Biomedical subjects

Mark Rolfe

Publications and source records attributed to Mark Rolfe.

17 recordsLinked to original sources

PubMed2006

Interleukin 6, a nuclear factor-kappaB target, predicts resistance to docetaxel in hormone-independent prostate cancer and nuclear factor-kappaB inhibition by PS-1145 enhances docetaxel antitumor activity.

PURPOSE: To investigate whether nuclear factor kappaB (NF-kappaB)/interleukin 6 (IL-6) was linked to docetaxel response in human prostate cancer cell lines, and whether inhibition of NF-kappaB sensitized tumor cells to docetaxel. We also aimed to correlate IL-6 (as a surrogate marker of NF-kappaB) and docetaxel response in hormone-independent prostate cancer (HIPC) patients. EXPERIMENTAL DESIGN: Hormone-dependent (LNCaP) and hormone-independent (PC-3 and DU-145) prostate cancer cell lines were exposed to docetaxel alone or combined with the NF-kappaB inhibitor PS-1145 (an inhibitor of IkappaB kinase-2). Effects of dose, exposure time, and schedule dependence were assessed. Activation of NF-kappaB was assayed by electrophoresis mobility shift assay and luciferase reporter assay, IL-6 levels by ELISA, and cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle and apoptosis were assessed by fluorescence-activated cell sorting analysis. Apoptosis was also measured by detection of cleavage of poly(ADP-ribose) polymerase. In patients with metastatic HIPC receiving docetaxel-based chemotherapy, IL-6 serum levels were assayed before chemotherapy and every 3 to 4 weeks thereafter. RESULTS: PC-3 and DU-145 cells had higher NF-kappaB activity, secreted more IL-6, and were more resistant to docetaxel than LNCaP cells. NF-kappaB activity was induced by docetaxel. Cotreatment with docetaxel and PS-1145 prevented docetaxel-induced NF-kappaB activation, reduced IL-6 production, and increased docetaxel effects on cell viability in PC-3 and DU-145 cells but not in LNCaP. Synergism with docetaxel and PS-1145, as assayed by median-effect principle, was observed in DU-145 and PC-3. In HIPC patients, pretreatment IL-6 serum levels correlated to prostate-specific antigen (PSA) response: median IL-6 level was 10.8+/-9.5 pg/mL in PSA responders versus 36.7+/-20.8 pg/mL (P=0.006) in nonresponders. A PSA response was also linked to a decline in IL-6 levels during treatment. Median overall survival was 6.8 months in patients with high IL-6 versus 16.6 months in those with low IL-6 (P=0.0007). On multivariate analysis, pretreatment IL-6 (P=0.05) was an independent prognostic factor for time to disease progression and survival. CONCLUSIONS: Inhibition of NF-kappaB emerges as an attractive strategy to enhance docetaxel response in prostate cancer. The interest of this view is further supported by a significant association between high IL-6 in sera of HIPC patients and decreased response to docetaxel.

Aged↗

PubMed2006

The combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide.

PURPOSE: To determine whether the combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen can sensitize human lymphoma to cyclophosphamide. EXPERIMENTAL DESIGN: Cytotoxicity assays were conducted to determine if there was any additive or synergistic interaction between the combinations of bortezomib, oblimersen, and cyclophosphamide using a standard trypan blue exclusion assay. Based on these experiments, in vivo experiments in severe combined immunodeficiency beige mice were done using human lymphoma xenografts in which different schedules were explored. Bcl-2 and oblimersen levels were determined in treated tumors, some of which were resected at the end of the in vivo experiment and evaluated pathologically. RESULTS: The results suggest that the combination of bortezomib and oblimersen seem to interact in at least an additive fashion, and that the addition of cyclophosphamide to this drug combination can markedly improve tumor cell kill. In addition, it seems that these drug combinations may be schedule-dependent, with a requirement for oblimersen pretreatment. Animals treated with the triplet drug combination in a schedule-dependent manner experienced pathologic complete regression of disease, which was not observed in other treatment cohorts. The addition of bortezomib also seemed to increase the levels of intracellular oblimersen, which resulted in a marked reduction in Bcl-2. Histologic studies confirmed marked necrosis and caspase-3 activation only in the cohort receiving all three drugs. CONCLUSION: The use of Bcl-2-directed therapy and a proteasome inhibitor sensitizes human lymphoma cells to cytotoxic drugs like cyclophosphamide. This combination may offer new opportunities for integrating novel targeted therapies with conventional chemotherapy.

Animals↗

PubMed2006

Drug discovery in the ubiquitin-proteasome system.

Regulated protein turnover via the ubiquitin-proteasome system (UPS) underlies a wide variety of signalling pathways, from cell-cycle control and transcription to development. Recent evidence that pharmacological inhibition of the proteasome can be efficacious in the treatment of human cancers has set the stage for attempts to selectively inhibit the activities of disease-specific components of the UPS. Here, we review recent advances linking UPS components with specific human diseases, most prominently cancer and neurodegenerative disorders, and emphasize potential sites of therapeutic intervention along the regulated protein-degradation pathway.

Animals↗

PubMed2006

Differential cellular and molecular effects of bortezomib, a proteasome inhibitor, in human breast cancer cells.

The cellular and molecular effects of the proteasome inhibitor bortezomib on breast cancer cells are as yet poorly characterized. Here, in a panel of six breast cancer cell lines, bortezomib reduced viability in a concentration-dependent, time-dependent, and cell line-dependent manner. Proteasome activity was relatively high in two of the three more resistant cell lines. No relationship was observed between bortezomib effects on cell viability and expression/phosphorylation of HER-2, epidermal growth factor receptor (EGFR), AKT, or extracellular signal-regulated kinase 1/2 (ERK1/2). Molecular effects of bortezomib were further studied in SK-BR-3 and BT-474 cells because they share expression of EGFR and overexpression of HER-2 while, in contrast, SK-BR-3 cells were 200-fold more sensitive to this agent. Proteasome activity was inhibited to a similar extent in the two cell lines, and known proteasome substrates accumulated similarly. In SK-BR-3 cells, a marked inhibition of EGFR, HER-2, and AKT phosphorylation was observed at a clinically relevant concentration of bortezomib. In contrast, phosphorylation of Raf/mitogen-activated protein kinase kinase 1/2 (MEK 1/2)/ERK1/2 increased by bortezomib. In BT-474 cells, the effects were much less pronounced. Treatment of SK-BR-3 cells with bortezomib combined with pharmacologic inhibitors of EGFR, phosphatidylinositol 3'-kinase, or MEK resulted in modest or no enhancement of the effects on cell viability. Collectively, these results show that bortezomib has differential cellular and molecular effects in human breast cancer cells. The bortezomib-observed effects on signaling transduction molecules might be relevant to help to design mechanistic-based combination treatments.

Boronic Acids↗

PubMed2006

Comparison of biochemical and biological effects of ML858 (salinosporamide A) and bortezomib.

Strains within the genus Salinospora have been shown to produce complex natural products having antibiotic and antiproliferative activities. The biochemical basis for the cytotoxic effects of salinosporamide A has been linked to its ability to inhibit the proteasome. Synthetically accessible salinosporamide A (ML858) was used to determine its biochemical and biological activities and to compare its effects with those of bortezomib. ML858 and bortezomib show time- and concentration-dependent inhibition of the proteasome in vitro. However, unlike bortezomib, which is a reversible inhibitor, ML858 covalently binds to the proteasome, resulting in the irreversible inhibition of 20S proteasome activity. ML858 was equipotent to bortezomib in cell-based reporter stabilization assays, but due to intramolecular instability is less potent in long-term assays. ML858 failed to maintain levels of proteasome inhibition necessary to achieve efficacy in tumor models responsive to bortezomib. Our results show that ML858 and bortezomib exhibit different kinetic and pharmacologic profiles and suggest that additional characterization of ML858 is warranted before its therapeutic potential can be fully appreciated.

Animals↗

PubMed2005

Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed--a phenotype partially reversed by selective estrogen receptor modulators.

The splicing factor SPF45 (RBM17) is frequently overexpressed in many solid tumors, and stable expression in HeLa cells confers resistance to doxorubicin and vincristine. In this study, we characterized stable transfectants of A2780 ovarian carcinoma cells. In a 3-day cytotoxicity assay, human SPF45 overexpression conferred 3- to 21-fold resistance to carboplatin, vinorelbine, doxorubicin, etoposide, mitoxantrone, and vincristine. In addition, resistance to gemcitabine and pemetrexed was observed at the highest drug concentrations tested. Knockdown of SPF45 in parental A2780 cells using a hammerhead ribozyme sensitized A2780 cells to etoposide by approximately 5-fold relative to a catalytically inactive ribozyme control and untransfected cells, suggesting a role for SPF45 in intrinsic resistance to some drugs. A2780-SPF45 cells accumulated similar levels of doxorubicin as vector-transfected and parental A2780 cells, indicating that drug resistance is not due to differences in drug accumulation. Efforts to identify small molecules that could block SPF45-mediated drug resistance revealed that the selective estrogen receptor (ER) modulators tamoxifen and LY117018 (a raloxifene analogue) partially reversed SPF45-mediated drug resistance to mitoxantrone in A2780-SPF45 cells from 21-fold to 8- and 5-fold, respectively, but did not significantly affect the mitoxantrone sensitivity of vector control cells. Quantitative PCR showed that ERbeta but not ERalpha was expressed in A2780 transfectants. Coimmunoprecipitation experiments suggest that SPF45 and ERbeta physically interact in vivo. Thus, SPF45-mediated drug resistance in A2780 cells may result in part from effects of SPF45 on the transcription or alternate splicing of ERbeta-regulated genes.

Antineoplastic Agents↗

PubMed2005

Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2).

The hypertrophic Gq-protein-coupled receptor agonist PE (phenylephrine) activates protein synthesis. We showed previously that activation of protein synthesis by PE requires MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and mTOR (mammalian target of rapamycin). However, it remained unclear whether ERK activation was required and which downstream components were involved in activating mTOR and protein synthesis. Using an adenovirus encoding the MKP3 (MAPK phosphatase 3) to inhibit ERK activity, we demonstrate that ERK is essential for the activation of protein synthesis by PE. Activation and phosphorylation of S6K1 (ribosomal protein S6 kinase 1) and phosphorylation of eIF4E (eukaryotic initiation factor 4E)-binding protein (both are mTOR targets) were also inhibited by MKP3, suggesting that ERK is also required for the activation of mTOR signalling. PE stimulation of cardiomyocytes induced the phosphorylation of TSC2 (tuberous sclerosis complex 2), a negative regulator of mTOR activity. TSC2 was phosphorylated only weakly at Thr1462, but phosphorylated at additional sites within the sequence RXRXX(S/T). This differs from the phosphorylation induced by insulin, indicating that MEK/ERK signalling targets distinct sites in TSC2. This phosphorylation may be mediated by p90RSK (90 kDa ribosomal protein S6K), which is activated by ERK, and appears to involve phosphorylation at Ser1798. Activation of protein synthesis by PE is partially insensitive to the mTOR inhibitor rapamycin. Inhibition of the MAPK-interacting kinases by CGP57380 decreases the phosphorylation of eIF4E and PE-induced protein synthesis. Moreover, CGP57380+rapamycin inhibited protein synthesis to the same extent as blocking ERK activation, suggesting that MAPK-interacting kinases and regulation of mTOR each contribute to the activation of protein synthesis by PE in cardiomyocytes.

Aniline Compounds↗

PubMed2005

Antibody-based therapeutics: focus on prostate cancer.

The recent clinical and commercial success of anti-cancer antibodies such as rituximab, trastuzumab, cetuximab and bevacizumab has continued to foster great interest in antibody-based therapeutics for the treatment of both hematopoietic malignancies and solid tumors. Given the likely lower toxicity for antibodies which, in contrast with traditional cytotoxic small molecule drugs, target tumor cells and have a lower impact on non-malignant by-stander organs, the potential increases in efficacy associated with conjugation to radioisotopes and other cellular toxins and the ability to characterize the target with clinical laboratory diagnostics to improve the drugs clinical performance, it is anticipated that current and future antibody therapeutics will find substantial roles alone and in combination therapy strategies for the treatment of patients with cancer. A significant number of cell surface proteins, glycoproteins, receptors, enzymes and peptides have been discovered that have become targets for the treatment of advanced hormone-refractory prostate cancer. A variety of naked antibodies and antibody conjugates have currently progressed through preclinical development and are in early or more advanced stages of clinical development. Clinicians, scientists and prostate cancer patients are all keenly interested to learn whether these agents when administered alone or in combination with other hormonal-based and cytotoxic therapies will show lasting benefit for sufferers of this common disease.

Antibodies, Monoclonal↗

PubMed2004

Targeted therapies for cancer 2004.

The regulatory agency approvals in the United States and Europe of imatinib mesylate (Gleevec) for patients with bcr/abl-positive chronic myelogenous leukemia, cetuximab (Erbitux) for patients with epidermal growth factor receptor overexpressing metastatic colorectal cancer, the antiangiogenesis agent bevacizumab (Avastin), and the proteasome inhibitor bortezomib (Velcade)--and the considerable public interest in new anticancer drugs that take advantage of specific genetic defects that render the malignant cells more likely to respond to specific treatment--are driving a new era of integrated diagnostics and therapeutics. The recent discovery of a drug response predicting activating mutation in the epidermal growth factor receptor gene for patients with non-small cell lung cancer treated with gefitinib (Iressa) has intensified this interest. In this review, the history of targeted anticancer therapies is highlighted, with focus on the development of molecular diagnostics for hematologic malignancies and the emergence of trastuzumab (Herceptin), an antibody-based targeted therapy for HER-2/neu overexpressing metastatic breast cancer: The potential of pharmacogenomic strategies and the use of high-density genomic microarrays to classify and select therapy for cancer are briefly considered. This review also considers the widely held view that, in the next 5 to 10 years, the clinical application of molecular diagnostics will further revolutionize the drug discovery and development process; customize the selection, dosing, route of administration of existing and new therapeutic agents; and truly personalize medical care for cancer patients.

Aminoglycosides↗

PubMed2003

Ca(2+)-independent protein kinase C activity is required for alpha1-adrenergic-receptor-mediated regulation of ribosomal protein S6 kinases in adult cardiomyocytes.

The alpha(1)-adrenergic agonist, phenylephrine (PE), exerts hypertrophic effects in the myocardium and activates protein synthesis. Both Ca(2+)-dependent protein kinase C (PKC, PKCalpha) and Ca(2+)-independent PKC isoforms (PKCdelta and epsilon ) are detectably expressed in adult rat cardiomyocytes. Stimulation of the alpha(1)-adrenergic receptor by PE results in activation of Ca(2+)-independent PKCs, as demonstrated by translocation of the delta and epsilon isoenzymes from cytosol to membrane fractions. PE also induces activation of p70 ribosomal protein S6 kinases (S6K1 and 2) in adult cardiomyocytes. We have studied the role of Ca(2+)-independent PKCs in the regulation of S6K activity by PE. Activation of S6K1/2 by PE was blocked by the broad-spectrum PKC inhibitor bisindolylmaleimide (BIM) I, whereas Gö6976, a compound that only inhibits Ca(2+)-dependent PKCs, did not inhibit S6K activation. Rottlerin, which selectively inhibits PKCdelta, also prevented PE-induced S6K activation. The isoform-specific PKC inhibitors had similar effects on the phosphorylation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1, a translation repressor that, like the S6Ks, lies downstream of the mammalian target of rapamycin (mTOR). Infection of cells with adenoviruses encoding dominant-negative PKCdelta or epsilon inhibited the activation of extracellular-signal-regulated kinase (ERK) by PE, and also inhibited the activation and/or phosphorylation of S6Ks 1 and 2. The PE-induced activation of protein synthesis was abolished by BIM I and markedly attenuated by rottlerin. Our data thus suggest that Ca(2+)-independent PKC isoforms play an important role in coupling the alpha(1)-adrenergic receptor to mTOR signalling and protein synthesis in adult cardiomyocytes.

Acetophenones↗

PubMed2003

Duplication and selection in the evolution of primate beta-defensin genes.

BACKGROUND: Innate immunity is the first line of defense against microorganisms in vertebrates and acts by providing an initial barrier to microorganisms and triggering adaptive immune responses. Peptides such as beta-defensins are an important component of this defense, providing a broad spectrum of antimicrobial activity against bacteria, fungi, mycobacteria and several enveloped viruses. Beta-defensins are small cationic peptides that vary in their expression patterns and spectrum of pathogen specificity. Disruptions in beta-defensin function have been implicated in human diseases, including cystic fibrosis, and a fuller understanding of the variety, function and evolution of human beta-defensins might form the basis for novel therapies. Here we use a combination of laboratory and computational techniques to characterize the main human beta-defensin locus on chromosome 8p22-p23. RESULTS: In addition to known genes in the region we report the genomic structures and expression patterns of four novel human beta-defensin genes and a related pseudogene. These genes show an unusual pattern of evolution, with rapid divergence between second exon sequences that encode the mature beta-defensin peptides matched by relative stasis in first exons that encode signal peptides. CONCLUSIONS: We conclude that the 8p22-p23 locus has evolved by successive rounds of duplication followed by substantial divergence involving positive selection, to produce a diverse cluster of paralogous genes established before the human-baboon divergence more than 23 million years ago. Positive selection, disproportionately favoring alterations in the charge of amino-acid residues, is implicated as driving second exon divergence in these genes.

Amino Acid Sequence↗

PubMed2003

Human SPF45, a splicing factor, has limited expression in normal tissues, is overexpressed in many tumors, and can confer a multidrug-resistant phenotype to cells.

Our effort to identify novel drug-resistant genes in cyclophosphamide-resistant EMT6 mouse mammary tumors led us to the identification of SPF45. Simultaneously, other groups identified SPF45 as a component of the spliceosome that is involved in alternative splicing. We isolated the human homologue and examined the normal human tissue expression, tumor expression, and the phenotype caused by overexpression of human SPF45. Our analyses revealed that SPF45 is expressed in many, but not all, normal tissues tested with predominant expression in normal ductal epithelial cells of the breast, liver, pancreas, and prostate. Our analyses using tissue microarrays and sausages of tumors indicated that SPF45 is highly expressed in numerous carcinomas including bladder, breast, colon, lung, ovarian, pancreatic, and prostate. Interestingly, this study revealed that overexpression of SPF45 in HeLa, a cervical carcinoma cell line, resulted in drug resistance to doxorubicin and vincristine, two chemotherapeutic drugs commonly used in cancer. To our knowledge, this is the first study showing tumor overexpression of an alternate splicing factor resulting in drug resistance.

Blotting, Western↗

PubMed2003

Anticancer antibodies.

The recent clinical and commercial success of anticancer antibodies such as rituximab and trastuzumab has created great interest in antibody-based therapeutics for hematopoietic malignant neoplasms and solid tumors. Given the likelihood of lower toxic effects of antibodies that target tumor cells and have limited impact on nonmalignant bystander organs vs small molecules, the potential increased efficacy by conjugation to radioisotopes and other cellular toxins, and the ability to characterize the target with clinical laboratory diagnostics to improve the drug's clinical performance, current and future antibody therapeutics are likely to find substantial roles alone and in combination therapeutic strategies for treating patients with cancer. It also is likely that conjugation strategies will add new radiolabeled and toxin-linked products to the market to complement the recent approvals of ibritumomab tiuxetan and gemtuzumab ozogamicin. This review considers the structure of anticancer therapeutic antibodies and the techniques used to reduce their antigenicity. Efficacy and toxic effects, conjugation with isotopes and toxins, and validation of the antibody targets also are discussed. Antibodies approved by the Food and Drug Administration are described in detail, as are antibodies in late and early stages of clinical development.

Animals↗

PubMed2003

Antibody-based therapeutics in oncology.

The recent clinical and commercial success of anticancer antibodies, such as rituximab (Rituxan) and trastuzumab (Herceptin) has created great interest in antibody-based therapeutics for hematopoietic malignancies and solid tumors. Given the likely lower toxicity for antibodies versus small molecules, the potential increase in efficacy by conjugation to radioisotopes and other cellular toxins and the ability to characterize the target with clinical laboratory diagnostics to improve the drug's clinical performance, it is anticipated that current and future antibody therapeutics will find substantial roles alone and in combination therapy strategies for the treatment of patients with cancer. It is also likely that conjugation strategies will add new radiolabeled and toxin-linked products to the market to complement the recent approvals of ibritumomab tiuxetan (Zevalin) and gemtuzumab ozogamycin (Mylotarg). However, although there are a large number of agents in both early and later stages of clinical development, only a handful will make it through regulatory approval and become successful products. This review considers the structure of anticancer therapeutic antibodies, the techniques used to reduce their antigenicity, factors that influence efficacy and toxicity, conjugation with isotopes and toxins and antibody target validation.

Antibodies, Monoclonal↗

PubMed2002

Differentiation of Hdm2-mediated p53 ubiquitination and Hdm2 autoubiquitination activity by small molecular weight inhibitors.

The oncoprotein hdm2 ubiquitinates p53, resulting in the rapid degradation of p53 through the ubiquitin (Ub)-proteasome pathway. Hdm2-mediated destabilization and inactivation of p53 are thought to play a critical role in a number of human cancers. We have used an in vitro enzyme assay, monitoring hdm2-catalyzed Ub transfer from preconjugated Ub-Ubc4 to p53, to identify small molecule inhibitors of this enzyme. Three chemically distinct types of inhibitors were identified this way, each with potency in the micromolar range. All three types of compounds display selective inhibition of hdm2 E3 ligase activity, with little or no effect on other Ub-using enzymes. Most strikingly, these compounds do not inhibit the autoubiquitination activity of hdm2. Steady-state analysis reveals that all three classes behave as simple reversible inhibitors of the enzyme and that they are noncompetitive with respect to both substrates, Ub-Ubc4 and p53. Studies of the effects of combinations of two inhibitory molecules on hdm2 activity indicate that the three types of compounds bind in a mutually exclusive fashion, suggesting a common binding site on hdm2 for all of these inhibitors. These compounds establish the feasibility of selectively blocking hdm2-mediated ubiquitination of p53 by small molecule inhibitors. Selective inhibitors of hdm2 E3 ligase activity could provide a novel mechanism for the development of new chemotherapeutics for the treatment of human cancers.

Biotinylation↗

PubMed2002

Identification and characterization of a novel murine beta-defensin-related gene.

Beta-defensins comprise a family of cationic peptides, which are predominately expressed at epithelial surfaces and have a broad-range antimicrobial activity. We have assembled two BAC-based contigs from the chromosomal region 8A4 that contain the murine defensins, and we have mapped six reported beta-defensin genes. In addition, we have isolated and functionally characterized a novel beta-defensin gene that deviates from the canonical six cysteine motif present in the mature functional peptide of all other beta-defensins. This defensin-related gene (Defr1) is most highly expressed in testis and heart. The genomic organization is highly similar to Defb3, 4, 5, and 6, and the exon 1 sequence is very highly conserved. A synthetic Defr1 peptide displayed antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Burkholderia cepacia. The antimicrobial activity of Defr1 against S. aureus, E.coli, and B. cepacia was found to be reduced in raised concentration of NaCl, but its action against P. aeruginosa was independent of NaCl concentration. This is the first report of a functional beta defensin that lacks one of the conserved cysteine residues in its predicted mature peptide. This study has major implications for the structure and functions of these important host defense molecules.

Amino Acid Sequence↗

PubMedDate not supplied

Longitudinally quantitative 2-deoxy-2-[18F]fluoro-D-glucose micro positron emission tomography imaging for efficacy of new anticancer drugs: a case study with bortezomib in prostate cancer murine model.

PURPOSE: The aim of this study was to validate quantitative metabolic response of tumors to a treatment measured by longitudinal 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) micro positron emission tomography (microPET) as a robust tool for preclinical evaluation of new anticancer agents. PROCEDURES: Severe combined immunodeficiency mice with CWR22 xenografts were intravenously treated with bortezomib (Velcade) at 0.8 mg/kg on days 0, 3, 7, 10, and 14 and imaged with FDG microPET before, during and after treatment. Quantitative indices of tumor FDG uptake were developed. RESULTS: FDG microPET images successfully revealed the gradual reduction of tumor FDG uptake on day 4 onward despite no absolute tumor shrinkage. The standardized uptake values of FDG in tumors was reduced to 43% of the baseline values. Using the total tumor FDG uptake as the viable tumor burden, we found 86% tumor inhibition, compared to a 55% tumor growth inhibition in tumor volume measurement. CONCLUSION: FDG microPET imaging can provide an additional dimension of the efficacy of anticancer therapies that may otherwise be underestimated by tumor volume measurement.

Animals↗