The CancerWeb Report, What's New In Cancer: November, 1996
Cancer in General

• Anti-p53 antibodies as early indicators of cancer - In yet another example of the growing potential importance of p53 (see for example the articles on p53 under Breast Cancer and under Bladder Cancer in this month's CancerWeb Report), researchers at the National Cancer Institute and the Mayo Clinic, claimed that anti-p53 antibodies (p53-Abs) may serve as an early indicator of cancer among smokers before any diagnosis could be made. Their report in the October, 1996 issue of Clinical Cancer Research, traced patients who were smokers with chronic obstructive pulmonary disease over a 5-year period. The 23 patients who developed cancer were matched for age, sex and smoking habits with 44 noncancer controls. Among the 19 patients who developed cancer and for whom serum and tumor samples were available, p53-Abs were detected in 5, and in 4 of these (2 lung, 1 breast and 1 prostate cancer) detection occurred 5-11 months before a diagnosis was made. None of the controls had p53-antibodies. (Trivers, Clin Cancer Res 2:1767, 1996)

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• p53, key to a viral cure for cancer? - A mutant adenovirus that grows in and destroys tumor cells deficient in the p53 gene was described in a report in the October 18, 1996 issue of Science by researchers at ONYX Pharmaceuticals in Richmond, California. This mutant form of a viral family associated with respiratory tract infections in humans, lacks expression of the E1B gene. The protein product of this gene inactivates the human cell's p53 protein, allowing virally-infected cells to proliferate. In experiments with various tumor cell lines growing in culture, the mutant grew 100-times less effectively in tumor cells with the "wild-type" functional p53. When these scientists injected the mutant virus into p53-negative human cervical cancer transplanted into immune-deficient nude mice, there was an 84% reduction in rate of tumor growth, including complete regression of 60% of the tumors. (Bischoff, Science 274:373, 1996)

  Editor's Comment: - Normal adenoviruses knock out the p53 system when they infect cells, so releasing the switch which prevents cells from entering the active proliferation cycle. The resulting division of cells with active viral growth inside, followed by their bursting (lysis), facilitates the spread of the infection. A viral mutant that can only grow in cells lacking p53, as do about 50% of human cancers, can have great specificity of action. As discussed by the authors of the paper, there are questions that need to be resolved before the technique can be applied in practice. The immune reaction of a person given the virus is not known, and this problem cannot be studied in animals which are not subject to infection by human adenoviruses. It is possible, however, that a virally-infected tumor might be a more provocative target for the immune system than the uninfected tumor, so the p53 effect might conceivably be enhanced. Intra tumoral injection as used in this study is not feasible in humans, since most tumors are not easily accessible. Early Phase I clinical trials of the mutant virus are underway in patients with head and neck cancers deficient in p53 at the University of Texas in San Antonio (Dr. Von Hoff) and the Beatson Institute, Glasgow, Scotland (Dr. Kaye)

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• Setting magnetism to work in chemotherapy - The major problem with many chemotherapy drugs is that they are not sufficiently selective, they often cause too much damage to normal human tissues to be used at the dose levels required to kill all cancer cells. For this reason, many different approaches are being tried to make the drugs more specific in their action, either by localizing them more effectively in the tumor, by circumventing tumor cell resistance, or by increasing the resistance of normal cells to the lethal effects of drugs. One novel approach to the first category of modulation being tried by researchers in Berlin, Germany, is to concentrate the drug in the tumor with the help of magnetism. In an article in the October 15, 1996 issue of Cancer Research, they describe an early trial in which the drug epirubicin was chemically bound to particles in a magnetic fluid (ferrofluid) and a magnetic field applied to the tumor area for 1-2 hours. The approach needs much refinement if it is to be widely applied, but ferrofluid was successfully concentrated in the tumor area in about half the patients, as shown by MRI, pharmacological and histological detection. Slight reductions in tumor size occurred in 6 of 14 patients, and toxicity was not increased by the procedure. (Lubbe, Cancer Res 56:4686, 1996)

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• Are older patients treated differently from younger ones? - The answer from a group of researchers in the Netherlands is a definite "Yes!" In an article in the September, 1996 issue of Annals of Oncology, they found that among patients with common solid tumors and lymphomas, the proportion who were not given treatment rose from 7% in the 50-59 year-old group, to 12% in the 60-69 year-olds, and to 22% in those patients aged over 70. This trend was particularly strong for lung cancer and metastatic colorectal and ovarian cancers, whereas 90-99% of patients with lymphoma, or breast, head and neck, and non-metastatic colorectal cancers were treated, although elderly patients with these diseases received combination treatment less often. From the viewpoint of diagnosis, the elderly with breast, colorectal, and lung cancers were more often diagnosed only on clinical grounds, with less recourse to cytological confirmation (83% for over 70 compared with 93% for the 50-59 age group). (De Rijke, Ann Oncol 7:677, 1996)

  Editors's Comment: - Although this study confirms generally-held beliefs, and agrees with data from the US and elsewhere, there is a gap in the study that undermines its value. The study did not include information on the health status (comorbidity) of the cancer patients. Were there legitimate grounds to judge the more elderly as being too frail for surgery or toxic chemotherapy combinations? Many recent studies suggest that age alone is not a decisive factor in choosing treatments. Elderly persons in good health may be as capable of tolerating stressful therapies as much younger individuals.

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• Treatment of cancer pain - Despite the availability of a range of effective pain medications, patients with cancer, as well as large numbers of individuals with other painful conditions, are not always treated effectively so as to minimize or eliminate their pain. This reflects a lack of education about and poor attitudes towards the nature of pain and the appropriateness of opioid therapy. A review article in the October 10, 1996 issue of the New England Journal of Medicine gives a detailed discussion of the issue. The three-step ladder approach of the World Health Organization is the basis. This starts with non-opioid drugs such as acetaminophen, aspirin and other NSAIDs, with or without adjuvant therapy, proceeds to the second step of combinations of less potent opioids such as codeine and hydrocodone with non-opioids and adjuvants as needed, and progresses to a third stage for severe pain using the most potent opioids such as morphine and oxycodone (methadone, a drug discussed under Cancer Pain Control in the October, 1996 issue of the CancerWeb Report was not recommended) together with other drugs as necessary. Specific topics headings are: appropriate drugs for each step; dosage; route of administration; dosing intervals; prevention of persistent pain and relief of breakthrough pain through such measures as round-the-clock dosing and rescue doses; titration of doses, especially in response to diminished need because of nerve blocks, neurosurgery or other measures; the treatment of side-effects such as constipation, nausea, and cognitive impairment, that might prevent effective analgesia; sequential trials of drugs to manage side-effects; and adjuvant therapy, which most commonly uses corticosteroids, tricyclic antidepressants often at lower doses than those needed for depression, anticonvulsants for neuropathic or tic-like pains, and such agents as pamidronate, strontium-89 or calcitonin for bone metastases. The author, Dr. Levy from the Fox Chase Cancer Center, stresses that priority should be given to pain relief, and that this will not happen unless clinicians receive appropriate and effective training. (Levy, New Eng J Med 335:1124, 1996)

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• A widely-used laxative found to be carcinogenic in rodents - Phenolphthalein has been very commonly used as a laxative, but has not been examined for possible carcinogenicity. When metabolized it can produce mutations in bacteria, and in mice given doses equivalent to double the recommended human dose, abnormal red blood cells (micronucleated) occur. The compound also interacts with the receptor for estrogens, and so might have estrogenic activity. Researchers at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, found that continuous feeding of phenolphthalein in the diet to both rats and mice for 2 years at doses of up to 50,000 and 12,000 ppm, respectively, produced a range of tumors. According to a report in the November 1, 1996 issue of Cancer Research, rats developed kidney and adrenal gland tumors, while lymphomas, histiocytic sarcomas, and cancer of the ovary occurred in mice. (Dunnick, Cancer Res 56:4922, 1996)

  Editor's Comment: - The researchers speculated at length on the mechanisms responsible for the carcinogenic effect, since phenolphthalein seems to produce a unique mix of tumors. Estrogen-like activity did not appear to be responsible. The doses used are cumulatively much higher than the average person would take intermittently in the course of treating constipation, but it should be remembered that in other work the abnormal red cells were seen in animals receiving only the equivalent of twice the human dose. The discussion focussed on the ovarian tumors, and a study is underway to see if there is a relationship between phenolphthalein use and ovarian cancer in humans.