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At least 613 records · Page 34Linked to original sources
PubMed1994

Effect of a bifunctional monoclonal antibody directed against a tumor marker and doxorubicin on the growth of epidermoid vulvar carcinoma grafted in athymic mice.

Even though the first monoclonal antibodies (MAbs) directed against tumor cells were produced 15 yr ago, the therapeutic application of immunoconjugates is still at the beginning. This is principally because of the enormous work that is required for the development of completely new therapeutic tools. An alternative could be to only use MAbs to improve conventional treatment such as chemotherapy. To this aim, a MAb directed against doxorubicin (DXR) was produced. DXR is an anthracycline antibiotic of which the clinical usefulness in cancer chemotherapy is limited by serious side effects, such as cardiomyopathy, bone marrow depression, and gastrointestinal tract mucositis. This toxicity was found to be reduced by treatment with the antidrug MAb, as shown by reduction in body weight loss and mortality of experimental mice. To improve the DXR therapeutic index, a bifunctional hybrid MAb (DOXER2), capable of simultaneously recognizing DXR and the epidermal growth factor (EGF) receptor, was produced. This reagent was found in vitro to increase the drug toxicity on the epidermoid carcinoma cell line A431, which overexpresses the EGF-R and, at the same time, to reduce DXR cytotoxicity on EGF-R negative cells. The effect of DOXER2 on the DXR biodistribution in vivo was also investigated. In mice previously injected ip with the DOXER2, the uptake of the drug, in comparison to the control group, was found to be reduced in the intestine and in myocardial tissue, and significantly increased in the tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Boron neutron capture therapy of primary and metastatic brain tumors.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron-10, is irradiated with low energy (0.025 eV) thermal neutrons (nth) to yield alpha (4He) particles and 7Li nuclei (10B+nth-->[11B]-->4He + 7Li + 2.79 MeV). The success of BNCT as a tumoricidal modality is dependent on the delivery of a sufficient quantity of 10B and nth to individual cancer cells to sustain a lethal 10B(n, alpha) 7Li reaction. Boron delivery agents include a variety of compounds, such as the sulfhydryl containing polyhedral borane sodium borocaptate (Na2B12H11SH, [BSH]), boronoporphyrins, boronophenylalanine, carboranyl uridines (CBU), and boronated monoclonal antibodies (MAb). The present review will focus on three delivery systems that currently are under investigation in our laboratories, boronated monoclonal antibodies, carboranyl uridines, and boronophenylalanine. Methodology has been developed to heavily boronate MAb using a precision macromolecule, a "starburst" dendrimer, which can be linked to MAb by means of heterobifunctional reagents. Although the resulting immunoconjugates retain their in vitro immunoreactivity, they lose their in vivo tumor localizing properties and accumulate in the liver. In order to obviate this problem, work is now in progress to produce bispecific MAb, which can simultaneously recognize a tumor-associated antigen and a boronated macromolecule. Boron containing nucleosides are potential vehicles for incorporating boron compounds into nucleic acids of neoplastic cells. For this purpose, carboranyl uridines have been synthesized with the boron moiety on either the pyrimidine base or on the carbohydrate component. Although such structures appear to be avidly taken up and retained by tumor cells in vitro, only the 5-carboranyl-nucleosides are converted biologically to the nucleotide. There is no evidence, however, that the latter are incorporated into nucleic acids. Other carboranyl nucleosides currently are being synthesized that may have better tumor localizing properties. The potential use of boronophenylalanine as a capture agent for the treatment of melanoma metastatic to the brain also is under investigation. A nude rat model has been developed using human melanoma cells that are stereotactically implanted into the brain. BNCT-treated animals have either had prolonged survival times or continue to live compared to control rats that invariably died of their tumors, thereby suggesting therapeutic efficacy.

Animals↗
PubMed1995

Localization and biodistribution of conjugate ATG-Dex-DNR in nude mice as models for human leukemia.

131I-labelled anti-thymoglobuline (ATG), 131I-labelled immunoconjugate ATG-Dex-DNR and 131I-labelled Ts-MoAb as control antibody, respectively, were injected by intraperitoneal (i.p.) administration into nude mice used as models for human T-cell leukemia. SPECT imaging was performed from day 1 to day 8 following i.p. injection. The results showed that radioimmunoimaging of human tumor xenografts was clearest day 3 after injection in both of ATG and ATG-Dex-DNR groups, whereas it's not the case in Ts-MoAb group. Nude mice were killed 8th day after injection with antibody or conjugate. The tumor, as well as different dissected normal organs including heart, liver, lungs, kidney, femur and intestine, were harvested, weighed precisely, and radioiodine-counted. T/NT ratios in experimental group was greater than 1.0 (ranged from 1.246-7.865), and in control group they were less than 1.0 (ranged from 0.263-0.757, except for tumor/femur ratio). Our results indicated that ATG and ATG-Dex-DNR had specific affinity to cell line of T-cell leukemia CEM.

Animals↗
PubMed1990

Preparation of AHTG-DNR conjugates and their antitumor effect in vitro.

100%, 75%, 50%, 25% and 12.5% oxidized dextran T10 (Dex T10) were used as intermediate carriers for conjugating drug daunorubicin (DNR) and antibody anti-human thymocytic globulin (AHTG), to form different immunoconjugates, AHTG:Dex:DNR. It was demonstrated that the conjugate with 25% oxidized Dex T10 as intermediate carrier linked more DNR molecules than the others. The degree of its substitution was 10-11 moles of DNR per mole of AHTG. Moreover, because the amount to reducing agent sodium borohydride (NaBH4), required for the reduction reaction, was relatively small, its damaging effect on AHTG and DNR was lessened accordingly. The antitumor effect of AHTG:Dex:DNR in vitro was tested by using 24-h cytotoxicity assay, with CEM as target cell. Cytotoxic effect of the conjugate was proven and the LD50 was 10.68 micrograms/ml. However, it showed only slight cytotoxic effect on non-target cell K562. When 10 min cytotoxicity assay was performed to show the specific tumor-killing effect of the conjugate, it revealed an obvious cytotoxic activity toward CEM, with the LD50 being 14.79 micrograms/ml, but hardly toward K562. These results suggest that AHTG:Dex:DNR possesses specific cytotoxic effect.

Antilymphocyte Serum↗
PubMed1984

Monoclonal antibodies in the treatment of cancer: preliminary observations and future prospects.

The need for improved specificity in cancer therapy is apparent. With the advent of monoclonal antibodies, the possibility of specifically targeted therapy is here. Early trials with monoclonal antibody in experimental animals and in man have demonstrated antibody can travel to specific tumor sites and localize on or around the tumor cells displaying antigens to which the antibody is directed. This evidence of specific targeting, along with early evidence of therapeutic efficacy for monoclonal antibodies and antibody immunoconjugates with drugs, toxins and isotopes, is encouraging. Some preliminary clinical observations from two monoclonal antibody trials are presented and the current status of clinical trials with monoclonal antibodies is reviewed.

Animals↗
PubMed2000

Prolonged survival of baboon renal allografts using idarubicin-conjugated anti-CD4 monoclonal antibodies.

Tolerance to organ allografts in rodents and pigs can be easily achieved. However, tolerance induction in a large primate model has been more elusive. In this study, we have used an anti-CD4, murine monoclonal antibody as a carrier for the cytotoxic drug idarubicin (IDA) to delete or inactivate alloreactive T-cells responding to a renal allograft in a baboon transplant model. Fourteen Chacma baboons weighing between 15-25 kg received heterotopic renal allografts. Recipient and donor pairs were selected on the basis of ABO compatibility. Seven animals were given no immunosuppression and served as the control group. The remaining 7 animals received anti-CD4 IDA. The first 2 animals in this group received 2 mg IVI intraoperatively and three doses at 48-h intervals thereafter. The last 5 animals received a larger dose of 1 mg/kg, starting 24 h preoperatively and again on postoperative days 2 and 5. The untreated animals promptly rejected their allografts with a mean survival of 10 days. The survival of the 2 animals treated with 2 mg anti-CD4 IDA was 7 days each. However, the animals treated with 1 mg/kg anti-CD4 IDA survived 7, 18, 20, 40 and > 40 days. Peritransplant administration of anti-CD4 IDA prolonged renal allograft survival in a large primate model. This unique immunoconjugate has the potential of tolerance induction.

Animals↗
PubMed2005

Active immunisation against nicotine blocks the reward facilitating effects of nicotine and partially prevents nicotine withdrawal in the rat as measured by dopamine output in the nucleus accumbens, brain reward thresholds and somatic signs.

We recently showed that active immunisation with the nicotine immunoconjugate IP18-KLH reduces the nicotine-induced increase in dopamine (DA) output in the nucleus accumbens (NAC) and prevents reinstatement of nicotine-seeking behaviour in rats. These effects are mediated by altered distribution of nicotine, resulting in reduced amounts of nicotine reaching the brain, thereby interfering with the rewarding properties of the drug. The present study was designed to explore the effect of immunisation against nicotine on mecamylamine-precipitated nicotine withdrawal as assessed by the reduction in DA output in the NAC in rats. Measuring brain reward thresholds and somatic signs of nicotine withdrawal, the effects of immunisation were also tested during chronic nicotine treatment and after its withdrawal. Finally, we examined the effect of immunisation on challenge injections of nicotine on brain reward thresholds after the increases in somatic signs and reward thresholds associated with nicotine withdrawal had dissipated. The results show that immunisation with IP18-KLH prevented the decrease in DA output in the NAC associated with mecamylamine-precipitated nicotine withdrawal. Moreover, immunisation against nicotine did not precipitate a withdrawal syndrome, as measured by brain reward thresholds and somatic signs, in rats chronically exposed to nicotine. Furthermore, the withdrawal syndrome elicited after cessation of chronic nicotine administration was attenuated in immunised rats compared to that of mock-immunised rats. Finally, the lowering in reward thresholds after nicotine challenge injections was attenuated in both naïve and previously nicotine-exposed immunised rats. In conclusion, the present results show that immunisation with IP18-KLH did not precipitate nicotine withdrawal in rats. Thus, immunisation with IP18-KLH may not elicit nicotine withdrawal in smokers either. Furthermore, since the withdrawal syndrome in rats was attenuated by immunisation, the nicotine withdrawal in smokers should not be worsened but may even be ameliorated during a quit attempt.

Animals↗
PubMed2001

Development of a sensitive enzyme immunoassay for the detection of phenyl-beta-D-thioglucuronide in human urine.

Immunoassays for the measurement of glucuronides in human urine can be a helpful tool for the assessment of human exposure to toxic chemicals. Therefore an enzyme imimunoassay (EIA) for the specific detection of phenyl-beta-D-thioglucuronide was developed. The immunoconjugate was formed by coupling p-aminophenyl-beta-D-thioglucuronide to the carrier protein thyroglobulin leaving an exposed glucuronic acid. The hapten-protein conjugate was adsorbed to gold colloids in order to enhance the immunogenic effect. Rabbits were injected with the immunogold conjugates to raise polyclonal antibodies. The resulting competitive assay showed an inhibition by phenyl-beta-D-thioglucuronide at sample concentrations of 23.0 +/- 1.3 ng/mL (50% B/B0) and a high cross-reactivity to p-aminophenyl-beta-D-thioglucuronide (120%). Little cross-reactivities (< 2%) were observed for potential urinary cross reactants. In addition human urine samples were incubated with beta-glucuronidase in order to investigate the EIA for specific matrix effects. An integration of high-performance liquid chromatography (HPLC) and EIA was developed in an attempt to decrease the matrix effects and increase the sensitivity of the overall method. The hyphenated technique HPLC-EIA may be used to monitor human exposure to toxic thiophenol which is excreted by mammals as urinary phenyl thioglucuronide.

Chromatography, High Pressure Liquid↗
PubMed2004

Pharmacokinetics and biodistribution of 177Lu-labeled multivalent single-chain Fv construct of the pancarcinoma monoclonal antibody CC49.

PURPOSE: Lutetium-177 (177Lu) is a radionuclide of interest for radioimmunoimaging (RII) and radioimmunotherapy (RIT) on account of its short half-life (161 h) and the ability to emit both beta and gamma radiation. Single-chain Fv (scFv) constructs have shown advancement in cancer diagnosis and therapy due to the pharmacokinetics advantage and seem to be intriguing tools in oncology. The objective of this study was to evaluate the pharmacokinetics and biodistribution characteristics of the 177Lu-labeled tetravalent scFv of CC49 MAb and intact CC49 IgG in vivo. METHODS: Conjugation and labeling conditions of multivalent scFv with 177Lu were optimized without affecting integrity and immunoreactivity. For this purpose, multivalent scFv constructs {dimer, sc(Fv)2; tetramer, [sc(Fv)2]2} of the MAb CC49 were expressed as secretory proteins in Pichia pastoris. The purified scFv constructs and IgG form of CC49 were conjugated with a bifunctional chelating agent, ITCB-DTPA, and labeled with 177Lu. The comparative biodistribution, blood clearance, and tumor-targeting characteristics of 177Lu-labeled tetravalent [sc(Fv)2]2 construct of CC49 MAb and intact CC49 IgG were investigated in the athymic mice bearing LS-174T xenografts. RESULTS: Approximately, 90% of 177Lu incorporation was achieved using ITCB-DTPA chelator, and the labeled immunoconjugates maintained integrity and immunoreactivity. Blood clearance studies demonstrated an alpha half-life (t1/2alpha) of 177Lu-labeled [sc(Fv)2]2 and IgG of CC49 at 4.40 and 9.50 min and a beta half-life (t1/2beta) at 375 and 2,193 min, respectively. At 8 h post administration, the percent of the injected dose accumulated/gram (%ID/g) of the LS-174T tumor was 6.4+/-1.3 and 8.9+/-0.6 for 177Lu-labeled [sc(Fv)2]2 and IgG of CC49, respectively, in the absence of L-lysine. The corresponding values were 8.0+/-0.6 and 8.4+/-1.2 in the presence of L-lysine. Renal accumulation of [sc(Fv)2]2 was significantly (p<0.005) reduced in the presence of L-lysine. CONCLUSION: The results of this study demonstrate that the ITCB-DTPA conjugation and 177Lu-labeling of scFvs are feasible without influencing the antibody characteristics. 177Lu-labeled [sc(Fv)2]2 showed faster clearance and equivalent tumor uptake at 8 h compared with its IgG form, with a markedly reduced renal uptake in the presence of L-lysine. Therefore, 177Lu-labeled [sc(Fv)2]2 may be a potential radiopharmaceutical for the treatment of cancer.

Animals↗
PubMed2005

Cancer radioimmunotherapy with alpha-emitting nuclides.

In lymphoid malignancies and in certain solid cancers such as medullary thyroid carcinoma, somewhat mixed success has been achieved when applying radioimmunotherapy (RIT) with beta-emitters for the treatment of refractory cases. The development of novel RIT with alpha-emitters has created new opportunities and theoretical advantages due to the high linear energy transfer (LET) and the short path length in biological tissue of alpha-particles. These physical properties offer the prospect of achieving selective tumoural cell killing. Thus, RIT with alpha-emitters appears particularly suited for the elimination of circulating single cells or cell clusters or for the treatment of micrometastases at an early stage. However, to avoid non-specific irradiation of healthy tissues, it is necessary to identify accessible tumoural targets easily and rapidly. For this purpose, a small number of alpha-emitters have been investigated, among which only a few have been used for in vivo preclinical studies. Another problem is the availability and cost of these radionuclides; for instance, the low cost and the development of a reliable actinium-225/bismuth-213 generator were probably determining elements in the choice of bismuth-213 in the only human trial of RIT with an alpha-emitter. This article reviews the literature concerning monoclonal antibodies radiolabelled with alpha-emitters that have been developed for possible RIT in cancer patients. The principal radio-immunoconjugates are considered, starting with physical and chemical properties of alpha-emitters, their mode of production, the possibilities and difficulties of labelling, in vitro studies and finally, when available, in vivo preclinical and clinical studies.

Alpha Particles↗
PubMed2007

Non-invasive visualisation of the development of peritoneal carcinomatosis and tumour regression after 213Bi-radioimmunotherapy using bioluminescence imaging.

PURPOSE: Non-invasive imaging of tumour development remains a challenge, especially for tumours in the intraperitoneal cavity. Therefore, the aim of this study was the visualisation of both the development of peritoneal carcinomatosis and tumour regression after radioimmunotherapy with tumour-specific 213Bi-Immunoconjugates, via in vivo bioluminescence imaging of firefly luciferase-transfected cells. METHODS: Human diffuse-type gastric cancer cells expressing mutant d9-E-cadherin were stably transfected with firefly luciferase (HSC45-M2-luc). For bioluminescence imaging, nude mice were inoculated intraperitoneally with 1x10(7) HSC45-M2-luc cells. On days 4 and 8 after tumour cell inoculation, imaging was performed following D-luciferin injection using a cooled CCD camera with an image intensifier unit. For therapy, mice were injected with 2.7 MBq 213Bi-d9MAb targeting d9-E-cadherin on day 8 after tumour cell inoculation. Bioluminescence images were taken every 4 days to monitor tumour development. RESULTS: After i.p. inoculation of HSC45-M2-luc cells into nude mice, development as well as localisation of peritoneal carcinomatosis could be visualised using bioluminescence imaging. Following 213Bi-d9MAb therapy on day 8 after intraperitoneal inoculation of HSC45-M2-luc cells, small tumour nodules were totally eliminated and larger nodules showed a clear reduction in size on day 12 after tumour cell inoculation. Subsequently a recurrence of tumour mass was observed, starting from the remaining tumour spots. By measuring the mean grey level intensity, tumour development over time could be demonstrated. CONCLUSION: Non-invasive bioluminescence imaging permits visualisation of the development of peritoneal carcinomatosis, localisation of tumour in the intraperitoneal cavity and evaluation of therapeutic success after 213Bi-d9MAb treatment.

Animals↗
PubMed1998

Reducing the renal uptake of radiolabeled antibody fragments and peptides for diagnosis and therapy: present status, future prospects and limitations.

Elevated renal uptake and prolonged retention of radiolabeled antibody fragments and peptides is a problem in the therapeutic application of such agents. Over recent years, one of the focuses of research has therefore been to develop suitable methods to reduce this renal uptake, and to evaluate whether the resulting methodology will benefit therapy with antibody fragments and peptides. In these studies it has been shown that the kidney uptake of antibody fragments in animals can be reduced in a dose-dependent manner by almost one order of magnitude by the systemic administration of cationic amino acids and their derivatives, whereas the uptake in all other organs, as well as the tumor, remains unaffected. A similar reduction in renal retention is achieved for all intracellularly retained radionuclides (e.g., radiometals) or radioiodinated immunoconjugates, as well as for smaller peptides. Lysine is usually the preferred agent, and its d- and l-isomers are equally effective whether given intraperitoneally or orally. Amino sugars are effective, but their N-acetyl derivatives, lacking the positive charge, are not. Basic polypeptides are also effective, and their potency increases with increasing molecular weight (i.e., the amount of positive charges per molecule). Urine analysis of treated individuals shows the excretion of unmetabolized, intact fragments or peptides, in contrast to mostly low-molecular-weight metabolites in untreated controls. In therapy studies using radiometal-conjugated Fab fragments, the kidney is the first dose-limiting organ. Administration of cationic amino acids results in a substantial increase in the maximum tolerated dose of such Fab fragments. No biochemical or histological evidence of renal damage has been observed under these conditions. As was the case in animal studies, in pilot clinical trials the renal uptake in patients injected with Fab' fragments and given amino acids could be decreased significantly, whereas the uptake by all other organs remained unaffected. These recent studies indicate that a variety of basic compounds are capable of inhibiting the tubular reabsorption of peptides and proteins, thus significantly lowering the renal uptake of antibody fragments or peptides in both animals and patients. On a molecular basis, the effect seems to rely essentially on the presence of a positively charged amino group. Thus, radiation nephrotoxicity of antibody fragments and peptides can be overcome successfully; this may provide new prospects for cancer therapy with radiolabeled antibody fragments and peptides.

Amino Acids↗
PubMed1996

New promising anticancer agents in development: what comes next?

Anticancer drug development has recently shifted in part to development of more innovative anticancer agents. The increasing knowledge of the pathogenetic mechanisms involved in cancer cell growth has enabled the introduction of drug screening that is more mechanism-based. The realization that new targets should be preferentially evaluated as sites for anticancer drug treatment has led to the introduction of drugs such as the taxanes. Following this logic, several new drugs are being developed. Minor groove-binding agents such as carzelesin and oral platins lacking organ toxicity, such as JM216, have recently entered clinical studies. The activity of gemcitabine is a result of its being a cytidine analogue and being competitively incorporated by DNA; the drug has shown interesting activity in non-small-cell lung cancer and, although registration is imminent, issues regarding the optimal dose and administration schedule have yet to be resolved. Tomudex is a thymidylate synthase inhibitor with interesting activity in colorectal cancer. Activity in colorectal cancer is also of interest for irinotecan, the first clinically applied topoisomerase I inhibitor, an enzyme that is another example of a new target for anticancer drugs. Irinotecan has produced consistent response rates of 20-30% in six different studies in colorectal cancer. The other topoisomerase I inhibitor that is in the advanced stage of development is topotecan. This drug has shown activity in second-line chemotherapy for ovarian cancer and small-cell lung cancer. Another interesting feature of topotecan is the availability of an oral formulation with consistent bioavailability. Drugs interfering with cellular signal transduction, such as the protein kinase C inhibitors, are in the development spotlight. Finally, the use of old drugs in new ways, such as immunoconjugates of doxorubicin, holds promise for the near future.

Antineoplastic Agents↗
PubMed1999

Alternative treatments for childhood brain tumors.

The treatment options for children with brain tumors are quite limited. Advances in tumor biology and neuroscience have opened new avenues of treatment. New approaches include gene therapy, agents designed to interfere with signal transduction, antiangiogenesis drugs, maturation agents, immunotherapy, and immunoconjugates. New means of drug/agent delivery, including drugs that selectively open the tumor-blood barrier and convection-infusional approaches, are under study. Such innovative treatments will be more widely employed in the years ahead and may improve outcome for children with brain tumors.

Antineoplastic Agents↗
PubMed2002

Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia.

Options for treatment of poor-prognosis or relapsed acute myeloid leukemia (AML) remain limited. Gemtuzumab ozogamicin (Mylotarg, Wyeth-Ayerst, Philadelphia, PA) is an immunoconjugate composed of recombinant humanized murine anti-CD33 antibody linked to calicheamicin, a potent cytotoxic agent. Phase II trials have shown the efficacy of gemtuzumab ozogamicin in the treatment of relapsed AML. Trials exploring this agent in other CD33+ hematologic malignancies and in combination with other agents for AML are ongoing. Gemtuzumab ozogamicin is associated with acceptable toxicity as a single agent. However, the incidence of veno-occlusive disease of the liver remains a concern when this agent is used in combination with chemotherapy or in the context of hematopoietic stem cell transplant.

Acute Disease↗
PubMed2002

Management of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) has become the most potentially curable subtype of acute myeloid leukemia (AML) in adults. With current treatment strategies that incorporate all-trans retinoic acid (ATRA), long-term disease-free survival and potential cure rates of 70% to 80% can be expected. Such progress reflects what can be accomplished with insights into the molecular pathogenesis of leukemia, identification of a molecular target, and rapid accrual to a series of clinical trials. The leukemic promyelocytes from patients with APL are uniquely susceptible to a variety of novel agents in addition to ATRA, including arsenic trioxide, and in preliminary studies, gemtuzumab ozogamicin, the immunoconjugate comprised of an anti-CD33 monoclonal antibody linked to the potent cytotoxic agent calicheamicin. Incorporation of such agents into the treatment of patients with high-risk disease may be an important future direction to pursue.

Antibiotics, Antineoplastic↗
PubMed1992

The effect of interferon gamma on epidermal growth factor receptor expression in normal and malignant ovarian epithelial cells.

OBJECTIVE: We examined the effect of interferon gamma on proliferation and epidermal growth factor receptor expression in ovarian cancer cell lines and normal ovarian epithelial cells. STUDY DESIGN: The tritiated thymidine incorporation assay was used to assess the effect of interferon gamma on proliferation. Scatchard analysis of anti-epidermal growth factor receptor antibody binding, and Western blotting of immunoprecipitates was used to assess the effect of interferon gamma on epidermal growth factor receptor expression. RESULTS: Although interferon gamma elicited 30% to 40% decreases in proliferation, epidermal growth factor receptor expression was strikingly increased in all four ovarian cancer cell lines. Scatchard analysis indicated that this increase occurred primarily at the cell surface, but total cellular receptor levels also were increased. In contrast, interferon gamma treatment of normal ovarian epithelial cells affected neither proliferation nor epidermal growth factor receptor levels. CONCLUSION: Because the up-regulation of epidermal growth factor receptors by interferon gamma appears to be confined to malignant cells, interferon gamma may facilitate immunotherapy and imaging of ovarian cancers by means of immunoconjugates directed against the epidermal growth factor receptor.

Antibodies, Monoclonal↗
PubMed1996

Characterization of novel anthracycline prodrugs activated by human beta-glucuronidase for use in antibody-directed enzyme prodrug therapy.

Antibody-directed enzyme prodrug therapy (ADEPT) aims at the specific activation of a prodrug by an enzyme-immunoconjugate localized in tumor tissue. The use of an enzyme of human origin is preferable in ADEPT because it might not be immunogenic when administered to patients. In the case of human beta-glucuronidase, prodrugs should be designed that are rapidly and completely activated at a neutral pH. Four new daunorubicin glucuronides were synthesized by coupling a glucuronide group to daunorubicin via an aliphatic (GA1 and GB1) or an aromatic (GA3, GB6) carbamate spacer, to be released by electron shift (A-type) or by ring closure (B-type). These prodrugs were characterized in vitro for their usefulness in ADEPT and were compared with the previously described prodrugs epirubicin-glucuronide and doxorubicin-nitrophenyl-glucuronide. The four new prodrugs were stable in serum, hydrophilic when compared to the lipophilic daunorubicin, and at least 20-fold less toxic than the parent compound. The hydrolysis rate at clinically relevant enzyme and prodrug concentrations (1 microgram/mL human beta-glucuronidase, 100 microM prodrug) at pH 6.8 were similar for GA3 (T1/2 160 min) and higher for GB6 (T1/2 40 min) when compared to that of doxorubicin-nitrophenyl-glucuronide (T1/2 170 min). Epirubicin-glucuronide, GA1, and GB1 showed a low hydrolysis rate (T1/2 > 400 min). GA1 and GA3, but not GB1 or GB6, were activated to the parent compound. Complete activation was confirmed in OVCAR-3 cells pretreated with a specific antibody-human beta-glucuronidase conjugate, where GA3 had similar antiproliferative effects to those of daunorubicin.

Female↗