[MOL] Focus On... Cancer: Trends in Treatment and Prevention-Leukemia [01148] Medicine On Line

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[MOL] Focus On... Cancer: Trends in Treatment and Prevention-Leukemia

Title: Focus On... Cancer: Trends in Treatment and Prevention

Good Morning My Friends,

Thought the following information may be of some educational benefit  for those that are interested in this particular type of malignancy.

Have a great day all and God Bless You all,
marty auslander

Medical Sciences Bulletin Contents

Focus On... Cancer: Trends in Treatment and Prevention

Reprinted from Medical Sciences Bulletin, published by Pharmaceutical Information Associates, Ltd.

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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