Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Philip L. Lorenzi is active.

Publication


Featured researches published by Philip L. Lorenzi.


Pharmaceutical Research | 2005

Floxuridine Amino Acid Ester Prodrugs: Enhancing Caco-2 Permeability and Resistance to Glycosidic Bond Metabolism

Christopher P. Landowski; Xueqin Song; Philip L. Lorenzi; John M. Hilfinger; Gordon L. Amidon

PurposeThe aim of this study was to synthesize amino acid ester prodrugs of 5-fluoro-2′-deoxyuridine (floxuridine) to enhance intestinal absorption and resistance to glycosidic bond metabolism.MethodsAmino acid ester prodrugs were synthesized and examined for their hydrolytic stability in human plasma, in Caco-2 cell homogenates, and in the presence of thymidine phosphorylase. Glycyl-l-sarcosine uptake inhibition and direct uptake studies with HeLa/PEPT1 cells [HeLa cells overexpressing oligopeptide transporter (PEPT1)] were conducted to determine PEPT1-mediated transport and compared with permeability of the prodrugs across Caco-2 monolayers.ResultsIsoleucyl prodrugs exhibited the highest chemical and enzymatic stability. The prodrugs enhanced the stability of the glycosidic bond of floxuridine. Thymidine phosphorylase rapidly cleaved floxuridine to 5-fluorouracil, whereas with the prodrugs no detectable glycosidic bond cleavage was observed. The 5′-l-isoleucyl and 5′-l-valyl monoester prodrugs exhibited 8- and 19-fold PEPT1-mediated uptake enhancement in HeLa/PEPT1 cells, respectively. Uptake enhancement in HeLa/PEPT1 cells correlated highly with Caco-2 permeability for all prodrugs tested. Caco-2 permeability of 5′-l-isoleucyl and 5′-l-valyl prodrugs was 8- to 11-fold greater compared with floxuridine.ConclusionsAmino acid ester prodrugs such as isoleucyl floxuridine that exhibit enhanced Caco-2 transport and slower rate of enzymatic activation to parent, and that are highly resistant to metabolism by thymidine phosphorylase may improve oral delivery and therapeutic index of floxuridine.


Journal of Pharmacology and Experimental Therapeutics | 2009

Cellular Inhibition of Checkpoint Kinase 2 (Chk2) and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor PV1019 [7-Nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide]

Andrew Jobson; George T. Lountos; Philip L. Lorenzi; Jenny Llamas; John Connelly; David Cerna; Joseph E. Tropea; Akikazu Onda; Gabriele Zoppoli; G. Zhang; Natasha J. Caplen; John H. Cardellina; Stephen S. Yoo; Anne Monks; Christopher Self; David S. Waugh; Robert H. Shoemaker; Yves Pommier

Chk2 is a checkpoint kinase involved in the ataxia telangiectasia mutated pathway, which is activated by genomic instability and DNA damage, leading to either cell death (apoptosis) or cell cycle arrest. Chk2 provides an unexplored therapeutic target against cancer cells. We recently reported 4,4′-diacetyldiphenylurea-bis(guanylhydrazone) (NSC 109555) as a novel chemotype Chk2 inhibitor. We have now synthesized a derivative of NSC 109555, PV1019 (NSC 744039) [7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide], which is a selective submicromolar inhibitor of Chk2 in vitro. The cocrystal structure of PV1019 bound in the ATP binding pocket of Chk2 confirmed enzymatic/biochemical observations that PV1019 acts as a competitive inhibitor of Chk2 with respect to ATP. PV1019 was found to inhibit Chk2 in cells. It inhibits Chk2 autophosphorylation (which represents the cellular kinase activation of Chk2), Cdc25C phosphorylation, and HDMX degradation in response to DNA damage. PV1019 also protects normal mouse thymocytes against ionizing radiation-induced apoptosis, and it shows synergistic antiproliferative activity with topotecan, camptothecin, and radiation in human tumor cell lines. We also show that PV1019 and Chk2 small interfering RNAs can exert antiproliferative activity themselves in the cancer cells with high Chk2 expression in the NCI-60 screen. These data indicate that PV1019 is a potent and selective inhibitor of Chk2 with chemotherapeutic and radiosensitization potential.


Drug Metabolism and Disposition | 2006

N-methylpurine DNA glycosylase and 8-oxoguanine DNA glycosylase metabolize the antiviral nucleoside 2-bromo-5,6-dichloro-1-(β-D-ribofuranosyl)benzimidazole

Philip L. Lorenzi; Christopher P. Landowski; Andrea Brancale; Xueqin Song; Leroy B. Townsend; John C. Drach; Gordon L. Amidon

The rapid in vivo degradation of the potent human cytomegalovirus inhibitor 2-bromo-5,6-dichloro-1-(β-d-ribofuranosyl)benzimidazole (BDCRB) compared with a structural l-analog, maribavir (5,6-dichloro-2-(isopropylamino)-1-β-l-ribofuranosyl-1H-benzimidazole), has been attributed to selective glycosidic bond cleavage. An enzyme responsible for this selective BDCRB degradation, however, has not been identified. Here, we report the identification of two enzymes, 8-oxoguanine DNA glycosylase (OGG1) and N-methylpurine DNA glycosylase (MPG), that catalyze N-glycosidic bond cleavage of BDCRB and its 2-chloro homolog, 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole, but not maribavir. To our knowledge, this is the first demonstration that free nucleosides are substrates of OGG1 and MPG. To understand how these enzymes might process BDCRB, docking and molecular dynamics simulations were performed with the native human OGG1 crystal coordinates. These studies showed that OGG1 was not able to bind a negative control, guanosine, yet BDCRB and maribavir were stabilized through interactions with various binding site residues, including Phe319, His270, Ser320, and Asn149. Only BDCRB, however, achieved orientations whereby its anomeric carbon, C1′, could undergo nucleophilic attack by the putative catalytic residue, Lys249. Thus, in silico observations were in perfect agreement with experimental observations. These findings implicate DNA glycosylases in drug metabolism.


Journal of Pharmacology and Experimental Therapeutics | 2009

Cellular Inhibition of Chk2 Kinase and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor Pv1019.

Andrew Jobson; George T. Lountos; Philip L. Lorenzi; Jenny Llamas; John Connelly; David Cerna; Joseph E. Tropea; Akikazu Onda; Gabriele Zoppoli; G. Zhang; Natasha J. Caplen; John H. Cardellina; Stephen S. Yoo; Anne Monks; Christopher Self; David S. Waugh; Robert H. Shoemaker; Yves Pommier

Chk2 is a checkpoint kinase involved in the ataxia telangiectasia mutated pathway, which is activated by genomic instability and DNA damage, leading to either cell death (apoptosis) or cell cycle arrest. Chk2 provides an unexplored therapeutic target against cancer cells. We recently reported 4,4′-diacetyldiphenylurea-bis(guanylhydrazone) (NSC 109555) as a novel chemotype Chk2 inhibitor. We have now synthesized a derivative of NSC 109555, PV1019 (NSC 744039) [7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide], which is a selective submicromolar inhibitor of Chk2 in vitro. The cocrystal structure of PV1019 bound in the ATP binding pocket of Chk2 confirmed enzymatic/biochemical observations that PV1019 acts as a competitive inhibitor of Chk2 with respect to ATP. PV1019 was found to inhibit Chk2 in cells. It inhibits Chk2 autophosphorylation (which represents the cellular kinase activation of Chk2), Cdc25C phosphorylation, and HDMX degradation in response to DNA damage. PV1019 also protects normal mouse thymocytes against ionizing radiation-induced apoptosis, and it shows synergistic antiproliferative activity with topotecan, camptothecin, and radiation in human tumor cell lines. We also show that PV1019 and Chk2 small interfering RNAs can exert antiproliferative activity themselves in the cancer cells with high Chk2 expression in the NCI-60 screen. These data indicate that PV1019 is a potent and selective inhibitor of Chk2 with chemotherapeutic and radiosensitization potential.


Cancer Research | 2017

Abstract 2134: Use of methionine gamma-lyase-loaded erythrocytes to induce effective methionine depletion in cancer therapy

Karine Aguera; Karine Senechal; Philip L. Lorenzi; Alexander Scheer; Françoise Horand; Vanessa Bourgeaux

Methionine (Met) dependence is a cancer-specific metabolic defect that has emerged as a target during the last two decades. The use of methionine gamma-lyase (MGL; EC number 4.4.1.11), a bacterial Met-catabolizing enzyme, is a promising strategy for treatment of Met-dependent cancers. However, one challenge is that MGL has a very short half-life (~2 hours), resulting in a short-term Met depletion in vivo. Additionally, its cofactor, pyridoxal 5’-phosphate (PLP) is rapidly eliminated from plasma (Yang et al., 2004). PEGylation extends the MGL half-life in mice to up to 38 hours. Nevertheless, frequent injections are still necessary for maintaining an effective Met depletion over time (Sun et al., 2003). In addition, the low bioavailability of PLP remains a major hurdle due to both scavenging by plasma proteins and very short half-life ( Citation Format: Fabien Gay, Karine Aguera, Karine Senechal, Philip Lorenzi, Alexander Scheer, Francoise Horand, Vanessa Bourgeaux. Use of methionine gamma-lyase-loaded erythrocytes to induce effective methionine depletion in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2134. doi:10.1158/1538-7445.AM2017-2134


Cancer Research | 2016

Abstract 4812: Arginine deiminase loaded in erythrocytes: a promising formulation for L-arginine deprivation therapy in cancers

Karine Aguera; Karine Senechal; Julie Bes; Anne-Marie Chevrier; Fanny Gallix; Christine Guicher; Philip L. Lorenzi; Vanessa Bourgeaux; Willy Berlier; Françoise Horand; Yann Godfrin

Based on the asparaginase paradigm, several arginine-catabolizing enzymes have been developed for the treatment of arginine-dependent cancers (Wheatley, 2004). The arginine deiminase (ADI) enzyme catalyzes the hydrolysis of arginine (Arg) (Sugimura, 1990). ADI purified from Mycoplasma has a short half-life (≈4h) in the circulation and was found to be highly immunogenic (Holstberg, 2002). In order to increase half-life and to limit immunogenicity, a pegylated form of the enzyme (ADI-PEG-20) was developed. Phase I/II clinical studies in hepatocarcinoma and in advanced melanoma concluded on its limited efficacy at the tested doses. Notably, reduction of the duration of Arg depletion was linked to the emergence of ADI-PEG-20 antibodies (Ascierto, 2006). Encapsulation of ADI into red blood cells (RBC) is a promising alternative to improve the half-life and reduce the immunogenicity of the protein. Argininosuccinate synthase (ASS1) is the key enzyme in arginine biosynthesis (Haines, 2011). ASS1 expression varies in tumors and ASS1 loss is associated with poor prognosis in different cancers (Qiu, 2015). All these data strengthen the importance of selecting ASS1-negative patients for Arg-depletion based enzymatic therapy. Using a scalable, standardized production process, we synthesized an ADI enzyme from an optimized M. arginini coding sequence. ADI was encapsulated into RBC by hypotonic dialysis (ERY-ADI) and PK-PD parameters were evaluated in CD1 mice, in comparison with free ADI. Sensitivity to ADI was assessed in vitro by measuring the cell viability of 3 cancer cell lines with different ASS1 expression levels. ASS1 expression was screened by immunohistochemistry (IHC) in a large panel of tissue microarrays (TMA) from 16 human cancer types. Administration of ERY-ADI (5.5IU/mL) reduced mouse plasmatic Arg level to 30% of control values and led to a maintained depletion for 5 days. The same dose of free ADI strongly depleted Arg ( All these results highlight that arginine depletion through ADI treatment is effective against ASS1-negative cancer cells. ERY-ADI represents an innovative product with an improved efficacy for sustained Arg depletion and suitable for the treatment of ASS1 deficient cancers. Citation Format: Fabien Gay, Karine Aguera, Karine Senechal, Julie Bes, Anne-Marie Chevrier, Fanny Gallix, Christine Guicher, Philip Lorenzi, Vanessa Bourgeaux, Willy Berlier, Francoise Horand, Yann Godfrin. Arginine deiminase loaded in erythrocytes: a promising formulation for L-arginine deprivation therapy in cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4812.


Atlas of genetics and cytogenetics in oncology and haematology | 2011

ASNS (asparagine synthetase)

Philip L. Lorenzi; Michael C. Ryan; Ogechi N. Ikediobi; John N. Weinstein

Review on ASNS (asparagine synthetase), with data on DNA, on the protein encoded, and where the gene is implicated.


Molecular Cancer Therapeutics | 2009

Abstract A120: Cellular inhibition of Chk2 kinase and potentiation of camptothecins and radiation by the novel Chk2 inhibitor PV1019

Andrew Jobson; George T. Lountos; Philip L. Lorenzi; John Connelly; Joseph E. Tropea; Gabriele Zoppoli; G. Zhang; Natasha J. Caplen; John H. Cardellina; Stephen S. Yoo; Anne Monks; Christopher Self; David S. Waugh; Robert H. Shoemaker; Yves Pommier

Chk2 is a checkpoint kinase involved in the ATM pathway, which is activated by genomic instability and DNA damage, leading to either cell death (apoptosis) or cell cycle arrest. Chk2 provides an unexplored therapeutic target against cancer cells. We recently reported NSC 109555 as a novel chemotype Chk2 inhibitor. We have now synthesized a derivative of NSC 109555, PV1019 (NSC 744039), which is a selective sub‐micromolar inhibitor of Chk2 in vitro. The co‐crystal structure of PV1019 bound in the ATP binding pocket of Chk2 confirmed enzymatic/biochemical observations that PV1019 acts as a competitive inhibitor of Chk2 with respect to ATP. PV1019 was found to inhibit Chk2 in cells. It inhibits Chk2 autophosphorylation (which represents the cellular kinase activation of Chk2), Cdc25C phosphorylation, and HDMX degradation in response to DNA damage. PV1019 also protects normal mouse thymocytes against IR‐induced apoptosis, and it shows synergistic antiproliferative activity with topotecan, camptothecin, and radiation in human tumor cell lines. We also show that PV1019 as well as Chk2 siRNA can exert antiproliferative activity themselves in the cancer cells with high Chk2 expression in the NCI60 screen. These data indicate that PV1019 is a potent and selective inhibitor of Chk2 with chemotherapeutic and radiosensitization potential. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A120.


Journal of Pharmacology and Experimental Therapeutics | 2009

Cellular Inhibition of Checkpoint Kinase 2 (Chk2) and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor PV1019 [7-Nitro-1H-indole-2-carboxylic acid -amide]

Andrew Jobson; George T. Lountos; Philip L. Lorenzi; Jenny Llamas; John Connelly; David Cerna; Joseph E. Tropea; Akikazu Onda; Gabriele Zoppoli; G. Zhang; Natasha J. Caplen; John H. Cardellina; Stephen S. Yoo; Anne Monks; Christopher Self; David S. Waugh; Robert H. Shoemaker; Yves Pommier

Chk2 is a checkpoint kinase involved in the ataxia telangiectasia mutated pathway, which is activated by genomic instability and DNA damage, leading to either cell death (apoptosis) or cell cycle arrest. Chk2 provides an unexplored therapeutic target against cancer cells. We recently reported 4,4′-diacetyldiphenylurea-bis(guanylhydrazone) (NSC 109555) as a novel chemotype Chk2 inhibitor. We have now synthesized a derivative of NSC 109555, PV1019 (NSC 744039) [7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide], which is a selective submicromolar inhibitor of Chk2 in vitro. The cocrystal structure of PV1019 bound in the ATP binding pocket of Chk2 confirmed enzymatic/biochemical observations that PV1019 acts as a competitive inhibitor of Chk2 with respect to ATP. PV1019 was found to inhibit Chk2 in cells. It inhibits Chk2 autophosphorylation (which represents the cellular kinase activation of Chk2), Cdc25C phosphorylation, and HDMX degradation in response to DNA damage. PV1019 also protects normal mouse thymocytes against ionizing radiation-induced apoptosis, and it shows synergistic antiproliferative activity with topotecan, camptothecin, and radiation in human tumor cell lines. We also show that PV1019 and Chk2 small interfering RNAs can exert antiproliferative activity themselves in the cancer cells with high Chk2 expression in the NCI-60 screen. These data indicate that PV1019 is a potent and selective inhibitor of Chk2 with chemotherapeutic and radiosensitization potential.


Molecular Pharmaceutics | 2005

Amino acid ester prodrugs of the anticancer agent gemcitabine: synthesis, bioconversion, metabolic bioevasion, and hPEPT1-mediated transport.

Xueqin Song; Philip L. Lorenzi; Christopher P. Landowski; Balvinder S. Vig; John M. Hilfinger; Gordon L. Amidon

Collaboration


Dive into the Philip L. Lorenzi's collaboration.

Top Co-Authors

Avatar

Natasha J. Caplen

National Institutes of Health

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Xueqin Song

University of Michigan

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Andrew Jobson

National Institutes of Health

View shared research outputs
Top Co-Authors

Avatar

Anne Monks

Science Applications International Corporation

View shared research outputs
Top Co-Authors

Avatar

Christopher Self

National Institutes of Health

View shared research outputs
Top Co-Authors

Avatar

David S. Waugh

National Institutes of Health

View shared research outputs
Top Co-Authors

Avatar

G. Zhang

National Institutes of Health

View shared research outputs
Top Co-Authors

Avatar

George T. Lountos

National Institutes of Health

View shared research outputs
Researchain Logo
Decentralizing Knowledge