Antiangiogenic treatment with linomide as chemoprevention for prostate, seminal vesicle, and breast carcinogenesis in rodents

Ingrid B J K Joseph, Jasminka Vukanovic, John Tod Isaacs

Research output: Contribution to journalArticle

Abstract

There are two distinct phases during prostatic carcinogenesis with regard to tumor blood vessel development. During the first or prevascular phase, which may persist for years, cells that have undergone some but not all of the transformation steps undergo a limited amount of net growth, producing premalignant prostatic intraepithelial neoplastic (PIN) lesions. Most of these PIN lesions do not continue net growth and do not progress to produce histologically detectable cancer. Even the PIN lesions that do progress to cancer remain of limited virulence unless they undergo conversion to the second or angiogenic phase. Once this angiogenic phase is reached, new blood vessel development is greatly enhanced within the cancer. It is this enhanced tumor angiogenesis which allows these cancers both to grow continuously and to metastasize. Thus, inhibition of angiogenesis should be an effective chemopreventive approach for prostatic carcinogenesis. Linomide is a low molecular weight, water-soluble agent with excellent p.o. absorption and bioavailability. We have previously demonstrated that daily p.o. treatment with Linomide has antiangiogenic abilities against a series of rat and human prostatic cancer xenografts growing in vivo. In the present studies, we have demonstrated using Matrigel in in vivo angiogenesis assays that daily p.o. Linomide at 25 mg/kg/day inhibits angiogenesis induced by tumor necrosis factor α, acidic fibroblast growth factor, basic fibroblast growth factor, and vascular endothelial growth factor. Using an N- methylnitrosourea initiation-androgen promotion model, Linomide was given p.o. at a daily dose as high as 25 mg/kg/day for at least 1 year without major toxicity while inhibiting the development of seminal vesicle/prostate cancers in male rats by >50%. Dose-response analysis demonstrated that a Linomide blood level of 50-100 μM is optimal for such chemoprevention. In addition, Linomide treatment at a dose of 25 mg/kg/day was able to inhibit by ≃60% the incidence of N-methylnitrosourea and ~50% of 7,12-dimethyl- benz(a)anthracine-induced mammary carcinogenesis in female rats.

Original languageEnglish (US)
Pages (from-to)3404-3408
Number of pages5
JournalCancer Research
Volume56
Issue number15
StatePublished - Aug 1 1996

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Seminal Vesicles
Chemoprevention
Prostate
Rodentia
Carcinogenesis
Breast
Methylnitrosourea
Neoplasms
Prostatic Neoplasms
Therapeutics
Vascular Tissue Neoplasms
Fibroblast Growth Factor 1
Fibroblast Growth Factor 2
Growth
Heterografts
Vascular Endothelial Growth Factor A
Biological Availability
Androgens
Blood Vessels
Virulence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Antiangiogenic treatment with linomide as chemoprevention for prostate, seminal vesicle, and breast carcinogenesis in rodents. / Joseph, Ingrid B J K; Vukanovic, Jasminka; Isaacs, John Tod.

In: Cancer Research, Vol. 56, No. 15, 01.08.1996, p. 3404-3408.

Research output: Contribution to journalArticle

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abstract = "There are two distinct phases during prostatic carcinogenesis with regard to tumor blood vessel development. During the first or prevascular phase, which may persist for years, cells that have undergone some but not all of the transformation steps undergo a limited amount of net growth, producing premalignant prostatic intraepithelial neoplastic (PIN) lesions. Most of these PIN lesions do not continue net growth and do not progress to produce histologically detectable cancer. Even the PIN lesions that do progress to cancer remain of limited virulence unless they undergo conversion to the second or angiogenic phase. Once this angiogenic phase is reached, new blood vessel development is greatly enhanced within the cancer. It is this enhanced tumor angiogenesis which allows these cancers both to grow continuously and to metastasize. Thus, inhibition of angiogenesis should be an effective chemopreventive approach for prostatic carcinogenesis. Linomide is a low molecular weight, water-soluble agent with excellent p.o. absorption and bioavailability. We have previously demonstrated that daily p.o. treatment with Linomide has antiangiogenic abilities against a series of rat and human prostatic cancer xenografts growing in vivo. In the present studies, we have demonstrated using Matrigel in in vivo angiogenesis assays that daily p.o. Linomide at 25 mg/kg/day inhibits angiogenesis induced by tumor necrosis factor α, acidic fibroblast growth factor, basic fibroblast growth factor, and vascular endothelial growth factor. Using an N- methylnitrosourea initiation-androgen promotion model, Linomide was given p.o. at a daily dose as high as 25 mg/kg/day for at least 1 year without major toxicity while inhibiting the development of seminal vesicle/prostate cancers in male rats by >50{\%}. Dose-response analysis demonstrated that a Linomide blood level of 50-100 μM is optimal for such chemoprevention. In addition, Linomide treatment at a dose of 25 mg/kg/day was able to inhibit by ≃60{\%} the incidence of N-methylnitrosourea and ~50{\%} of 7,12-dimethyl- benz(a)anthracine-induced mammary carcinogenesis in female rats.",
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