Concurrent or sequential letrozole with adjuvant breast radiotherapy: final results of the CO-HO-RT phase II randomized trial.

BACKGROUND: We present here final clinical results of the COHORT trial and both translational sub-studies aiming at identifying patients at risk of radiation-induced subcutaneous fibrosis (RISF): (i) radiation-induced lymphocyte apoptosis (RILA) and (ii) candidates of certain single-nucleotide polymorphisms (SNPs). PATIENTS AND METHODS: Post-menopausal patients with stage I-II breast cancer (n = 150) were enrolled and assigned to either concurrent (arm A) or sequential radiotherapy (RT)-letrozole (arm B). Among them, 121 were eligible for RILA and SNP assays. Grade ≥2 RISF were the primary end point. Secondary end points were lung and heart events and carcinologic outcome. RILA was performed to predict differences in RISF between individuals. A genome-wide association study was performed to identify SNPs associated with RILA and RISF. Analyses were done by intention to treat. RESULTS: After a median follow-up of 74 months, 5 patients developed a grade ≥2 RISF. No significant difference was observed between arms A and B. Neither grade ≥2 lung nor symptomatic cardiac toxicity was observed. Median RILA value of the five patients who had grade ≥2 RISF was significantly lower compared with those who developed grade ≤1 RISF (6.9% versus 13%, P = 0.02). Two SNPs were identified as being significantly associated with RILA: rs1182531 (P = 4.2 × 10(-9)) and rs1182532 (P = 3.6 × 10(-8)); both located within the PHACTR3 gene on chromosome 20q13.33. CONCLUSIONS: With long-term follow-up, letrozole can safely be delivered concomitantly with adjuvant breast RT. Translational sub-studies showed that high RILA values were correlated with patients who did not develop RISF. REGISTERED CLINICAL TRIAL: NCT00208273.

[Radiomics: Definition and clinical development]. / Définition et applications cliniques des radiomics.

The ultimate goal in radiation oncology is to offer a personalized treatment to all patients indicated for radiotherapy. Radiomics is a tool that reinforces a deep analysis of tumors at the molecular aspect taking into account intrinsic susceptibility in a long-term follow-up. Radiomics allow qualitative and quantitative performance analyses with high throughput extraction of numeric radiologic data to obtain predictive or prognostic information from patients treated for cancer. A second approach is to define biological or constitutional that could change the practice. This technique included normal tissue individual susceptibility but also potential response of tumors under ionizing radiation treatment. These "omics" are biological and technical techniques leading to simultaneous novel identification and exploration a set of genes, lipids, proteins.

Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy.

AXL receptor tyrosine kinase (RTK) is implicated in proliferation and invasion of many cancers, particularly in pancreatic ductal adenocarcinoma (PDAC), for which new therapeutic options are urgently required. We investigated whether inhibition of AXL activity by specific monoclonal antibodies (mAbs) is efficient in limiting proliferation and migration of pancreatic cancer cells. Expression of AXL was evaluated by immunohistochemistry in 42 PDAC. The AXL role in oncogenesis was studied using the short hairpin RNA approach in a pancreatic carcinoma cell line. We further generated antihuman AXL mAbs and evaluated their inhibitory effects and the AXL downstream signaling pathways first in vitro, in a panel of pancreatic cancer cell lines and then in vivo, using subcutaneous or orthotopic pancreatic tumor xenografts. AXL receptor was found expressed in 76% (32/42) of PDAC and was predominantly present in invasive cells. The AXL-knockdown Panc-1 cells decreased in vitro cell migration, survival and proliferation, and reduced in vivo tumor growth. Two selected anti-AXL mAbs (D9 and E8), which inhibited phosphorylation of AXL and of its downstream target AKT without affecting growth arrest-specific factor 6 (GAS6) binding, induced downexpression of AXL by internalization, leading to an inhibition of proliferation and migration in the four pancreatic cancer cell lines studied. In vivo, treatment by anti-AXL mAbs significantly reduced growth of both subcutaneous and orthotopic pancreatic tumor xenografts independently of their KRAS mutation status. Our in vitro and preclinical in vivo data demonstrate that anti-human AXL mAbs could represent a new approach to the pancreatic cancer immunotherapy.

[Intrinsic radiosensitivity: predictive assays that will change daily practice]. / Radiosensibilité individuelle : les tests vont changer nos pratiques.

The impact of curative radiotherapy depends mainly on the total dose delivered homogenously in the targeted volume. Nevertheless, the dose delivered to the surrounding healthy tissues may reduce the therapeutic ratio of many radiation treatments. In a same population treated in one center with the same technique, it appears that individual radiosensitivity clearly exists, namely in terms of late side effects that are in principle non-reversible. This review details the different radiobiological approaches that have been developed to better understand the mechanisms of radiation-induced late effects. We also present the possibilities of clinical use of predictive assays in the close future.

[Anti-HER2 vaccines: The HER2 immunotargeting future?]. / Vaccination anti-HER2 : l'avenir du ciblage immunologique de HER2 ?

Breast cancer is a widely spread women's disease. In spite of progress in the field of surgery and adjuvant therapies, the risk of breast cancer metastatic relapses remains high especially in those overexpressing HER2. Different studies have shown cellular and/or humoral immune responses against HER2 in patients with HER2-overexpressing tumors. This immune response is associated with a lower tumor development at early stages of the disease. These observations, associated with the efficiency today demonstrated by a trastuzumab-based anti-HER2 immunotherapy, allowed to envisage various vaccinal strategies against HER2. These findings have so led to the hypothesis that the generation of an anti-HER2 immune response should protect patients from HER2-overexpressing tumor growth, and induction of a stable and strong immunity by cancer vaccines is expected to lead to establishment of immune memory, thereby preventing tumor recurrence. However, an immunological tolerance against HER2 antigen exists representing a barrier to effective vaccination against this oncoprotein. As a consequence, the current challenge for vaccines is to find the best conditions to break this immunological tolerance. In this review, we will discuss the different anti-HER2 vaccine strategies currently developed; considering the strategies having reached the clinical phases as well as those still in preclinical development. The used antigen can be composed of tumoral allogenic cells or autologous cells or be specific of HER2. It can be delivered by denditric cells or in a DNA, peptidic or proteic form. Another area of the research concerns the use of anti-idiotypic antibodies mimicking HER2.

Sentinel node procedure of the sigmoid using indocyanine green: feasibility study in a goat model.

BACKGROUND: The sentinel lymph node (SLN) procedure alter the strategy for the treatment of patients with colon cancer. New techniques emerge that may provide the surgeon with a tool for accurate intraoperative detection of the SLNs. METHODS: An SLN procedure of the sigmoid was used in six goats. During laparoscopy, the near-infrared dye indocyanine green (ICG) was injected into the subserosa of the sigmoid via a percutaneously inserted needle during four experiments and in the submucosa during colonoscopy in two experiments. After injection, the near-infrared features of a newly developed laparoscope were used to detect the lymph vessels and SLNs. At the end of the procedure, 2 h after injection, all the goats were killed, and autopsy was performed. During postmortem laparotomy, the sigmoid was removed and used for confirmation of ICG node uptake. RESULTS: In all the procedures, the lymph vessels were easily detected by their bright fluorescent emission. In the first two experiments, no lymph nodes were detected. In the subsequent four experiments, human serum albumin was added to the ICG solution before injection to enable better lymph node entrapment. In all four experiments, at least one bright fluorescent lymph node was found after the lymph vessels had been tracked by their fluorescent guidance. The mean time between injection and SLN identification was 10 min. In two cases, the SLNs were located up to 5 mm into the fat tissue of the mesentery and were not seen by regular vision of the laparoscope. By switching on the near-infrared features of the scope, a clear bright dot became visible, which increased in intensity after opening of the mesentery. CONCLUSION: The SLN procedure for the sigmoid using near-infrared laparoscopy in the goat is a very promising technique. Achievements described in this report justify a clinical trial on the feasibility of ICG-guided SLN detection in humans.

Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts.

BACKGROUND: Pancreatic carcinoma remains a treatment-refractory cancer with a poor prognosis. Here, we compared anti-epidermal growth factor receptor (EGFR) and anti-HER2 monoclonal antibodies (2mAbs) injections with standard gemcitabine treatment on human pancreatic carcinoma xenografts. MATERIALS AND METHODS: Nude mice, bearing human pancreatic carcinoma xenografts, were treated with either combined anti-EGFR (cetuximab) and anti-HER2 (trastuzumab) or gemcitabine, and tumor growth was observed. RESULTS AND CONCLUSION: In first-line therapy, mice survival was significantly longer in the 2mAbs group compared with gemcitabine (P < 0.0001 for BxPC-3, P = 0.0679 for MiaPaCa-2 and P = 0.0019 for Capan-1) and with controls (P < 0.0001). In second-line therapy, tumor regressions were observed after replacing gemcitabine by 2mAbs treatment, resulting in significantly longer animal survival compared with mice receiving continuous gemcitabine injections (P = 0.008 for BxPC-3, P = 0.05 for MiaPaCa-2 and P < 0.001 for Capan-1). Therapeutic benefit of 2mAbs was observed despite K-Ras mutation. Interestingly, concerning the mechanism of action, coinjection of F(ab')(2) fragments from 2mAbs induced significant tumor growth inhibition, compared with controls (P = 0.001), indicating that the 2mAbs had an Fc fragment-independent direct action on tumor cells. This preclinical study demonstrated a significant improvement of survival and tumor regression in mice treated with anti-EGFR/anti-HER2 2mAbs in first- and second-line treatments, compared with gemcitabine, independently of the K-Ras status.

Phase II randomised trial of raltitrexed-oxaliplatin vs raltitrexed-irinotecan as first-line treatment in advanced colorectal cancer.

The purpose of this phase II randomised trial was to determine which of two schemes, raltitrexed-irinotecan or raltitrexed-oxaliplatin, offered better activity and less toxicity in patients with advanced colorectal cancer (CRC). A total of 94 patients with previously untreated metastatic CRC were included and randomised to receive raltitrexed 3 mg m(-2) followed by oxaliplatin 130 mg m(-2) on day 1 (arm A), or CPT-11 350 mg m(-2) followed by raltitrexed 3 mg m(-2) (arm B). In both arms treatment was repeated every 3 weeks. Intent-to-treat (ITT) analysis showed an overall response rate of 46% (95% CI, 29.5-57.7%) for arm A, and 34% (95% CI, 19.8-48.4%) for arm B. Median time to progression was 8.2 months for arm A and 8.8 months for arm B. After a median follow-up of 14 months, 69% of patients included in arm A were still alive, compared to 59% of those included in arm B. Overall, 31 patients (65%) experienced some episode of toxicity in arm A and 32 patients (70%) in arm B, usually grade 1-2. The most common toxicity was hepatic, with 29 patients (60%) in arm A and 24 patients (62%) in arm B, and was grade 3-4 in four (8%) and four (9%) patients, respectively. In all, 14 patients (29%) from arm A and 24 patients (52%) from arm B had some grade of diarrhoea (P<0.03). Neurologic toxicity was observed in 31 patients (64%) in arm A, and was grade 3-4 in five patients (10%), while a cholinergic syndrome was detected in nine patients (19%) in arm B. There were no differences in haematologic toxicity. One toxic death (2%) occurred in arm A and three (6.5%) in arm B. In conclusion, both schemes have high efficacy as first-line treatment in metastatic CRC and their total toxicity levels are similar. Regimens with raltitrexed seem a reasonable alternative to fluoropyrimidines.

The development and characterisation of porphyrin isothiocyanate-monoclonal antibody conjugates for photoimmunotherapy.

A promising approach to increase the specificity of photosensitizers used in photodynamic therapy has been through conjugation to monoclonal antibodies (MAb) directed against tumour-associated antigens. Many of the conjugations performed to date have relied on the activated ester method, which can lead to impure conjugate preparations and antibody crosslinking. Here, we report the development of photosensitizer-MAb conjugates utilising two porphyrin isothiocyanates. The presence of a single reactive isothiocyanate allowed facile conjugation to MAb FSP 77 and 17.1A directed against internalizing antigens, and MAb 35A7 that binds to a non-internalizing antigen. The photosensitizer-MAb conjugates substituted with 1-3 mol of photosensitizer were characterised in vitro. No appreciable loss of immunoreactivity was observed and binding specificity was comparable to that of the unconjugated MAb. Substitution with photosensitizer had a minimal effect on antibody biodistribution in vivo for the majority of the conjugates, although a decreased serum half-life was observed using a cationic photosensitizer at the higher loading ratios. Tumour-to-normal tissue ratios as high as 33.5 were observed using MAb 35A7 conjugates. The internalizing conjugate showed a higher level of phototoxicity as compared with the non-internalizing reagent, using a cell line engineered to express both target antigens. These data demonstrate the applicability of the isothiocyanate group for the development of high-quality conjugates, and the use of internalizing MAb to significantly increase the photodynamic efficiency of conjugates during photoimmunotherapy.

Concomitant use of tamoxifen with radiotherapy enhances subcutaneous breast fibrosis in hypersensitive patients.

Concomitant use of adjuvant tamoxifen (TAM) and radiation therapy (RT) is not widely accepted. We aim to assess whether this treatment is associated with an increased risk of developing subcutaneous fibrosis after conservative or radical surgery in breast cancer patients. We analysed 147 women with breast cancer treated with adjuvant RT, and who were included in the KFS 00539-9-1997/SKL 00778-2-1999 prospective study aimed at evaluating the predictive value of CD4 and CD8 T-lymphocyte apoptosis for the development of radiation-induced late effects. TAM (20 mg day(-1)) with concomitant RT was prescribed in 90 hormone receptor-positive patients. There was a statistically significant difference in terms of complication-relapse-free survival (CRFS) rates at 3 years, 48% (95% CI 37.2-57.6%) vs 66% (95% CI 49.9-78.6%) and complication-free survival (CFS) rates at 2 years, 51% (95% CI 40-61%) vs 80% (95% CI 67-89%) in the TAM and no-TAM groups, respectively. In each of these groups, the CRFS rates were significantly lower for patients with low levels of CD8 radiation-induced apoptosis, 20% (95% CI 10-31.9%), 66% (95% CI 51.1-77.6%), and 79% (95% CI 55-90.9%) for CD8 24%, respectively. Similar results were observed for the CFS rates. The concomitant use of TAM with RT is significantly associated with an increased incidence of grade 2 or greater subcutaneous fibrosis; therefore, caution is needed for radiosensitive patients.

Isolation and characterisation of a human anti-idiotypic scFv used as a surrogate tumour antigen to elicit an anti-HER-2/neu humoral response in mice.

HER-2/neu is a tumour antigen that is overexpressed in human breast tumours. Among the vaccine strategies developed to overcome immune tolerance to self-proteins, vaccination with anti-idiotypic (anti-Id) antibodies has been described as a promising approach for treatment of several malignant diseases. To develop an active immunotherapy for cancer patients positive for HER-2/neu, we investigated immunisation with human anti-Id single-chain fragments (scFv) mimicking the conformation of HER-2/neu protein to induce a humoral response in mice. We selected by phage display two human anti-Id scFv (Ab2beta) directed against trastuzumab F(ab')2 fragments (Ab1), a humanised anti-HER-2/neu monoclonal antibody. Using competitive ELISA and Biacore biosensor analysis, we showed that anti-Id scFv 40 and scFv 69 could inhibit HER-2/neu binding to trastuzumab. Following vaccination of BALB/c mice with the soluble or phage-displayed scFv, Ab3 polyclonal antibodies, and among them Ab1' antibodies able to bind HER-2/neu, were detected in the sera of the immunised mice. These results demonstrate that the human anti-Id scFv could act as a surrogate antigen for HER-2/neu. The present study strongly suggests that the novel 30 kDa human mini-antibody could be used as an anti-idiotype-based vaccine formulation to induce an effective humoral response in patients bearing HER-2/neu-positive tumours.

[Concomitant use of radiotherapy and gemcitabine: preclinical findings and clinical practice]. / Association concomitante de la radiothérapie et de la gemcitabine: données précliniques et études cliniques.

Gemcitabine is pyrimidine analog which has demonstrated antitumoral activity in a variety of solid tumors. Laboratory studies demonstrating that gemcitabine is a potent radiosensitizer led to a variety of trials combining radiation and gemcitabine. In the clinic, phase I-II studies are still trying to determine the optimal dose and schedule which could be use in daily clinical practice. This review summarizes the mechanisms of interaction between radiotherapy and gemcitabine and presents several therapeutic schemes for each tumor location.

Potentiation of ionising radiation by targeting tumour necrosis factor alpha using a bispecific antibody in human pancreatic cancer.

The aim of this study was to treat carcinoembryonic antigen (CEA)-expressing pancreatic carcinoma cells with tumour necrosis factor alpha (TNFalpha) and simultaneous radiation therapy (RT), using a bispecific antibody (BAb) anti-TNFalpha/anti-CEA. TNFalpha used alone produced a dose-dependent inhibition of the clonogenic capacity of the cultured cells. Flow cytometry analysis of cell cycle progression confirmed the accumulation of cells in G(1) phase after exposure to TNFalpha. When TNFalpha was added 12 h before RT, the surviving fraction at 2 Gy was 60% lower than that obtained with irradiation alone (0.29 vs 0.73, respectively, P<0.00001). In combination treatment, cell cycle analysis demonstrated that TNFalpha reduced the number of cells in radiation-induced G(2) arrest, blocked irreversibly the cells in G(1) phase, and showed an additive decrease of the number of cells in S phase. In mice, RT as a single agent slowed tumour progression as compared with the control group (P<0.00001). BAb+TNFalpha+RT combination enhanced the delay for the tumour to reach 1500 mm(3) as compared with RT alone or with RT+TNFalpha (P=0.0011). Median delays were 90, 93, and 142 days for RT alone, RT+TNFalpha, and RT+BAb+TNFalpha groups, respectively. These results suggest that TNFalpha in combination with BAb and RT may be beneficial for the treatment of pancreatic cancer in locally advanced or adjuvant settings.

Internalisation enhances photo-induced cytotoxicity of monoclonal antibody-phthalocyanine conjugates.

Immunophototherapy of cancer combines the specificity of a monoclonal antibody (MAb) to an overexpressed tumor marker with the phototoxic properties of the conjugated dye. To analyze the potential role of internalisation of the dye on photo-induced cytotoxicity, we compared two target antigens, carcinoembryonic antigen (CEA) that does not internalise and ErbB2 that does. Human ovarian carcinoma SKOv3 cells that express a high level of ErbB2 were transfected with the CEA cDNA. Using FACS analysis, the resulting cell line, SKOv3-CEA-1B9, demonstrated comparable levels of expression of the two target antigens. Aluminium tetrasulfophthalocyanine (AlPcS(4)) was covalently coupled to anti-CEA MAb 35A7, anti-ErbB2 MAb FSP77 and a non-specific MAb PX, via a five-carbon sulfonamide spacer chain (A(1)) at molar ratios ranging from 6 to 9 moles of AlPcS(4) per mole of MAb. The 35A7-(AlPcS(4)A(1))(8) conjugate induced 68% growth inhibition of the SKOv3-CEA-1B9 cell line after a 20 h incubation at 2.50 microg/ml (based on AlPcS(4)A(1) content) following light exposure. However, the FSP77-(AlPcS(4)A(1))(6) conjugate gave a 51% growth inhibition for an AlPcS(4)A(1) concentration as low as 0.04 microg/ml after the same incubation time and exposure to the same light dose. At a 1.25 microg/ml AlPcS(4)A(1) concentration, the FSP77-(AlPcS(4)A(1))(6) conjugate gave a 67% growth inhibition after an incubation time as short as 1 h, reaching a 96% inhibition after an 8 h incubation time. Using an unique cell line that expresses two different target antigens, we demonstrated a clear advantage of an internalising over a non-internalising MAb-dye conjugate in terms of phototoxic efficacy. In vivo evaluation of the photodynamic properties of the conjugates is in progress.

Intraoperative immunophotodetection for radical resection of cancers: evaluation in an experimental model.

The aim of our study was to assess the technique of immunophotodetection (IPD) in intraoperative situations in an experimental model and to determine its capacity to detect very small tumor masses. IPD is a recent technology involving fluorescent dye-labeled monoclonal antibodies (MAbs) directed against tumor-associated antigens. Up to now, no intraoperative device for IPD has been developed, and limits of detection of the technique are unknown. MAb-dye conjugates were prepared using the anti-carcinoembryonic antigen MAb 35A7 labeled with indocyanine and (125)I. Time-dependent (6, 12, 24, 48, and 96 h post i.v. injection) and dose-dependent (10, 40, and 100 microg of conjugate) biodistribution studies were performed in nude mice bearing an LS174T peritoneal carcinomatosis demonstrating high tumor uptake (up to 21% of the injected dose/g of tumor 48 h postinjection). Intraoperative IPD was studied, using a newly developed device, in 16 mice 48 h after i.v. injection of 40 microg of the (125)I-MAb 35A7-indocyanine conjugate. The fluorescent status of 333 biopsies was compared with their histological analysis. Sensitivity was 90.7%, specificity was 97.2%, the positive predictive value was 94.7%, and the negative predictive value was 94.9%. Detection of very small nodules (<1 mg in weight or <1 mm in diameter) was possible. However, we observed a decrease in sensitivity as a function of tumor mass: 100% for nodules >10 mg versus 78% for nodules < or =1 mg. These experiments demonstrate that intraoperative IPD is easy to use and associated with high sensitivity and specificity, even for low tumor masses. On the basis of these encouraging results, intraoperative IPD should be assessed in a clinical study.

Carcinoembryonic antigen continuous epitopes determined by the spot method.

Carcinoembryonic antigen (CEA) is a heavily glycosylated tumor-associated protein with an N-A1-B1-A2-B2-A3-B3 domain structure. Circulating CEA immunoassays are used for monitoring digestive cancer patients, and radiolabeled anti-CEA monoclonal antibodies (MAb) are used for the diagnosis and therapy of CEA-positive tumors. The five major nonoverlapping epitopes (Gold 1-5) have been broadly correlated with the domain organization, but there is no precise localization of the epitopes at the sequence level. In an attempt to identify the peptide sequences corresponding to the five Gold epitopes on the CEA molecule, we prepared a set of 227 overlapping fifteen-mer peptides corresponding to the complete CEA sequence with the SPOT method. Using five high affinity MAbs directed against the five CEA Gold epitopes, we demonstrated that none of these epitopes could be mimicked by a fifteen-mer peptide sequence. However, using rabbit and goat anti-CEA sera, we identified six major continuous antigenic regions. All are included in the Ig-like domains of the CEA: two in the A1 domain (residues 120-134 and 153-164), one each in the A2 (329-337) and A3 domains (508-513), one at the junction between the A3 and B3 domains (553-561) and one in the B3 domain (565-573). A very homologous sequence (common residues VSPRL) was mapped in each of the three A domains. Thus, in terms of occurrence of continuous epitopes, the Ig-like domains A1, A2, A3 and B3 seem to be the most antigenic parts of CEA. These peptide sequences should be good candidates for the future development of site-specific anti-CEA MAbs.

Combination of thymidine phosphorylase gene transfer and deoxyinosine treatment greatly enhances 5-fluorouracil antitumor activity in vitro and in vivo.

We reported previously that 5-fluorouracil (FUra) efficacy could be enhanced by increasing tumoral thymidine phosphorylase (TP) activity. Potentiated TP yield was achieved by either transfecting cells with human TP gene (A. Evrard et al., Br. J. Cancer, 80: 1726-1733, 1999) or associating FUra with 2'-deoxyinosine (d-Ino), a modulator providing the tumors with TP cofactor deoxyribose 1-phosphate (J. Ciccolini et al., Clin. Cancer Res., 6: 1529-1535, 2000). The purpose of the present work was to study the effects of a combined modulation (TP gene transfer + use of d-Ino) on the sensitivity to FUra of the LS174T human colorectal cell line. Results showed a near 4000 times increase of cell sensitivity in vitro after double (genetic + biochemical) modulation. This potentiation of tumor response was accompanied by a total change in the FUra anabolic pathway with a 5000% increase of cytosolic fluorodeoxyuridine monophosphate, a stronger and longer inhibition of thymidylate synthase, and 300% augmentation of DNA damage. Besides, whereas thymidine failed to inhibit FUra cytotoxicity in LS174T wild-type cells, the potentiation of the antitumor activity observed in the modulating regimen was partly reversed by thymidine, indicative of thymidylate synthase as the main drug target. The impact of this double modulation was next investigated in xenograft-bearing nude mice. Results showed that whereas FUra alone was completely ineffective on wild-type tumor growth, the size of TP-transfected tumors in animals treated with the FUra/d-Ino combination was reduced by 80% (P < 0.05). Our results suggest that FUra exhibits stronger antiproliferative activity when activated via TP through the DNA pathway and that high tumoral TP activity therefore leads to enhanced sensitivity to fluoropyrimidines.

[Immunotargeting of tumors: state of the art and prospects in 2000]. / Immunociblage des tumeurs: situation et perspectives en 2000.

Following 15 years of experimental studies, tumor immunotargeting using monoclonal antibodies directed against tumor associated antigens shows now important monoclonal antibodies directed against tumor associated antigens shows now important clinical developments. This is mainly due to encouraging therapeutic results which have obtained using humanized antibodies such as the anti-CD20 rituximab in follicular B lymphomas and the anti-DrbB2 herceptin in breast carcinomas. Thanks to genetic engineering it is possible to graft variable or hypervariable regions from murine antibodies to human IgG, and even to obtain fully human antibodies by using either transgenic mice containing a large part of the human repertoire of human IgG, or selection of human antibody fragments expressed by phages. Radiolabeling of antibodies played a major role to demonstrate the tumor immunotargeting specificity and remains attractive for the diagnosis by immunoscintigraphy as well as for the treatment by radioimmunotherapy of some cancers. In this review, the current results and the prospects of diagnostic and therapeutic uses of anti-tumor antibodies and their fragments will be described. Concerning diagnosis, 123-iodine or 99m-technetium labeled Fab fragments allowed very demonstrative tumor images but this technique has a limited effect upon the therapeutic attitude. Immuno-PET (positron emission tomography) could enhance the sensitivity of this imaging method. Radio-immunoguided surgery and immunophotodetection are attractive techniques still under evaluation. Concerning therapy, 131-iodine labeled anti-CD20 antibodies gave spectacular results in non-Hodgkin's B lymphomas. In solid tumors which as less radiosensitive, radioimmunotherapy could concern small tumors and need the use of two-steps targeting and/or alpha emitters radioisotopes. Some other strategies will be described such as bispecific antibodies directed against tumors and immune effector cells, some antibody fragments expressed on T cells called T-bodies or some biological studies using intrabodies. Published data and works in progress demonstrate that immunotargeting of tumors will have a growing place in the treatments of cancer patients.

[Cancer immunophotodetection and immunophototherapy]. / Immunophotodétection et immunophotothérapie des cancers.

Some dyes can be used for cancer diagnosis and therapy. Following administration, the dye concentrate with some specificity in the tumor and can react to an irradiation with light. Some excited dyes can be fluorescent allowing detection of very small tumors. Some other dye can be phototoxic and lead to the destruction of the tumor. These attractive techniques are however limited because of the too low tumor specificity of the currently used dyes (hematoporphyrin and phthalocyanine). A new strategy has be developed in which the fluorescent or phototoxic dye is coupled to an antibody directed against a tumor associated antigen. This approach allow the selection of the dye only for its optimal photochemical properties, the antibody being used as carrier to concentrate the dye in the tumor. Many experimental immunophototherapy studies have been performed with different phototoxic dyes. Some results are encouraging but the involved mechanisms are complex and they limit the current clinical applications of immunophototherapy. Concerning immunophotodetection, two dyes have been coupled to anti-tumor antibodies: fluorescein and indocyanin. The antibody-dye conjugates have been evaluated in experimental studies and in pilot clinical trials. The most recent results concern the use of this technique in intraoperative situation and to visualize neo-vascularization. Immunophotodetection gives a very precise image of tumors. The detected tumor nodules are in the millimeter range. However, according to the limited light pathway in the tumor, this technique can be applied only to cutaneous areas, endoscopy accessible areas and intraopearative situations. Immunophotodetection is an attractive imaging technique using antibodies.