Mechanistic considerations in chemopreventive drug development

Kelloff, Gary J.; Boone, Charles W.; Steele, Vernon E.; Fay, Judith R.; Lubet, Ronald A.; Crowell, James A.; Sigman, Caroline C.

doi:10.1002/jcb.240560903

Cited by 153 publications

(52 citation statements)

References 186 publications

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“…A number of therapeutic approaches that interfere with aberrant EGFR family signaling are being investigated (16). A relatively new therapeutic approach to kinase inhibition is the use of ATP-competitive small molecules (17)(18)(19)(20). Several groups have shown that certain 4-anilinoquinazoline derivatives are both selective and effective inhibitors of the EGFR kinase (21).…”

mentioning

confidence: 99%

Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor

Stamos¹,

Sliwkowski

Eigenbrot³

2002

Journal of Biological Chemistry

1,264

1,037

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The crystal structure of the kinase domain from the epidermal growth factor receptor (EGFRK) including forty amino acids from the carboxyl-terminal tail has been determined to 2.6-Å resolution, both with and without an EGFRK-specific inhibitor currently in Phase III clinical trials as an anti-cancer agent, erlotinib (OSI-774, CP-358,774, Tarceva TM ). The EGFR family members are distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains. Despite its lack of phosphorylation, we find that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor. Surprisingly, key residues of a putative dimerization motif lying between the EGFRK domain and carboxyl-terminal substrate docking sites are found in close contact with the kinase domain. Significant intermolecular contacts involving the carboxyl-terminal tail are discussed with respect to receptor oligomerization.Growth factor interactions with cell surface receptors influence proliferation, survival, differentiation, and metabolism (1). The loss of control over these vital cellular processes is a hallmark of oncogenesis (2). For instance, aberrant signaling from overexpressed growth factor receptor ErbB2 is causal in approximately 30% of invasive breast cancers (3). Growth factors bind to a cognate membrane-bound receptor system and mediate changes in the intracellular portion of the receptor, often through the formation of dimers or oligomers of receptors that initiate signal transduction cascades. The epidermal growth factor receptor (EGFR, 1 also ErbB1 or HER1) and its ligands, epidermal growth factor (EGF) and transforming growth factor-␣, are among the earliest characterized members of the growth factor/receptor tyrosine kinase (RTK) family. In contrast to the widely applicable ligand-induced receptor dimerization paradigm, there is evidence that EGFR family members exist as preformed dimers (4) and form higher oligomer signaling complexes (5). Normal signaling in the EGFR system involves ligand-induced homo-oligomerization or hetero-oligomerization with the closely related RTKs ErbB2 (HER2), ErbB3 (HER3) and/or ErbB4 (HER4) (6). Autophosphorylation of key tyrosine residues within the carboxyl-terminal portion of the receptor provides sites for direct interaction with SH2-containing proteins, leading to subsequent signal transduction events.The EGFR system, including receptor homologues and relevant ligands, is complex. There are at least 12 different ligands that bind to the EGF receptor family with partially redundant specificity for certain receptors. Several of the ligands including EGF, transforming growth factor-␣, heparin-binding EGF, and betacellulin are reported to bind to EGFR with nanomolar dissociation constants (7). Betacellulin also binds ErbB4 with high affinity. Similarly, heregulin binds to ErbB3 or ErbB4 with dissociation constants in the nanomolar range. So ...

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mentioning

confidence: 99%

Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor

Stamos¹,

Sliwkowski

Eigenbrot³

2002

Journal of Biological Chemistry

1,264

1,037

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“…There are three possible chemopreventive mechanisms that involve DNA repair (70,71). The first is an increase in the overall level of DNA repair.…”

Section: Target Populationsmentioning

confidence: 99%

“…Calcium induces differentiation in a number of epithelial tissues, including mouse skin (101), rat esophagus (102), human colon (103), and human mammary gland (104,105 (70,71).…”

Section: Target Populationsmentioning

confidence: 99%

“…For example, agents such as the retinoids and PKC inhibitors, which affect activities at the cell membrane, cytoplasmic, and nuclear membrane levels, can also affect other connected events such as growth factor expression and polyamine metabolism (70,71 (117,118) showed that D-limonene, found in citrus oils, inhibits the progression of mammary tumors induced in rats by either MNU or DMBA. They also showed that D-limonene inhibits farnesylation of small G proteins; these data suggest that D-limonene prevents oncogene activation by inhibiting posttranslational farnesylation of the ras p21 protein (119).…”

Section: Target Populationsmentioning

confidence: 99%

“…Kelloff et al (70,71) have discussed other mechanisms by which suppressing agents might inhibit molecular and cellular events associated with the promotion/progression stages of carcinogenesis; e.g., restoration of tumor suppressor function, inhibition of angiogenesis, and activation of antimetastasis genes. Although these are logical targets for chemoprevention, at present there is little evidence to suggest that known chemopreventive agents act through these mechanisms.…”

Section: Target Populationsmentioning

confidence: 99%

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Perspectives in cancer chemoprevention.

Stoner

Morse

Kelloff

1997

Environ Health Perspect

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Cancer chemoprevention can be defined as prevention of cancer by the administration of one or more chemical entities, either as individual drugs or as naturally occurring constituents of the diet. Based largely on the time period that chemopreventive agents exhibit activity in animal models of carcinogenesis, they can be classified as inhibitors of carcinogen formation, blocking agents, and suppressing agents. The majority of compounds that inhibit the formation of carcinogens prevent the formation of nitrosamines from secondary amines and nitrite in an acidic environment. Blocking agents are inhibitors of tumor initiation, while suppressing agents are inhibitors of tumor promotion/progression. Many well-characterized chemopreventive agents act at one or more steps in both tumor initiation and promotion/progression. The objective of this paper is to provide a general discussion of the mechanisms through which chemopreventive agents inhibit carcinogenesis. Examples of agents that act through these mechanisms are given; however, a complete listing of effective chemopreventive agents is not possible within the context of this paper. At the conclusion is a brief discussion of future prospects in cancer chemoprevention and obstacles to overcome. Environ Health Perspect 1 05(Suppl 4): 945-954 (1997)

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High grade prostatic intraepithelial neoplasia in military working dogs with and without prostate cancer

et al. 1998

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BACKGROUND High grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of human prostate cancer and is commonly found in men undergoing prostatic needle biopsy for suspected cancer. Recent work has demonstrated that pet dogs, like humans, develop PIN spontaneously and in association with prostate cancer. Pet dogs are the most domesticated animal, sharing the habitat and oftentimes the diet of their owners. If PIN and prostate cancer are strongly related to environmental factors, then the prevalence of these findings might differ in a population of dogs such as military working dogs which is not exposed to the habitat and diet of humans. In this study, we determined the prevalence of PIN in prostates of aged military working dogs with and without prostatic adenocarcinoma. METHODS Cases were selected from the military working dog slide and tissue archive at the Armed Forces Institute of Pathology, Washington, DC. The most recent 329 necropsies (1991 to 1996) were examined histologically by multiple reviewers; of these, 199 dogs (60%) were found to have evaluable prostatic tissue. In addition, the most recent 50 necropsies (1958 to 1996) with the diagnosis of prostatic cancer were examined, of which 25 cases (50%) were found to have evaluable prostatic adenocarcinoma. In most cases, a single large transverse section of prostatic tissue was available for review. Medical records for each dog were reviewed independently, and age, clinical history, indications for euthanasia, and other health problems were recorded. RESULTS High grade PIN was identified in 3% of dogs (6 of 199 dogs) without prostate cancer. A total of 50.8% of dogs in this study group (101 of 199 dogs) were known to be sexually intact, 26.7% of dogs (53 of 199 dogs) were castrated, and the status of the remaining 22.6% of dogs (45 of 199 dogs) was unknown. High grade PIN was present in 18 of 25 dogs (72%) with prostatic adenocarcinoma. Of these cases, 11 dogs (44%) were castrated, 4 dogs (16%) were intact, and the status of 10 dogs (40%) dogs was unknown. Gleason scores ranged from 6 to 10, with a mean of 8.4 and a median of 8. CONCLUSIONS High grade PIN is present in a small but substantial number (3%) of military working dogs. Of military working dogs with prostatic adenocarcinoma, 72% had high grade PIN. The true prevalence in each of these cohorts is likely to be higher given the sampling variation inherent in evaluating a single random histologic section. Aged male dogs seem to have substantial clinical utility as an animal model for prostatic carcinogenesis. We recommend that serial sectioning and total embedding of the prostate should be used to more thoroughly characterize premalignant and malignant diseases in aged military working dogs. This method will provide important data to determine whether a model of spontaneous PIN in elderly dogs may have clinical utility in developing strategies directed toward preventing and treating prostate. Prostate 36:189–193, 1998. © 1998 Wiley‐Liss, Inc.

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Mechanistic considerations in chemopreventive drug development

Cited by 153 publications

References 186 publications

Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor

Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor

Perspectives in cancer chemoprevention.

High grade prostatic intraepithelial neoplasia in military working dogs with and without prostate cancer

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