The human hepatic tumor cells (Bel-7204) with different concentrations of 5-Fu-PAEAPM (the content of polymeric drug (wt%): 5-Fu 25.6, PM 3.3) in the growth medium in

culture were incubated for 24h in incubator (37℃, 5% CO2). Induction of apoptosis was

confirmed by formation of apoptotic bodies and fragmentation of cellular DNA (Figure 16).

5-Fu-PAEA-PM at 18µg/ml, 36µg/ml, 62.5µg/ml and 135µg/ml concentration induced

apoptosis in about 27.6%, 43.1%, 50.7% and 62%, respectively, of human hepatic tumor cells

168 Guo-Ping Yan, Xiao-Yan Wang, Li-Li Mei

after 48h incubation. When the concentration of 5-Fu-PAEA-PM (3) increased, the

percentage of apoptosis in the human hepatic tumor cells became considerably larger. The

apoptosis experiments showed the polymeric drugs could exhibit obviously high anticancer

efficiencies and induce apoptosis in the human hepatic tumor cells (Bel-7204).

0 200 400 600 800

30

40

50

60

70

80

90

100

Viability Relative to Control (%)

Concentration (¦Ì g/mL)

 5-Fu-PAEA-PM (3)

 FT-207

Figure 15. Cytotoxicity assay of anticancer drugs in L-02 cells.

 A B

Figure 16. Induced apoptosis photo of 5-Fu-PAEA-PM in the human hepatic tumor cells. A: control

cells; B: 5-Fu-PAEA-PM (the content of polymeric drug (wt%): 5-Fu 25.6, PM 3.3) (135µg/mL).

SUMMARY

Although the liver-targeting mechanism and kinetic procedure of vitamin B6 for MRI

contrast agent and drug delivery have not described detailedly, previous researches have

demonstrated that the incorporation of pyridoxine into MRI contrast agent and anticancer

conjugates can increase their uptake by the liver, and that these molecules containing

Vitamin B6 as Liver-targeting Group in Drug Delivery 169

pyridoxine groups exhibit liver-targeting properties. Thus it is important to come to devote

greater efforts to solving these problems.

One important approach in drug design for the disease in the liver is that the drugs can be

targeted to the liver. By this method, the toxic side effects of the drugs can be suppressed and

the distribution of drugs will be changed after administered, to improve the efficiency toward

malignant cells and reduce the drugs dose. In future, the ideal drugs will be focused on the

liver-targeting property with low toxicity and side effect, low doses in vivo, and minimal cost

of procedure.

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In: Vitamin B: New Research ISBN: 978-1-60021-782-1

Editor: C. M. Elliot, pp. 175-191 © 2008 Nova Science Publishers, Inc.

Chapter X

THE ROLE AND STATUS OF VITAMIN B12:

NEED FOR CLINICAL

REEVALUATION AND CHANGE

Ilia Volkov∗ , Inna Rudoy and Yan Press

Department of Family Medicine, Faculty of Health Sciences, Ben-Gurion University of

the Negev, Beer-Sheva, Israel.

ABSTRACT

Vitamin B12 plays a functional role in a variety of organs and body systems and the

list of these organs and body systems is growing. It affects the peripheral and central

nervous systems, bone marrow, skin and mucous membranes, bones, and vessels, as well

as the normal development of children. Vitamin B12 (cobalamin) is unique among all the

vitamins in that it contains not only a complex organic molecule but also an essential

trace element, cobalt. Vitamin B12 plays an important role in DNA synthesis and has

important immunomodulatory and neurotrophic effects. According to our “working

hypothesis” a vitamin B12 has some unique, but still unrecognized functions.

Multifunctional systems in the human body need to maintain homeostasis. Man is an

ideal example of a system that constantly aspires to attain optimal regulation, even under

the stress of severe pathology. We assume that there are universal, interchangeable (as

required) propose that one of these substances is vitamin B12.Why vitamin B12? It is

possible that even when the serum cobalamin level is normal, treatment with vitamin B12

can correct defects caused by other biologically active substances. In our studies this has

been proved successful in the treatment of recurrent aphthous stomatitis with vitamin B12

(irrespective of its blood level!). We call this phenomenon the “Master Key” effect.

Vitamin B12 deficiency is a common problem that affects the general population.

Early detection of vitamin B12 deficiency is clinically important, and there is evidence

∗

 Correspondence concerning this article should be addressed to Dr. Ilia Volkov, Lea Imenu St. 59/2, Beer-Sheva,

84514, Israel. Tel: 972-8-6431530; Cell phone: 972-54-7829623; Fax: 972-8-6413135; E-mail:

r0019@zahav.net.il.

176 Ilia Volkov, Inna Rudoy and Yan Press

that such deficiency occurs more frequently than would be expected. Vitamin B12

deficiency can occur in individuals with dietary patterns that exclude animal foods and

patients who are unable to absorb vitamin B12 in food. In addition there is an overall

tendency to avoid eating those foods which are high in Vitamin B12, such as beef,

because of the relationship between meat, cholesterol and cardiovascular diseases. Also

there is a tendency, particularly among the younger generation, to be vegetarians for

ideological motives. Changes in life style among segments of the population with high

socioeconomic level, on one hand, and the existence of poverty, on the other, are two

main factors in the decreasing consumption of animal products, particularly red meat.

Thus, there is a decrease in the level of vitamin B12 in general population, and as a

consequence, an increase in pathology due to vitamin B12 deficiency (such as

neurological and hematological disorders). If future research will corroborate the

relationship between vitamin B12 and homocystein, we may observe an increase in

cardiovascular disease as well. In lieu of these developments and in order to prevent

serious health problems, vitamin B12 fortification should be seriously considered and

discussed.

BACKGROUND

Vitamin B12 plays a functional role in a variety of organs and body systems and the list of

these organs and body systems is growing. It affects the peripheral and central nervous

systems, bone marrow, skin and mucous membranes, bones, and vessels, as well as the

normal development of children. Vitamin B12 (cobalamin) is unique among all the vitamins

in that it contains not only a complex organic molecule but also an essential trace element,

cobalt. Vitamin B12 plays an important role in DNA synthesis and has important

immunomodulatory and neurotrophic effects. According to our “working hypothesis” a

vitamin B12 has some unique, but still unrecognized functions.

Multifunctional systems in the human body need to maintain homeostasis. Man is an

ideal example of a system that constantly aspires to attain optimal regulation, even under the

stress of severe pathology. We assume that there are universal, interchangeable (as required)

propose that one of these substances is vitamin B12.Why vitamin B12? It is possible that even

when the serum cobalamin level is normal, treatment with vitamin B12 can correct defects

caused by other biologically active substances. In our studies this has been proved successful

in the treatment of recurrent aphthous stomatitis with vitamin B12 (irrespective of its blood

level!). We call this phenomenon the “Master Key” effect [1].

Vitamin B12 deficiency is a common problem. Early detection of vitamin B12 deficiency

is essential in order to prescribe opportune treatment, and there is evidence that such

deficiency occurs more frequently than would be expected. Vitamin B12 deficiency can occur

in individuals with dietary patterns that exclude animal food products and patients who are

unable to absorb vitamin B12. Persons with B12 deficiency may be asymptomatic, but in

patients presenting with myelopathy, cognitive decline, neuropathy, psychiatric disturbances

or specific hematological signs and symptoms, B12 deficiency should be suspected. There are

no generally accepted guidelines for the definition, diagnosis, treatment, and follow-up of

cobalamin deficiency. Total serum vitamin B12 may not reliably indicate vitamin B12 status.

Probability of "functional" vitamin B12 deficiency decreases upon increasing the blood level

The Role and Status of Vitamin B12: Need for Clinical Reevaluation and Change 177

of vitamin B12. To increase specifity and sensitivity in diagnosing vitamin B12 deficiency, the

concept of measuring homocystein (HCY), methylmalonic acid (MMA), holotranscobalamin

II (holoTC),- a sub-fraction of vitamin B12, has aroused great interest. HoloTC, as a

biologically active vitamin B12 fraction, promotes uptake of its vitamin B12 by all cells [2].

However, diagnostic algorithms using vitamin B12, MMA, and HCY measurements reflect

studies in some academic centers, and their negative predictive values have not been

established. Therefore, this problem remains controversial [3].

We will attempt to demonstrate vitamin B12 critical roles by surveying and analyzing

available reports, as well as reporting our own clinical experience.