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Nitrosamines have been suspected in the etiology of esophageal/gastric cardia
cancer in the high incidence area of Linxian of the Henan Province in northern
China, but marginal deficiencies in riboflavin, vitamins A and C, and other
micronutrients may also be involved. A joint U.S.-China nutritional intervention
study with investigators from the Cancer Institute of the Chinese Academy of
Medical Sciences and the U.S. National Cancer Institute tested the effects of
the following four combinations of nutrients on 29,584 subjects in an
eight-group design: 1) retinol and zinc; 2) riboflavin and niacin; 3) vitamin C
and molybdenum; and 4) vitamin E, beta-carotene and selenium. Supplementation with Group 4 nutrients significantly decreased mortality rate from stomach cancer, primarily due to the decrease in deaths resulting from adenocarcinomas of the gastric cardia; it lowered the total mortality rate and showed signs of other beneficial effects. Another study of nutrition and gastric cancer in a high incidence area of Linqu of the Shangdong province in northern China (in collaboration with the Beijing Institute for Cancer Research and the U. S. National Institutes of Health) found significantly lower serum concentrations of vitamin C and beta-carotene among individuals with intestinal metaplasia; an
intervention trial with vitamins C and E and selenium (combined) is ongoing in
Linqu. Other studies are also elucidating the mechanisms for the pathogenesis of adenocarcinoma at the gastroesophageal junction with the use of a rat model.
Such studies are expected to shed light on the etiology and prevention of
gastroesophageal cancers in humans.

Reactive oxygen species (ROS), represented by superoxide, hydrogen peroxide and hydroxyl radicals, have been implicated in many diseases including cancer. ROS have been known to play an important role in the initiation and promotion of multistep carcinogenesis. The cellular antioxidants play a crucial role in
protection against neoplastic disease. However, very little is known about the
antioxidant defense in cervical carcinoma. This is addressed in the present
study. Lipid peroxides, glutathione content and the activities of antioxidant
enzymes, together with vitamin C and E content, were estimated in patients who
had carcinoma of the cervix, and the values were compared with those of normal women. The results showed a remarkable reduction in the content of glutathione, vitamin E and C. Activities of glutathione peroxidase and superoxide dismutase were also reduced in cervical cancer compared to normal controls (P < 0.001). This reduction was more marked in late stages (III, IV) than in early stages (I, II) (P < 0.001). Glutathione was reduced more in poorly differentiated tumors (grade III) than in well and moderately differentiated ones (grade I, II) (P < 0.05). Levels of lipid peroxides were found to be significantly higher in
malignant than in normal tissue samples and their levels were correlated with
advanced clinical stage (P < 0.001). Our results suggest impaired antioxidant
status in carcinoma of the cervix. This impairment is related to tumor
progression.

Treatment of human tongue squamous carcinoma cell, SCC-25, with physiological concentrations of vitamin E succinate (VES) which varied from 0.001 to 50 mumoles/L resulted in significant dose-dependent stimulation of cell growth. Whereas, pharmacological doses of the vitamin (100-154 microM) induced significant inhibition in cell growth. The possible anticarcinogenic mechanisms of action of vitamin E are discussed.

An increasing number of reports suggest that diet has an impact on oesophageal cancer risk in Western countries, where alcohol and tobacco are held to be the major determinants of the risk. The aim of our study was to identify dietary factors influencing the risk of oesophageal cancer in France and to determine whether certain of these could explain some of the geographical variations. We conducted a multicentre case-control study in 3 regions expected to have different diet and drinking habits (Normandy, Burgundy and Midi Pyrenees). Two hundred eight cases and 399 controls, all males, were interviewed about their eating, drinking and smoking habits. After proper adjustment for drinking and smoking, high consumption of butter and low consumption of fresh fish, vegetables and fruits were associated strongly and independently with an increase in oesophageal-cancer risk. Consistently, cholesterol appeared as a risk factor and vitamin E, vitamin D and phosphorus as independent protective factors. The protective effect of citrus and other fresh fruits (vitamin C) was confined strictly to heavy drinkers. Our findings suggest that more than one-third of the high incidence of oesophageal cancer in northwest France could be explained by the local excess in butter consumption, whereas geographical variations in consumption of dietary protective factors could explain no more than 10% of it. Overall, a large proportion (57%) of the excess incidence of oesophageal cancer in northwest France could be explained by local dietary habits, e.g., drinking hot Calvados liquor and excessive consumption of butter.

Second primary cancers often occur in head and neck cancer patients successfully treated by radiation therapy. Experimental and epidemiological data suggest that these second primaries might be prevented by antioxidant vitamins, in particular beta-carotene and alpha-tocopherol. A randomized double-blind clinical trial is being conducted in Canada to determine whether vitamin supplementation with beta-carotene (30 mg/d) and alpha-tocopherol (400 IU/d) reduces the incidence of second primaries in head and neck cancer patients treated by radiation therapy.

Previous studies have shown that prostaglandin E2 (PGE2) and vitamin E succinate can act in an additive manner to inhibit the proliferation of human oral
squamous carcinoma cells (SCC-25). The initial studies on the additive
anticancer activity of PGE2 and vitamin E succinate have been extended to
include antineoplastic PGs, delta 12-PGJ2 and PGJ2. Treatment of oral squamous carcinoma cells (SCC-15) with delta 12-PGJ2, PGJ2, and vitamin E succinate, individually, caused significant concentration-dependent inhibition of cell proliferation to various degrees. PGJ2 was most potent and caused an inhibition that corresponded to 85.55% at 10(-5) M. Addition of 1 microM of vitamin E succinate to delta 12-PGJ2 or PGJ2 resulted in a significant increase in the inhibitory potency of the lower concentrations of the two PGs. These results suggest a novel role for a mixture of PGs and vitamin E as potent antitumor proliferative agents.

BACKGROUND: Radiation fibrosis represents a severe complication of radiation
therapy; standardized treatment protocols are lacking so far. Surgical excision
rarely results in complete healing. PATIENT AND METHODS: We report on a
58-year-old female patient who developed a squamous cell carcinoma within the
fibrotic area of the irradiation field on the right chest, resulting from a
radiotherapy following mastectomy for breast cancer 17 years ago. After surgical
excision of the carcinoma a combined treatment with pentoxifylline tablets (3 x
400 mg/d p.o.) and vitamin-E capsules (1 x 400 mg/d p.o.) was initiated. Skin
thickness was quantified by 20 MHz-ultrasound before and during treatment.
RESULTS: The patient noted an increasing improvement of the condition of the
affected skin starting from 4 months. A continuing decrease of skin thickness as
documented by 20 MHz-ultrasound could be demonstrated from the 6th month on. The treatment was tolerated well, no side effects were observed. CONCLUSION: The data indicate a beneficial therapeutic effect of pentoxifylline and vitamin E on radiation-induced fibrosis. Little is known about the mechanism of action of this combined treatment protocol including pentoxifylline and vitamin E. Controlled clinical trials should be performed to confirm this observation.

Epidermoid carcinomas were induced in hamster buccal pouches with use of 7.12 dimethylbenz[a]anthracene (DMBA). In five animals that served as tumor controls (Group 1), right buccal pouches were painted with DMBA (0.5% solution in mineral oil) thrice weekly for 14 weeks. In five animals (Group 2), right buccal pouches were painted with DMBA and reduced glutathione (GSH) was administered systemically by mouth. Five animals (Group 3) received vitamin E instead of glutathione. An additional 20 animals (Groups 4, 5, 6, and 7) were untreated, vehicle, glutathione, and vitamin E controls, respectively. Glutathione and vitamin E were given in doses of 10 mg/kg in 0.5 ml of mineral oil thrice weekly on days alternate to DMBA painting. Treatment by GSH and vitamin E reduced the number and size of tumors that were formed. Histopathologically, there were also fewer sites of dysplasia, carcinoma in situ, and early invasive epidermoid carcinoma than in the tumor control animals. The formalin-fixed and
paraffin-embedded buccal pouch sections were stained immunohistochemically with use of monoclonal antibodies for cytokeratins. These included
high-molecular-weight keratins (50,000-68,000 mol wt) 10, 13, and 8 (k10, k13,
and k8, respectively). Oral carcinomas and dysplastic sites exhibited basal and
suprabasal (spinous layer) high levels of k10, k13, and k8 staining. Treatment
with GSH or vitamin E increased the suprabasal staining for
high-molecular-weight keratins and reduced the protein expression for k10, k13,
or k8. This pattern of staining was observed in dysplastic as well as in
carcinoma sites. These results indicate that cytokeratin protein expression
could contribute to a common biomarker analysis for chemoprevention.

The primary objective of this investigation was to study the effect of
D-alpha-tocopherol acid succinate (vitamin E succinate) and prostaglandin E2
(PGE2), individually and in combination, on the proliferation of human tongue
squamous carcinoma cells (SCC-25) in vitro. Test compounds in varying
concentrations were incubated with cells in serum-free Dulbecco's Modified
Eagle's Medium-Ham's F-12 Medium (50:50), supplemented with 0.1% albumin for sixteen hours. Cell proliferation was measured by the incorporation of [3H]
thymidine in acid-insoluble material (i.e. DNA). Prostaglandin E2 and vitamin E
succinate, individually at 10(-9)-10(-6) M, caused significant dose-dependent
inhibition in DNA synthesis. A combined dose of each compound at 10(-5) M
resulted in significant additive inhibition which averaged 43.53% (p < 0.005).
Addition of indomethacin (INDO) to cell cultures induced significant
dose-dependent stimulation in DNA synthesis. Hence, we might suggest that the
overall potential of vitamin E in controlling malignant cell proliferation in
vivo could be due to its own effect combined with that of endogenous PGs which
are normally produced in excessive amounts by malignant cells.

The antioxidant alpha-tocopherol and the weaker antioxidant and prooxidant
chemopreventative, beta-carotene have been shown to inhibit tumor cell growth in vivo and in vitro. In some epidemiologic studies their serum levels were
demonstrated to be inversely related to the incidence of malignant tumor. We
hypothesized two basic pathways triggered by antioxidants and prooxidants, which resulted in the control of tumor cell growth. These included changes in
phosphorylation and ultimately transcription. Specifically, the prooxidant
beta-carotene treatment produced an oxidative stress resulting in the selective
induction of heat shock proteins (hsps). These proteins and other proteins that
were possibly oxidized were associated with the increased expression of cyclins
(A and D) and increased cdc2 kinase expression. An increase in expression of
phosphoproteins, such as p53 (tumor suppressor form) was also discerned. The
level of expression for the transcription factor c-fos was reduced. Growth
factors that contribute to tumor cell growth were also reduced. Increased DNA
fragmentation, depression of proliferation and intracellular calcium levels, the
accumulation of tumor cells in G0-->G1, and morphologic changes, were consistent with programmed cell death. Antioxidants such as alpha-tocopherol bound to membrane-associated proteins could inhibit the development of peroxidation products (hydroxyl radicals (.OH)), which attack proteins and modify their function and promote their degradation. Some kinases such as, cdc2 may be increased in activity, which would explain the observed increased expression of tumor suppressor p53, the accumulation of the tumor cells in G1 of the cell cycle and the inhibition of tumor cell proliferation. A reduction in oxidant radicals could also reduce transcription factor products, such as c-myb.
Indirectly this result may occur through changes in nuclear translocation
(signaling) NF-AT or the Rel-related family of transcription factors, including
NF-kB (p50 or p65) or inhibition of immunophilin-calmodulin activity. Although
the data remains fragmentary there are common points for control for tumor cell
growth resulting from the effects of alpha-tocopherol or beta-carotene
treatment. These changes involve phosphorylation and protein expression.
Ultimately there is a reduction of important transcription factor protein
products, a reduction in response to growth factors, and suppression of cell
proliferation, resulting in increased control of the cell cycle.