18 FDG, [ 18 F]FLT, [ 18 F]FAZA, and 11 C-Methionine Are Suitable Tracers for the Diagnosis and In Vivo Follow-Up of the Efficacy of Chemotherapy by miniPET in Both Multidrug Resistant and Sensitive Human Gynecologic Tumor Xenografts (original) (raw)
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Anticancer Research, 2019
Background/Aim: The aim of the study was to evaluate the antitumor potential and combination effects of chemotherapeutic drugs. Materials and Methods: The cytotoxicity of 20 drip-type classical and molecular-targeted anticancer drugs was examined against 4 human oral squamous cell carcinoma cell lines and 5 human oral normal mesenchymal and epithelial cells. Cell cycle progression was monitored by a cell sorter. Combination effect was evaluated by combination index. Results: Most of the classical anticancer drugs showed much higher antitumor activity than moleculartargeted drugs, except bortezomib. Among 12 classical anticancer drugs, taxanes and gemsitabine showed the highest tumor-specificity (TS) and potency-selectivity expression (PSE) values, whereas platinum analogs showed the least TS value. Combination of two classical or a classical and a moleculartargeted drug showed mostly additive or antagonistic effect. 5-FU and cisplatin did not produce a subG 1 population, but induced G 2 /M or G 1 /S arrest, regardless of the addition of cetuximab. Cetuximab, nibolumab and bortezomib showed potent keratinocyte toxicity. Conclusion: The present TS monitoring system may provide useful information for building up the treatment regimens of anticancer drugs.
Cancer research, 1992
In a European joint project carried out in 6 laboratories a disease-oriented program was set up consisting of a panel of 7 tumor types, each represented by 4 to 8 different human tumor lines, for secondary screening of promising anticancer drugs. Human tumor lines were selected on the basis of differences in histology, growth rate, and sensitivity to conventional cytostatic agents. Xenografts were grown s.c. in nude mice, and treatment was started when tumors reached a mean diameter of 6 mm in groups of mice where at least 6 tumors were evaluable. Drugs were given at the maximum tolerated dose. For evaluation of drug efficacy, median tumor growth curves were drawn, and specific growth delay and treated/control x 100% were calculated. Doxorubicin (8 mg/kg i.v. days 1 and 8) was effective (treated/control < 50%, and specific growth delay > 1.0) in 0 of 2 breast cancers, 1 of 3 colorectal cancers, 2 of 5 head and neck cancers, 3 of 6 non-small cell lung cancers, 4 of 6 small cell...
British Journal of Cancer, 1996
The low-affinity monoclonal antibody (MAb) chimeric 17-lA(c-17-lA) and the high-affinity MAb mouse 323/A3 (m-323/A3) were used to study the effect of the MAb affinity on the tumour uptake and efficacy of radioimmunotherapy in nude mice bearing subcutaneously the human ovarian cancer xenografts FMa, OVCAR-3 and Ov.Pe. Both MAbs are directed against the same pancarcinoma glycoprotein. In vitro, the number of binding sites on tumour cells at 40C was similar for both MAbs, but m-323/A3 had an approximately 5-fold higher affinity (1.3 -3.0 x 109M-') than c-17-lA (3.0 -.4 x IO' M-). This difference in affinity was more extreme at 37°C, when no binding of c-17-IA could be observed. MAb m-323/A3 completely blocked the binding of c-17-lA to tumour cells, whereas the reverse was not observed. Immunohistochemistry showed a similar but more intense staining pattern of m-323/A3 in human ovarian cancer xenografts than of c-17-1A. In vivo, the blood clearance in non-tumour-bearing nude mice was similar for both MAbs with terminal half-lives of 71.4 h for m-323/A3 and 62.7 h for c-17-lA. MAb m-323/A3 targeted better to tumour tissue, but was more heterogeneously distributed than c-17-lA. The cumulative absorbed radiation dose delivered by m-323/A3 to tumour tissue was 2.5to 4.7-fold higher than that delivered by c-17-lA. When mice were treated with equivalent radiation doses of ['311]m-323/A3 and ['31I]c-17-lA, based on a correction for the immunoreactivity of the radiolabelled MAbs, m-323/A3 induced a better growth inhibition in two of the three xenografts. When the radiation doses were adjusted to obtain a similar amount of radiation in the tumour c-17-lA was more effective in tumour growth inhibition in all three xenografts.
The efficacy of the anthracycline prodrug daunorubicin-GA3 in human ovarian cancer xenografts
British Journal of Cancer, 1998
The prodrug N[4-(daunorubidn-N-carbony -oxymethyl)phenyl] 04i-glucuronyl carbamate (DNR-GA3) was synthesized for specific acfivation by human fi-glucuronidase, released in necrotic areas of tumour lesions. In vitro, DNR-GA3 was 18 times less toxic than daunorubicin (DNR) and the prodrug was completely activated to the parent drug by human 0-glucuronidase. The maximum tolerated dose of DNR-GA3 in nude mice bearing s.c. human ovarian cancer xenografts was 6-10 times higher than that of DNR. The prodrug was cleared more rapidly from the circulation (elimination t,2 = 20 min) than the parent drug (elimination t12= 720 min). The anti-tumour effects of DNR-GA3 and DNR were investigated in four different human ovarian cancer xenografts OVCAR-3, FMa, A2780 and MRI-H-207 at a mean tumour size between 100 and 200 mm3. In three out of four of these tumour lines, the prodrug given i.v. at the maximum tolerated dose ranging from 150 to 250 mg kg-' resulted in a maximum tumour growth inhibition from 82% to 95%. The standard treatrnent with DNR at a dose of 8 mg kg-' given i.v. weekly x 2 resulted only in a maximum tumour growth inhibition from 400/o to 47%. Tumour line FMa did not respond to DNR, nor to DNR-GA3. Treatment with DNR-GA3 was also given to mice with larger tumours that would contain more necrosis (mean size 300-950 mm3). The specific growth delay by DNR-GA3 was extended from 2.1 to 4.4 in OVCAR-3 xenografts and from 4.4 to 6.0 in MRI-H-207 xenografts. Our data indicate that DNR-GA3 is more effective than DNR and may be especially of use for treatnent of tumours with areas of necrosis.
PloS one, 2014
P-glycoprotein (Pgp) extrudes a large variety of chemotherapeutic drugs from the cells, causing multidrug resistance (MDR). The UIC2 monoclonal antibody recognizes human Pgp and inhibits its drug transport activity. However, this inhibition is partial, since UIC2 binds only to 10-40% of cell surface Pgps, while the rest becomes accessible to this antibody only in the presence of certain substrates or modulators (e.g. cyclosporine A (CsA)). The combined addition of UIC2 and 10 times lower concentrations of CsA than what is necessary for Pgp inhibition when the modulator is applied alone, decreased the EC50 of doxorubicin (DOX) in KB-V1 (Pgp+) cells in vitro almost to the level of KB-3-1 (Pgp-) cells. At the same time, UIC2 alone did not affect the EC50 value of DOX significantly. In xenotransplanted severe combined immunodeficient (SCID) mice co-treated with DOX, UIC2 and CsA, the average weight of Pgp+ tumors was only ∼10% of the untreated control and in 52% of these animals we coul...
International Journal of Cancer, 1989
Human ovarian carcinomas (HOC) were established S.C. and i.p. in nude mice and the biological characteristics were investigated for 4 xenografts. HOC8 and HOC 18, derived respectively from a primary tumor of the ovary and a pleural effusion (from 2 different patients) were established S.C. in nude mice. HOCIO and HOC22, derived from the ascites of 2 patients, were directly established as ascites after i.p. injection in nude mice. The S.C. and i.p. growth behavior of the 4 HOC lines was investigated. HOC 18, HOC8 and HOC22 cells produced progressively growing tumor after S.C. injection but HOCIO ascites would not grow S.C. The cell suspension derived from HOC18 only produced carcinomatosis upon i.p. injection, while HOC8 cells produced both ascites and carcinomatosis. The 2 ascites HOC 10 and HOC22 produced ascites in nude mice, but only HOC22 formed i.p. carcinomatosis. Histopathological characteristics of the patients' primary tumors persisted in nude mice, regardless of the site of tumor implantation. D N A histograms of the xenografts closely matched the patients' tumors and remained stable at different passages. Cisplatin, adriamycin and cyclophosphamide given i.v. were tested against HOC8 and HOC18 growing S.C. and HOC22 and HOCIO growing i.p. HOC8 showed a rignificant response to DDP and almost no sensitivity to ADR and CTX. HOC18 showed only moderate growth delay with all 3 drugs. Mice bearing HOCIO and HOC22 ascites had a prolonged survival time after DDP and ADR treatment.
PLoS ONE, 2013
A combination of carboplatin and paclitaxel is often used as first line chemotherapy for treatment of ovarian cancer. Therefore the use of imaging biomarkers early after initiation of treatment to determine treatment sensitivity would be valuable in order to identify responders from non-responders. In this study we describe the noninvasive PET imaging of glucose uptake and cell proliferation using 2-deoxy-2-[ 18 F]fluoro-D-glucose (FDG) and 3'deoxy-3'-[ 18 F]fluorothymidine (FLT) for early assessment of treatment response in a pre-clinical mouse model of human ovarian cancer treated with carboplatin and paclitaxel.
Biochemical Pharmacology, 1999
phenyl] O--glucuronyl carbamate (DNR-GA3) is a glucuronide prodrug of daunorubicin (DNR) which induced a better tumor growth delay than DNR when studied at equitoxic doses in three human ovarian cancer xenografts. These results suggested that the prodrug DNR-GA3 was selectively activated by human -glucuronidase present in tumor tissue. We determined the pharmacokinetics and distribution of DNR-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3, FMa, A2780, and MRI-H-207). Administration of DNR at 10 mg/kg i.v. (maximum tolerated dose) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 12.18 M (t ϭ 1 min). DNR-GA3 at 100 mg/kg i.v. (approximately 50% of the maximum tolerated dose [MTD]) resulted in a peak plasma concentration of DNR that was 28-fold lower than that after DNR itself; in normal tissues, prodrug injection resulted in 5-to 23-fold lower DNR concentrations. DNR showed a relatively poor uptake into OVCAR-3 tumors with a peak concentration of 2.05 nmol ⅐ g Ϫ1 after injection. In the same xenograft, DNR-GA3 resulted in a significantly higher DNR peak concentration of 3.45 nmol ⅐ g Ϫ1 (P Ͻ 0.05). The higher area under the curve of DNR in tumor tissue after DNR-GA3 than after DNR itself would be the result of prodrug activation by -glucuronidase. In this respect, a considerably higher -glucuronidase activity was found in tumor tissue when compared to plasma. The specific activation of DNR-GA3 by -glucuronidase at the tumor site relative to normal organs leads to a more tumor-selective therapy, resulting in greater efficacy without increased toxicity. BIOCHEM PHARMACOL 57;6:673-680, 1999. targeting index; saccharolactone, D-glucaric acid-1,4-lactone monohydrate; and MTD, maximum tolerated dose.