negativas. Realizamosbiopsias por sextantes mediante ecografía transrectal aintervalos de 6 meses, después de determinar los valoresde PSA. La RME y E-RME se realizó para intentarlocalizar el CaP y de este modo intentar minimizar elnúmero de biopsias.RESULTADOS: Todos los pacientes en esta serie presentaronuna lesión de baja intensidad localizada en lahipointensidad normal de la glándula central, pero conuna clara alteración metabólica en la espectroscopiaque sugería la existencia de un CaP, tal como sedemostró posteriormente por biopsia.CONCLUSIONES: La E-RME es un método poco invasivoque ofrece la capacidad de detectar el CaP en laglándula central con mayor fiabilidad en pacientesseleccionados. La glándula central es una zona en laque el CaP se localiza con menor frecuencia, pero amenudo adopta la misma intensidad de señal que eltejido hiperplásico, y por tanto, resulta difícil de detectarpor métodos puramente morfológicos. La E-RME permiteevaluar las alteraciones metabólicas en toda laglándula y aumentar así la fiabilidad en la deteccióndel CaP, tanto en la glándula central como en la periférica

OBJECTIVES: The endorectal MRspectroscopic imaging is a new imaging test whichallows more accurate and reliable localization andstaging of prostate cancer than simple endorectal MRI.The combination of spectroscopic MR and MRI hasrecently achieved technical improvements that increasedreliability in the detection of prostate cancer. Our groupis now working in the detection of prostate cancer withthe spectroscopic MR, in co-operation with the Agencyfor the Evaluation of Technology for Medical Research(Agencia de Evaluación de Tecnología para laInvestigación Médica-AATRM); although we are waitingfor definitive results, we can advance that this techniquemay be used as a good alternative for localization ofprostate cancer in patients with previous negative biopsiesin whom the suspicion of prostate cancer persists.METHODS: We present a series of 5 patients undercontrol for permanent elevation of PSA with previousnegative biopsies. We were performing ultrasound guidedsextant biopsies every 6 months, after blood test forPSA. Endorectal MRI and spectroscopic MRI wereperformed to try to localize the prostate cancer sodiminishing the number of biopsies.RESULTS: All patients in the series had a low intensitylesion within the normal low intensity of the centralgland, with an obvious spectroscopic metabolicabnormality suggesting the existence of prostate cancer,as it was then demonstrated by biopsy.CONCLUSIONS: The endorectal MR spectroscopicimaging is a non invasive method which offers theability to detect prostate cancer within the central glandwith a higher reliability in selected patients. The centralgland is an area in which prostate cancer is lesscommonly localized, but it often shows the same signalintensity than hyperplastic tissue, so that it is difficult tobe detected by purely morphological methods.Endorectal MR spectroscopic imaging allows evaluatingthe metabolic disturbances in the whole gland, increasingthe reliability of detection of prostate cancer both in thecentral and peripherical glands

Adenovirus-mediated retinoblastoma 94 gene transfer induces human pancreatic tumor regression in a mouse xenograft model.

PURPOSE: Gene transfer of a truncated variant of the retinoblastoma (RB) gene encoding a M(r) 94000 protein that lacks the NH(2)-terminal 112 amino acid residues, termed RB94, has been shown to inhibit proliferation of several human tumor cell types. We have assessed its therapeutic effectiveness on pancreatic cancer, one of the most aggressive and therapy-resistant types of cancer. For this purpose, preclinical studies aimed to evaluate the therapeutic potential of RB94 gene transfer in pancreatic cancer were carried out. EXPERIMENTAL DESIGN: We have compared the antiproliferative effects of adenovirus-mediated gene transfer of RBwt and RB94 at the in vitro and in vivo levels in three RB-positive human pancreatic tumor cell lines: (a). NP-9; (b). NP-18; and (c). NP-31. We have also examined their effects on cell cycle and their capacity to induce apoptosis. RESULTS: In vitro results indicate that RB94 gene transfer has stronger antiproliferative effects compared with RBwt. RB94 transduction correlated with accumulation at the S-G(2) phase of the cell cycle in the three cell lines tested and induction of apoptosis in two of them. In vivo studies show significant decreases in the growth rate of tumors treated with Ad-RB94 when compared with those treated with Ad-RBwt. Moreover, terminal deoxynucleotidyl transferase-mediated nick end labeling analyses of Ad-RB94-treated tumor sections revealed that only RB94 is able to significantly induce apoptosis. CONCLUSIONS: RB94 gene expression has antiproliferative effects also in human pancreatic tumor cells, being more effective than wild-type RB in preventing tumor growth.