[MOL] Some important info. for our mol friends! [02725] Medicine On Line


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[MOL] Some important info. for our mol friends!



Vitamins: Tretinoin for Promyelocytic Leukemia

The natural and synthetic derivatives of vitamin A -- the retinoids -- are
involved in a number of vital physiologic processes, including vision, cell
differentiation and proliferation, and embryonic development. Each cell
type appears to manufacture its own pool of retinoids, and these interact
with retinoic acid receptors in the cell nucleus to modulate gene
transcription. Two large families of nuclear retinoic acid receptors have
been described and are part of the steroid- thyroid-retinoid receptor
super-family. Because they can stimulate cell differentiation, retinoids
have been clinically investigated in a number of premalignant and malignant
conditions and have proved active in cutaneous T- cell lymphomas,
leukoplakia, and some skin cancers. 

All-trans-retinoic acid is a natural vitamin A metabolite formed by
enterocytes from beta-carotene and from tissue metabolism of retinol and
retinaldehyde. Topical all-trans-retinoic acid (tretinoin, Retin-A/Ortho
Pharmaceuticals) has attracted attention because it improves the appearance
of photoaged skin. All- trans-retinoic acid has also attracted attention
because it induces remission in patients with acute promyelocytic leukemia
(APL). About 10% of the acute myeloblastic leukemias in adults are
promyelocytic. Patients often present with a bleeding diathesis that is
exacerbated by cytotoxic chemotherapy. Early mortality rates are high (8%
to 47%) and are related to the extent of leukocytosis, thrombocytopenia,
and hypofibrinogenemia. Conventional chemotherapy involves the use of an
anthracycline combined with cytarabine. Complete remission occurs in 60% to
80% of patients; five-year survival ranges from 35% to 45%. 

In the mid-1970s, researchers found that patients with APL show a
consistent chromosomal abnormality, an exchange of information between
chromosomes 15 and 17. It wasn't until the late 1980s that the transposed
material on chromosome 17 was found to contain the gene for the retinoic
acid receptor. For this reason, researchers began the clinical
investigation of all-trans-retinoic acid for the treatment of APL. They
found that all-trans-retinoic acid in a dose of 45 mg/m2 per day (given
once daily or in two equally divided doses) appears to induce promyelocytes
to differentiate into mature granulocytes. By 1993, 1500 or so patients
with a clinical diagnosis of APL had been treated worldwide with all-
trans-retinoic acid. The initial rate of response was 95% in patients shown
by cytogenetic or molecular analysis to have the 15:17 translocation, and
clinical effectiveness correlated with in vitro response. Median time to
achieve remission was 38 to 44 days. 

All-trans-retinoic acid is highly effective for inducing remission, but it
does not seem to maintain remission. Still, follow-up with standard
chemotherapy results in remission at least as long as and probably longer
than with conventional chemotherapy alone. All-trans-retinoic acid therapy
is considerably safer than most other regimens. Side effects include
headaches, dermatol-ogic problems, xerostomia, and cheilitis. According to
Memorial Sloan-Kettering oncologist RP Warrell, "Perhaps the most important
advance in this field is not the specific actions of all-trans-retinoic
acid in acute promyelocytic leukemia, but rather the conclusive
documentation of differentiation as a practical and consistently effective
method of treating human cancer... Just as the practical usefulness of
all-trans-retinoic acid in combination with conventional treatments
continues to evolve, the use of differentiation agents in combination
represents a novel and promising approach for oncologic therapy in the next
decade." (Warrell RP et al. N Engl J Med. 1993; 329: 177-189. Kurzrock R et
al. J Clin Oncol. 1993; 11: 1489- 1495.) 

Antibiotics: Amoxicillin/Metronidazole for Gastric Cancer

It is widely documented that the bacterium Helicobacter pylori causes both
gastric and duodenal ulcers and is a contributing factor in gastric
carcinoma. Nevertheless, ulcers are still treated with antacids and
antisecretory agents rather than antibiotics, and many patients still
believe their ulcers are caused by stress and anchovy pizza. According to
Lancet editorialist CS Goodwin, "Many doctors continue to claim that these
bacteria are irrelevant, even in duodenal and gastric ulcer, blithely
ignoring the hundreds of papers (980 during 1992 alone) indicating its
importance, particularly in peptic ulcer." What about its importance in
gastric cancer? "H. pylori does not shout at us," said Goodwin, who asks,
"Do we hear a whisper that some gastric cancer can be prevented by
antibiotic treatment?" Can some gastric cancer can actually be reversed
with antibiotics? 

Peptic ulceration occurs when acid/peptic attack overcomes a gastric mucosa
weakened by chronic gastritis associated with long-standing H. pylori
infection. Chronic infection causes inflammation and increased acid
secretion, and eventually atrophic gastritis, gastric metaplasia, and
achlorhydria. Achlorhydria and low luminal concentrations of ascorbic acid
promote gastric colonization by other pathogenic bacteria. Duodenal
ulceration is similar to peptic ulceration in that ulcers occur where the
mucosa has been damaged by chronic infection and inflammation. H. pylori
does not colonize the normal duodenal epithe-lium but resides in areas of
gastric metaplasia within the duodenum. Chronic inflammation of these areas
compromises the duodenal mucosa, and excess acid reaching the duodenum
causes further damage. (Dixon M. Lancet. 1993; 342: 384- 385.) 

Not all patients infected with H. pylori have duodenal ulcers, but those
who do show increased gastrin release and an exaggerated acid secretion in
response to gastrin stimulation. In one study, H. pylori-positive duodenal
ulcer patients showed a 6-fold increase in gastrin-stimulated acid
secretion compared with H. pylori-negative subjects, and eradication of the
organism resulted in a 66% reduction in gastrin-mediated acid secretion 1
month after treatment. (El-Omar E et al. Gut. 1993; 34: 1060-1065.) Moss
and Calam also showed that eradication of H. pylori significantly decreases
basal acid secretion in duodenal ulcer patients, thus healing the ulcers.
(Moss SF, Calam J. Gut. 1993; 34: 888-892.) 

What about gastric cancer? In their evaluation of data from 13 countries,
the Eurogast Study Group found a close association between high gastric
cancer rates and H. pylori infection. This was expected since gastric
carcinoma is commonly preceded by atrophic gastritis and intestinal
metaplasia, which are caused by H. pylori. On the cellular level,
persistent H. pylori infection and inflammation induce cell proliferation
(possibly by increased production of epidermal growth factor) and damage
DNA, which can lead to activation of oncogenes or inactivation of tumor
suppressor genes. Low intakes of fruits and vege-tables and a high-salt
diet are proposed co-factors for gastric carcinoma, although study results
are inconsistent. Overcrowding living conditions are highly associated with
H. pylori infection, and inadequate housing is associated with gastric
cancer. 

Since survival rates are lower after diagnosis of gastric cancer than for
other common cancers, methods of detection and treatment are needed.
Detection is a problem, since gastric cancer is often silent. Studies have
shown that up to 70% of patients do not have dyspepsia until late in the
course of the disease. Treatment is also a problem, since antibiotic
therapy induces antibiotic resistance. Even so, attempts to eradicate H.
pylori may still be the best protective measure against gastric carcinoma.
Studies have shown that H. pylori infection can be cleared with a 2-week
course of tetracycline plus metronidazole and bismuth, or alternately with
amoxicillin plus omeprazole or amoxicillin plus ranitidine plus
metronidazole. 

Clearance of H. pylori infection may be useful not only for preventing
cancer, but also for treating certain malignancies. Several investigators
have reported that clearance of H. pylori is accompanied by tumor
regression in a specific type of gastric B-cell lymphoma, referred to as
gastric MALT lymphoma. The acquisition of lymphoid tissue resembling
intestinal tissue (mucosa-associated lymphoid tissue or MALT) precedes the
onset of B-cell lymphomas of the MALT type. The normal stomach contains no
MALT; acquisition of this tissue is a result of chronic infection of the
mucosa with H. pylori, indeed, this organism is present in more than 90% of
gastric MALT lymphomas. Apparently the organism stimulates the production
of oncogenic products by T-cells. Co-culture of H. pylori and cells from
MALT lymphomas resulted in the proliferation of neoplastic B-cells and
non-neoplastic T-cells, with different strains of H. pylori capable of
different stimulatory effects. Removal of the T-cells reduced this
proliferation. (Hussell T et al. Lancet. 1993; 342: 571-574.) 

To investigate whether eradication of H. pylori could influence tumor
growth, Wotherspoon et al treated six patients with primary gastric B-cell
MALT lymphoma with antibiotics (ampicillin with metronidazole and a bismuth
compound, or ampicillin with omeprazole). Clearing the infection caused
tumor regression in five of the six patients. Follow-up biopsies showed
eradication of H. pylori in all six, with no morphological or molecular
evidence of lymphoma in five of the patients and only a residual infiltrate
in the sixth. Stolte and Eidt also administered antibiotics to patients
with suspected low-grade MALT lymphomas. After 10 to 14 days of amoxicillin
plus omeprazole, lymphatic aggregates regressed in 19 of 32 patients. In 12
patients with confirmed low- grade MALT lymphomas, tumors regressed when H.
pylori was eradicated. "Compared with surgery or chemotherapy, antibiotic
treatment of H. pylori is harmless and inexpensive," said Wotherspoon et
al. "There is no urgency for radical treatment, and anti-H. pylori
treatment should, therefore, be the first line of treatment." (Wotherspoon
AC et al. Lancet. 1993; 324: 575-577. Stolte M, Eidt S. Lancet. 1993; 342:
568.) 



Dietary Modification: The Role of Red Meat in Prostate Cancer

In the United States, prostate cancer is the second leading cause of cancer
mortality, after lung cancer. Approximately 122,000 American men had new
diagnoses of prostate cancer in 1991, and 32,000 died of the disease.
Worldwide, prostate cancer is a common occurrence, with 15% to 30% of men
over the age of 50 showing histologic evidence of this malignancy.
Cross-cultural and migrant studies have shown differences in dietary fat
intake between high- and low-risk areas, which may explain why latent
cancers found at autopsy show a similar frequency worldwide, while the
incidence of clinically evident cancers is higher in western Europe,
Canada, and the United States, where dietary fat intake is higher. Because
American men obtain approximately 36% of daily calories from dietary fat,
Giovannucci et al. decided to study the effects of dietary fat intake on
the risk of prostate cancer. They used data from the on-going Health
Professionals Follow-Up Study, which had 51,529 participants aged 40 to 75
when the study began in 1986. Questionnaires were evaluable from 47,855 of
these participants; 300 had been diagnosed with prostate cancer during the
study period (1988-1990), and 126 had advanced cases. 

The investigators found the higher the intake of dietary fat, especially
fat from red meat, the greater the risk of advanced pros-tate cancer. This
association was not valid for early prostate cancer. Men with the highest
fat intake had a 79% higher risk of advanced prostate cancer than men with
the lowest intake, and red meat (beef, pork, and lamb) was associated with
a 164% increased risk in the high-intake group compared with the
lowest-intake group. Fats from fish and dairy products (except butter) and
from vegetables were not related to the risk of advanced prostate cancer.
Ingestion of chicken with skin was assoc-iated with an elevated risk, but
ingestion of chicken without skin was inversely associated with risk.
Advanced prostate can-cer was associated with various fatty acids --
saturated and monounsaturated fatty acids and alpha-linolenic acid (but not
linoleic acid) -- but when these fatty acids were controlled for each
other, only the association with alpha-linolenic acid persisted. 

The association between the risk of advanced prostate cancer and
consumption of red meat and alpha-linolenic acid persisted after
adjustments for age, energy intake, body mass index, physical activity,
geographic residence, ancestry, marital status, vasectomy status, and
dietary intake of other nutrients (long-chain omega-3 fatty acids,
trans-fatty acids, cholesterol, retinol, carotene, and other antioxidants,
protein, carbohydrates, fiber, vitamins, and alcohol). The effects of fat
on prostate cancer progression are unknown. Animal fats (or carcinogens in
cooked fats) may alter sex hormone levels, immune responses, cell membrane
function, cell proliferation, tissue invasiveness, and metastasis. The
investigators concluded that their findings support recommendations to
lower the intake of red meat to reduce the risk of prostate cancer. "The
potential roles of carcino- gens formed in cooking animal fat and of
alpha-linolenic acid in the progression of prostate cancer need to be
explored." (Gio-vannucci E et al. J Natl Cancer Inst. 1993; 85: 1571-1579.
Pienta KJ, Esper PS. J Natl Cancer Inst. 1993; 85: 1538-1540.) 

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