Biomedical subjects

D Krebs

Publications and source records attributed to D Krebs.

At least 37 records · Page 2Linked to original sources

PubMed1999

Exercise--it's never too late: the strong-for-life program.

OBJECTIVES: This investigation determined whether an in-home resistance training program achieved health benefits in older adults with disabilities. METHODS: A randomized controlled trial compared the effects of assigning 215 older persons to either a home-based resistance exercise training group or a waiting list control group. Assessments were conducted at baseline and at 3 and 6 months following randomization. The program consisted of videotaped exercise routines performed with elastic bands of varying thickness. RESULTS: High rates of exercise adherence were achieved, with 89% of the recommended exercise sessions performed over 6 months. Relative to controls, subjects who participated in the program achieved statistically significant lower extremity strength improvements of 6% to 12%, a 20% improvement in tandem gait, and a 15% to 18% reduction in physical and overall disability at the 6-month follow-up. No adverse health effects were encountered. CONCLUSIONS: These findings provide important evidence that home-based resistance exercise programs designed for older persons with disabilities hold promise as an effective public health strategy.

Aged↗

PubMed1999

[Monoclonal anti-idiotype antibodies in immunotherapy of ovarian carcinoma (MAb ACA125) and breast carcinoma (MAb ACA14C5)].

Anti-idiotypic antibodies, which imitate a tumor-associated antigen by their variable region, offer an elegant method for the induction of a specific immune response, when used as a surrogate antigen for immunization. We generated anti-idiotypic antibodies imitating 2 different tumor-associated antigens. I. CA125 for ovarian carcinomas and II. 14C5, a tumor-associated cell substrate adhesion molecule on breast cancer cells, whereas the first approach could be introduced in a first clinical trial and the second was evaluated in an immunocompetent animal model. For the induction of an immune response against CA125, 18 patients with advanced ovarian cancer (n = 6) or heavily pretreated recurrences (n = 12) were immunized with the anti-idiotypic antibody MAb ACA125. Patients were treated with 2 mg anti-idiotype antibody every two weeks for 4 injections i.m. and then monthly. 12 of 18 patients demonstrated an anti-anti-idiotypic (Ab3) response, which was to a lower extent also directed against CA125 and 9 of 18 patients developed a CA125 specific cellular immune response by their peripheral blood lymphocytes. Based on this data a follow-up clinical trial in advanced ovarian cancer patients with minimal residual disease in an adjuvant approach after primary therapy was started to evaluate the effect of the immune response on the progression free survival. For immunotherapy of breast cancer, we generated a murine monoclonal anti-idiotypic antibody (MAb ACA14C5), which imitates a cell substrate adhesion molecule on breast cancer cells. The anti-idiotype was introduced in an immunocompetent animal to prove his capability on induction of an immune and tumor response. The results showed a highly significant difference in the tumor growth of the ACA14C5 treated group in contrast to the controls starting the immunization on day 6 after tumor cell application with 10 of 12 animals being cured from their tumor burden. Prophylactic immunization against the invasion antigen of breast cancer by anti-idiotypic antibodies showed protection against increasing tumor burden. However, in the situation of established tumors only minor responses could be detected. Vaccination with anti-idiotypic antibodies comprises an effective method for induction of a specific immune response against non-immunogenic tumor-associated antigens and should be therefore considered in immunological approaches to tumor therapy, where the primary structure and sequence of the antigen, e.g. CA125, is up to now not available.

Antibodies, Monoclonal↗

PubMed1999

Clinical application of maternal serum cytokine determination in premature rupture of membranes--interleukin-6, an early predictor of neonatal infection?

BACKGROUND: In cases of premature rupture of membranes (PROM), an early detection of fetal infection is necessary in order to weigh infectious complications against prematurity. As routine parameters (leukocytes, C-reactive protein (CRP), fever, and fetal tachycardia) lack satisfactory sensitivity and specificity, this study evaluates whether the determination of interleukin-6 (IL-6), interleukin-8 (IL-8) or soluble interleukin-2 receptor (IL-2R) in maternal serum could supplement or replace routine inflammation parameters. METHODS: In this prospective study results of clinical and laboratory parameters were investigated with respect to neonatal infection in 71 patients with PROM. IL-6, IL-8 and IL-2R were determined by enzyme immunoassays. RESULTS: Best specificity and sensitivity could be demonstrated for CRP and IL-6. Both elevation of CRP and IL-6 correlated significantly (p<0.01 and p<0.001, respectively) with the onset of neonatal infection. At a cutoff of 11 pg/ml, IL-6 reaches a sensitivity of 81% and a specificity of 76%; CRP a specificity of 76% (cutoff 1.2 mg/dl) and a sensitivity of 56%. In 4/16 (25%) cases developing neonatal infection, IL-6 increased earlier than CRP. IL-8 and IL-2R results showed a less significant correlation with fetal outcome. CONCLUSIONS: Determination of IL-6 in maternal serum can significantly contribute to an earlier detection of fetal infection in patients with PROM.

Area Under Curve↗

PubMed1998

Expression of the ATM gene is significantly reduced in sporadic breast carcinomas.

The gene mutated in ataxia telangiectasia (A-T) patients (ATM) is located on chromosome 11q22-23, a region frequently altered in mammary tumors. Patients homozygous for ATM mutations are prone to develop a variety of different neoplasms. Female heterozygotes have been reported to carry a 5- to 8-fold increased risk of breast cancer. However, germline mutations in the ATM gene are rare in women with sporadic breast carcinomas. Most of the alterations described in A-T patients result in a functionally inactive ATM protein. Moreover, it has been suggested that mutations of the ATM gene in A-T patients influence the amount of ATM mRNA and that this may affect the severity of the disease. In the present study, we have analyzed ATM transcripts in a series of 39 breast carcinomas, 14 benign breast lesions and 12 normal breast tissue samples. ATM mRNA levels were determined by semiquantitative competitive RT-PCR. Competitor RNA molecules for the ATM gene and the housekeeping gene beta-2-microglobulin (B2M) were generated by PCR mutagenesis. Low concentrations of ATM transcripts were detected in breast carcinomas, intermediate levels in benign lesions and highest levels in normal breast tissue specimens (F-test, p = 0.0013). Our results indicate that reduced expression of the ATM gene may contribute to the development and/or malignant progression of breast carcinomas.

Ataxia Telangiectasia Mutated Proteins↗

PubMed1998

Helical and coiled-coil-forming properties of peptides derived from and inhibiting human immunodeficiency virus type 1 integrase assessed by 1H-NMR--use of NH temperature coefficients to probe coiled-coil structures.

Human immunodeficiency virus type 1 integrase (HIV-1 IN) which catalyzes viral DNA integration into the host genome of infected cells represents an attractive target for AIDS therapy. We have previously demonstrated the ability of the IN-(147-175)-peptide derived from the catalytic core domain of HIV-1 IN to inhibit the enzyme activity in vitro. IN-(147-175)-peptide contains four heptad repeats and displays a high propensity for coiled-coil formation while its [P159]IN-(147-175)-peptide analog (Lys159-->Pro in the protein, Lys13-->Pro in the peptide) is unable to form a stable coiled-coil and is devoid of inhibitory activity [Sourgen, F., Maroun, R. G., Frère, V., Bouziane, M., Auclair, C., Troalen, F. & Fermandjian, S. (1996) Eur. J. Biochem. 240, 765-773]. Now, we report results from an NMR study on IN-(147-175)-peptide and [P159]IN-(147- 175)-peptide as well as on an optimized [E156, A163, A167]IN-(147-175)-peptide that is a better inhibitor of IN than IN-(147-175)-peptide. While in aqueous solution, IN-(147-175)-peptide and [P159]IN-(147-175)-peptide display only nascent helical features, [E156, A163, A167]IN-(147-175)-peptide exhibits 20% of helical content. In 20% trifluoroethanol/80% H2O, the helix content is the highest for [E156, A163, A167]IN-(147-175)-peptide (approximately 70%) and the lowest for [P159]IN-(147-175)-peptide (approximately 40%), due to a local helix break caused by the Pro residue. The NHs of residues in the two central helical heptads (a-g) of IN-(147-175)-peptide and [E156, A163, A167]IN-(147-175)-peptide display a regular periodic variation of their temperature coefficients in 20% trifluoroethanol. The b, c and f residues on the hydrophilic face of the amphipathic helix show high coefficients reflecting hydrogen bonded NHs, while the a and d residues on the hydrophobic face exhibit low coefficients, near random-coil values. The particular arrangement of the hydrophobic side-chains of a and d residues at the coiled-coil interface reduces the access of trifluoroethanol molecules to their amide groups. The inability of trifluoroethanol molecules to create interactions with the amide C=O groups, these being required to strengthen the intrahelical C=O...H-N hydrogen bonds, is the main cause for observation of heptadic a and d residues with low NH temperature coefficients. Such effects concern mostly the two central helical heptads of IN-(147-175)-peptide and [E156, A163, A167]IN-(147-175)-peptide implying that these ones are engaged in stable parallel coiled coils. Our results provide a link between the propensity of peptides for helix formation, their coiled-coil properties and their efficiency to inhibit IN.

Amino Acid Sequence↗

PubMed1998

HLA-G polymorphisms and allele frequencies in Caucasians.

HLA-G, a nonclassical class I MHC molecule, is uniquely expressed on extravillous cytotrophoblasts of the maternal-fetal interface and is suggested to be essential for establishment of maternal-fetal immune tolerance. Although the level of polymorphism in HLA-G has originally been considered low, number, nature and site of polymorphisms seem to vary between different ethnic populations. We investigated HLA-G polymorphisms in a population of German and Croatian origin by SSCP-analysis and direct sequencing as well as RFLP analysis for presence of the 1597delC mutation. HLA-A alleles associated with the different HLA-G alleles were determined by SSP PCR-typing. In Caucasians, HLA-G exhibits a low degree of polymorphism on the amino-acid level and only slightly higher variability on the nucleotide level. In 264 independent chromosomes, 4 HLA-G alleles on the level of amino acid polymorphisms and an additional 6 variations of nucleotide sequences could be identified. The null-allele G*0105N was present at an allele frequency of 2.3%, which is higher than initially suggested for Caucasians but lower than in Hispanics and African-Americans. Furthermore, some HLA-G alleles exhibit strong linkage disequilibrium with HLA-A.

Adult↗

PubMed1998

Remission of bone metastases after combined chemotherapy and radionuclide therapy with Re-186 HEDP.

A patient with disseminated osseous metastases due to breast cancer reported multifocal pain. Because of persisting pain after a first cycle of chemotherapy, 1,295 MBq Re-186 HEDP was administered intravenously. Excellent pain relief was observed. Subsequently, the patient received further combined chemotherapy and Re-186 HEDP therapy and remained pain free. Tc-99m MDP bone imaging showed a significant regression of osseous metastases. It may be speculated that the combination of Re-186 HEDP and chemotherapy results in significantly increased palliation of metastatic bone disease.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

HLA-G polymorphisms: ethnic differences and implications for potential molecule function.

PROBLEM: Human leukocyte antigen (HLA)-G is uniquely expressed on extravillous cytotrophoblasts of the placenta and is postulated to be a mediator of maternal immune tolerance. Although it was originally considered to be nonpolymorphic, variations of the HLA-G DNA sequence have been reported, and a limited number of HLA-G alleles been defined. METHOD OF STUDY: The HLA-G wild-type sequence was compared with HLA-A2 with regard to the conservation of functionally essential parts of classical HLA-I molecules. HLA-G polymorphisms were analyzed under the aspect of ethnic differences, site, and consequences for postulated molecule functions. RESULTS: HLA-G exhibits a high degree of conservation relative to HLA-A2 in functionally relevant sites of HLA-class I molecules. However, polymorphic sites in HLA-G and classical HLA loci are not congruent. CONCLUSION: The type and localization of HLA-G polymorphisms suggest that different parts of HLA-G molecule underlie different selective constraints.

Ethnicity↗

PubMed1998

[Pain therapy in multiple bone metastases in breast carcinoma with rhenium 186 HEDP].

Therapeutic means for patients with disseminated painful bone metastases in breast cancer are strongly limited. There is a big need of an effective and well tolerated therapy. The aim of this study was to evaluate the efficacy of rhenium-186 HEDP for pain palliation in patients with bone metastases in breast cancer. 17 patients with painful bone metastases taking analgesics received one or more injections of 1295 MB9 rhenium-186 HEDP. In 59% of the patients the therapy resulted in a significant reduction of pain. The duration of pain relief partially hold on up to nine weeks. The main side effects of therapy were a short decrease of platelets and leucocytes and an increase of pain for 1-2 days. As conclusion we found out that therapy with rhenium-186 HEDP can be used complementarily to analgesic therapy and radiation in patients with painful disseminated bone metastases in breast cancer.

Bone Neoplasms↗

PubMed1998

[TNF-alpha secretion by peritoneal macrophages in endometriosis].

Beside of other cytokines and growth-factors Tumor Necrosis Factor Alpha (TNF-alpha) exerts as a macrophage-derived cytotoxic product a variety of immunologic effects in the human organism. It is also an important angiogenetic factor and regarding its cytotoxicity toward gametes TNF-alpha plays an essential role as pelvine mediator of sterility. The purpose of our study was to evaluate the TNF-alpha-synthesis of Peritoneal-Macrophages (PM) in patients with and without endometriosis and to determine if a correlation exists between TNF-alpha-synthesis and various degrees of the activity of endometriosis. For reasons of sterility 40 women underwent diagnostic laparoscopy and were staged according to the rAFS-classification as well as the macroscopic aspect of activity into a control group with endometriosis-free pelvic situs (n = 14) and three subgroups characterized by the increasing stage of the disease (n = 26). The TNF-alpha-concentrations (median) in the control group were 3.3 pg/ml, in group 2 with stage I/II rAFS and only low active endometriosis 60.2 pg/ml, in group 3 with stage I/II rAFS but high active endometriosis 83.2 pg/ml and in group 3 with stage III/IV rAFS 168 pg/ml. These data were statistically high significant and showed good conformity with the histological findings. We found significant higher TNF-alpha-concentrations in the peritoneal fluid of patients with endometriosis than in the peritoneal fluid of healthy women. There is a correlation between TNF-alpha-concentrations and the degree of disease.

Adult↗

PubMed1997

Fiber transformations in multifidus muscle of young patients with idiopathic scoliosis.

STUDY DESIGN: In this study, the authors investigated the superficial multifidus muscle in patients with idiopathic scoliosis. During spinal fusion, biopsies were taken bilaterally at the apex of the curve, and at the upper and lower end vertebrae. OBJECTIVES: To analyze the muscular reactions in response to bracing in patients with idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: The extent to which intervertebral mobility is restricted by an orthosis is still controversial. In addition, the effect of bracing on the erector spinae has not been investigated. METHODS: Of a total 30 patients, 11 had been treated with a corset for a year or more before surgery. Biopsies were investigated histochemically and the muscle fibers classified as Type I, IIA, IIB, or IIC (transitional fibers). The relative distribution of the fibers was calculated and their diameter was measured. RESULTS: In unbraced patients, a shift in the fiber distribution (from "slow" to "fast") was observed exclusively at the concave side of the apex. This shift was paralleled by an increased percentage of the intermediate Type IIC fiber (indicative of fiber transformation). In patients who always wore a corset, the relative amount of Type IIC fibers was increased, without preference for a specific location. CONCLUSIONS: Corset treatment elicits muscle fiber transformation processes at different levels along the scoliosis. This general reaction of the paraspinal muscles provides strong evidence against the existence of muscular disorders that are restricted to the area of the apex and are thus causing the scoliosis. As such, it must be assumed that the muscular changes in the apical region are secondary.

Adenosine Triphosphate↗

PubMed1997

Peptide fragments of DNA topoisomerase II with helix-forming and coiled-coil-forming properties act as inhibitors of the enzyme.

We have previously shown that a synthetic peptide (dL) consisting of amino acids 1013-1056 of human alpha topoisomerase II adopted an alpha-helix structure and formed a stable dimer coiled-coil in solution [Frère, V., Sourgen. F., Monnot, M., Troalen, F. & Fermandjian, S. (1995) J. Biol. Chem. 270, 17502-17507]. Here we studied two peptides, dP and dLshort, which are related to dL but which have a double substitution Leu1026-->Pro, Leu1037-->Pro and a deletion of the 15 C-terminal residues, respectively. The peptides were studied for their ability to form alpha-helix structures, coiled coils, and to inhibit topoisomerase II activity. In combining circular dichroism spectra with AGADIR prediction for helix structures, we demonstrated that the dLshort peptide, like its parent dL peptide, adopts an alpha-helix structure and can autoassociate into coiled-coils, while dP is completely devoid of such properties. Remarkably, only the dL and dLshort peptides act as good inhibitors of topoisomerase II in various in vitro assays. However, the dLshort peptide has a stronger helix potential and behaves as a much more potent inhibitor (5 microM versus 200 microM) compared to the dL peptide. All these data strongly suggest that the greater inhibitory effect demonstrated by the dLshort peptide is related to its higher ability to form a stable amphiphilic helix, which in turn better recognizes its homologous helical segment in topoisomerase II. Finally, we propose that the dL and the dLshort peptides could interfere with the enzymatic activity of topoisomersase II in modifying its autoassociation or translocation properties. Such peptides may serve as useful models for developing simpler and more specific inhibitors of topoisomerase II.

Amino Acid Sequence↗

PubMed1997

Genomic deletions in the BRCA1, BRCA2 and TP53 regions associate with low expression of the estrogen receptor in sporadic breast carcinoma.

Sporadic breast carcinoma is associated with multiple genetic alterations. The clinical relevance of these alterations, however, needs further clarification. In the present study we analyzed 266 spontaneously arising breast carcinomas for allelic losses in the BRCA1 and TP53 regions on chromosome 17, the BRCA2 region on chromosome 13, the ATM (mutated in ataxia-telangiectasia) region on chromosome 11 and on the chromosomal arms 7q and 16q. In addition the following clinical and pathological parameters were evaluated: age at diagnosis, tumor size, presence or absence of regional and distant metastases, hormone-receptor status, histopathological classification and tumor grading. The analysis of genetic and clinical observations revealed significant associations: absence of expression of the estrogen receptor was linked to a high rate of allelic losses of markers in the BRCA1, TP53 and BRCA2 regions. Expression of the progesterone receptor coincided with allelic loss on the long arm of chromosome 16. High-grade malignant lesions and ductal differentiation were frequently associated with allelic losses in the proximal portion of chromosome 17q. The accumulation of multiple allelic deletions was linked to high-grade malignant tumors, to tumor size, and to loss of expression of the estrogen receptor. Our data point to a relationship between clinically relevant prognostic factors and specific genomic deletions in the BRCA1, BRCA2 and TP53 region.

Breast Neoplasms↗

PubMed1997

Comparison of fluorine-18 fluorodeoxyglucose positron emission tomography and technetium-99m methoxyisobutylisonitrile scintimammography in the detection of breast tumours.

The aim of this study was to compare, in breast cancer patients, the diagnostic accuracy of positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) and scintimammography (SMM) using technetium-99m methoxyisobutylisonitrile (MIBI). A total of 20 patients (40 breasts with 22 lesions) were evaluated serially with MIBI and, on the following day, with FDG. For SMM, planar and single-photon emission tomography imaging in the prone position was performed starting at 10 min following the injection of MIBI (740 MBq). For PET, scans were acquired 45-60 min after the injection of FDG (370 MBq) and attentuation correction was performed following transmission scans. Results from SMM and PET were subsequently compared with the histopathology results. True-positive results were obtained in 12/13 primary breast cancers (mean diameter=29 mm, range 8-53 mm) with both FDG and MIBI. False-negative results were obtained in two local recurrences (diameter <9 mm) with both FDG and MIBI. In benign disease, FDG and MIBI did not localize three fibrocystic lesions, two fibroadenomas and one inflammatory lesion (true-negative), but both localized one fibroadenoma (false-positive). Collectively, the results demonstrate a sensitivity of 92%, and a specificity of 86%, for primary breast cancer regardless of whether FDG or MIBI was used. In contrast to MIBI scintigraphy, FDG PET scored the axillae correctly as either positive (metastatic disease) or negative (no axillary disease) in all 12 patients. The tumour/non-tumour ratio for MIBI was 1.97 (range 1.43-3.1). The mean standard uptake value (SUV) for FDG uptake was 2.57 (range 0.3-6.2). The diagnostic accuracy of SMM was equivalent to that of FDG PET for the detection of primary breast cancer. For the detection of in situ lymph node metastases of the axilla, FDG seems to be more sensitive than 99mTc-MIBI.

Axilla↗

PubMed1997

Synthesis and FTIR conformational studies of peptides from the basic region of c-Jun: a critical analysis on the basis of CD and NMR data.

The peptide (35 residues) corresponding to the basic subdomain (bSD) of c-Jun (residues 252-281) and its fragments NP (N-terminal peptide, 1-19) and CP (C-terminal peptide, 16-35) were synthesized in stepwise solid-phase using the tert-butyloxycarbonyl/benzyl strategy. In a previous paper, we have shown that during its binding to the DNA site CRE (cAMP-responsive element) the bSD structure was converted into alpha-helix from an initial random coil conformation [Krebs, D., Dahmani, B., El Antri, S., Monnot, M., Convert, O., Mauffret, O., Troalen, F. & Fermandjian, S. Eur. J. Biochem. 231, 370-380 (1995)]. Our results suggested both a high flexibility and a helical potential in bSD, these two properties seeming crucial for the accommodation of the basic subdomain of c-Jun to its specific DNA targets. In this work, we assessed the conformational variability of bSD through the study of the secondary structures of its NP and CP fragments in trifluoroethanol (TFE)/2H2O mixtures, using Fourier transform infrared (FTIR) spectroscopy. The IR results were critically analyzed in light of our previously reported circular dichroism (CD) and NMR data [Krebs, D., Dahmani, B., Monnot, M., Mauffret, O., Troalen, F. & Fermandjian, S. Eur. J. Biochem, 235, 699-712 (1996)]. Upon addition of TFE, the relative areas of the seven components of the amide I. band (1700-1620 cm-1) reflected the conversion of a large amount of random coil conformation into alpha-helix for the two fragments and bSD. This effect was accompanied by more subtle variations of the less populated structures, in agreement with the results of CD and NMR experiments. The IR results stipulated the conservation of the parent bSD secondary structures in both fragments; however, NP and CP peptides did not display similar random-to-alpha-helix stabilization pattern upon additions of TFE to aqueous solutions. The profile from CD signal at 222 nm was found sigmoidal for NP and almost linear for CP, while that corresponding to the parent peptide bSD was just in between those of its fragments. Thus, the present study confirms the high flexibility and helix propensity of the c-Jun basic subdomain and suggests that the N- and C-terminal parts of the peptide do not follow the same random-to-helix conversion profile during their complexation with DNA.

Amides↗

PubMed1997

Immunological responses to the tumor-associated antigen CA125 in patients with advanced ovarian cancer induced by the murine monoclonal anti-idiotype vaccine ACA125.

We have generated an immunoglobulin G1 (IgG1) murine monoclonal anti-idiotype antibody (Ab2) designated ACA125, which mimics a specific epitope on the tumor-associated antigen CA125. This antigen is expressed by most of malignant ovarian tumors. Patients with CA125-positive tumors are immunologically tolerant to CA125. We used ACA125 as a surrogate for the tumor-associated antigen CA125 for vaccine therapy of 16 patients with advanced epithelial ovarian cancer or recurrences. Each of the patients received a minimum of 3 injections up to 19 injections of the complete anti-idiotype MAb ACA125 at a dosage of 2 mg per injection. Nine of 16 patients developed anti-anti-idiotypic (Ab3) responses to the ACA125. All 9 patients generated specific anti-CA125 antibody demonstrated by reactivity with purified CA125. Nine of 16 patients developed a CA125-specific cellular immune response by their peripheral blood lymphocytes (PBL) and 3 of 16 showed an increase in gamma-interferon concentrations accompanied by Ab3 responses. Toxicity was limited to abdominal pain in one case, which led to the withdrawal of further immunizations. The median progression free survival in those patients, who showed a specific immune response to the tumor-associated antigen CA125, was 11.0 +/- 5.6 months without any other therapy, in contrast to 8.0 +/- 4.2 months in the anti-anti-idiotype negative group. This is the first report of the induction of a specific active immunity to the tumor-associated antigen CA125 in patients with advanced ovarian cancer treated with an anti-idiotype antibody that "mimics" CA125. Patients showed the development of a specific humoral and cellular immune response to an otherwise nonimmunogenic tumor antigen. The immune responses in patients treated with this anti-idiotype vaccine, the low rate of side effects, and the improved time to progression after the induction of a specific immune response against the tumor-associated antigen CA125 justify follow-up clinical trials in advanced ovarian cancer patients with minimal residual disease in an adjuvant approach.

Animals↗

PubMed1997

Anti-TAG-72 antibody B72.3--immunological and clinical effects in ovarian carcinoma.

Based on the network theory, anti-tumor antibodies (Ab1) can trigger the immune system of the host into a response against tumor cells. Through an immunological cascade, anti-idiotypic antibodies bearing the internal image of epitopes of the nominal antigen (Ab2 beta) are produced that themselves can induce cellular and humoral cytotoxic effects against the antigen-expressing tumor cell. Formation of such antibodies has been shown to be associated with prolonged survival of melanoma, colorectal, and ovarian carcinoma patients. We studied anti-idiotypic antibody (Ab2) responses and clinical outcome of 31 ovarian cancer patients receiving the monoclonal antibody (MAb) B72.3, which targets the ovarian carcinoma associated antigen TAG-72. All patients were treated by surgery and polychemotherapy, which was followed by repeated (mean of 4) injections of 1 mg of the MAb B72.3. A remarkable anti-idiotypic anti-B72.3 response arose in 19 patients, with 9 of them showing a major response with Ab2 serum concentrations greater than 1,000 U/ml ("high-responders"). The median disease-free survival time, as well as the median survival time of these high-responders, was increased as compared to the low- or no responders. Evaluating our data, we conclude that monoclonal antibody treatment with the MAb B72.3 may induce humoral immunological responses in about two-thirds of our study group, although a positive clinical effect may only be expected in patients with excessive anti-idiotypic antibody formation.

Animals↗

PubMed1997

Are human anti-idiotypic anti-OC125 antibodies formed after immunization with the anti-CA125 antibody B43.13?

The two monoclonal antibodies (MAb) OC125 and B43.13 both recognize antigenic determinants on the cancer antigen 125 (CA125) molecule. The aim of the present study was to clarify how far antibodies formed by patients treated with B43.13 may cross-react with idiotopes of OC125. Serum samples from 15 ovarian cancer patients treated with B43.13 were tested for the presence of anti-idiotypic anti-OC125 antibodies; 4 of these patients previously had received OC125 F(ab')2 fragments. Six patients treated only with B43.13 and all patients pretreated with OC125 fragments developed a considerable increase of human anti-mouse anti-bodies after B43.13 infusion, indicating an immune response to antibody infusion. However, none of the patients treated only with B43.13 developed detectable levels of anti-idiotypic anti-OC125 antibodies, whereas in 2 patients pretreated with OC125 fragments, the pre-existing concentration of anti-idiotypic anti-OC125 antibodies further increased after B43.13 infusion. The binding of these newly formed antibodies to OC125 was not inhibited by the B43.13, but about 70% of the binding was inhibited by the CA125 antigen. The present data suggest that the idiotopes expressed on the antibodies B43.13 and OC125, respectively, are completely different. Thus, anti-idiotypic anti-B43.13 antibodies may not cross-react with OC125. A greater number of cases is needed to clarify how far the increase of anti-idiotypic anti-OC125 antibodies observed in 2 patients pretreated with OC125 fragments really is due to B43.13 infusion.

Animals↗