Page 309 - Vitamin D and Cancer

296 M. Fakih et al.

decreased mortality from other cancers [1]. Peller attributed this reverse association
to a protective effect of skin cancer against the development of other cancers rather
than on the protective effects of sunlight [1]. In an attempt to confirm the correlation
between skin cancer and protection against non-skin cancers, Apperly studied skin
cancer mortality between 1934 and 1938 in the USA [2]. He noted a decreased risk
of skin cancer in States with mean annual temperatures < 42°F. His subsequent inves-
tigations confirmed an inverse association between solar radiation and general
cancer rates. Apperly attributed the solar protective effects to the induction of anti-
cancer immunity [2]. It was in 1980 that Garland and Garland first reported the link
between vitamin D deficiency, as a result of limited sun exposure, and an increased
risk of colorectal cancer [3]. Garland noted an increased rate of colorectal cancer in
states with low levels of solar radiation as well as in large cities where population
life style limits sunlight exposure [3]. Garland pointed to a parallel increase in the
risk of rickets and low vitamin D levels in low solar exposure areas and drew atten-
tion to a potential association between vitamin D levels and risk of colorectal cancer
[3]. Other supporting data for the protective role of sunlight come from Grant’s
ecological study on ultra violet (UV-B) light exposure and risk of cancer between
1950 and 1994 [4]. Higher exposure to UV-B protected against colorectal cancer in
both White and African Americans [4]. Grant estimated that more than 10% of the
deaths from colorectal cancer were premature and related to inadequate UV-B expo-
sure [4]. Case–control studies also strongly support an inverse association between
solar radiation and colon cancer. Freedman et al. conducted a death certificate based
case–control study of five different types of cancers including colon cancer [5].
Cases were identified as cancer deaths in 24 states in the USA between 1984 and
1995. Controls were frequency matched by 5-year age groups and excluded death
from cancer and other neurological illnesses linked with residential sunlight expo-
sure. The risk of colorectal cancer in the highest residential exposure areas was 0.73
(95% CI 0.71–0.74) suggesting a protective effect of sunlight exposure against
colorectal cancer mortality [5].

13.1.2 Vitamin D Status and Risk of Colorectal Neoplasia

13.1.2.1 Vitamin D Metabolism

The two universally accepted prerequisites for eliciting vitamin D antitumor
3
effects are the tissue expression of the vitamin D receptor (VDR) and adequate
supply of vitamin D . Current data suggest that response to vitamin D therapy is
3 3
highly dose dependent and exhibits substantial inter-patient variability. Furthermore,
the physiological range of serum vitamin D metabolite levels required for healthy
3
bones may be different from that required for cell growth inhibition, differentiation
and programmed cell death.
The biological basis for the variable vitamin D status in cancer patients could
3
stem from an inadequate supply of vitamin D precursors and inter-patient
3