ACROLEIN AND URINARY BLADDER CARCINOGENESIS

Project: Research project

Description

Cigarette smoking has been identified as a major etiologic factor for
urinary bladder cancer in the United States and is estimated to account for
approximately 50% of all cases. Although several carcinogens,
co-carcinogens, and promoters have been identified in cigarette smoke,
which of these are relevant to the development of human bladder cancer is
unknown. Acrolein is present in relatively large quantities in cigarette
smoke (10-140 Mug/cigarette) and is also an economically important
intermediate in the chemical industry, where process workers often have an
increased incidence of bladder cancer. Cyclophosphamide, a
chemotherapeutic alkylating agent used in the treatment of neoplastic and
autoimmune diseases, has as a side-effect the induction of hemorrhagic
cystitis and eventually carcinoma of the bladder. Data from human and
animal studies have identified acrolein (a metabolite of cyclophosphamide)
as the agent responsible for the hemorrhagic and the carcinogenic effects
of cyclophosphamide on the bladder. We propose to investigate the
interactions of acrolein on the bladder epithelium in vitro and in vivo.
Short-term assays will be performed utilizing scanning electron microscopy
and autoradiography to determine a dose response for the effects on
acrolein on urothelial cytotoxicity and consequent regenerative
proliferation. Based on the short-term studies, long-term bioassays will
be performed evaluating the possible carcinogenic, initiating, and
promoting activity of acrolein for the bladder. To develop an understanding of the molecular events which underlie such
changes in morphology, extensive biochemical investigations are also
proposed. Acrolein will be reacted with deoxynucleotides in vitro and the
products identified. These will be used for the qualitative and
quantitative determination of adducts after reaction of acrolein with DNA
in vitro and after exposure of cultured cells to acrolein. Ultimately,
these studies will be extended to the detection and quantitation of adducts
formed in the bladder epithelium of the rat following acrolein
administration. The miscoding potential of acrolein adducts in DNA will
also be evaluated. In addition, the amounts of acrolein in biological
fluids, particularly urine, will be determined by methods that will be
developed. Ultimately, these analytical procedures should be useful for
examination on humans exposed to acrolein.
StatusFinished
Effective start/end date5/1/874/30/92

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $138,148.00
  • National Institutes of Health

Fingerprint

Acrolein
Carcinogenesis
Urinary Bladder
Urinary Bladder Neoplasms
Cyclophosphamide
Tobacco Products
Carcinogens
Epithelium
Chemical Phenomena
Chemical Industry
DNA Adducts
Alkylating Agents
Human Development
Autoradiography
Smoke
Biological Assay
Cultured Cells
Smoking
Urine
Electrons

ASJC

  • Medicine(all)