NCI monographs : a publication of the National Cancer Institute最新文献

Metabolism of glucose via the pentose cycle is a principal source of NADPH, an important cellular reducing species. Both aerobic and hypoxic irradiation stimulate the pentose cycle activity of A549 human lung carcinoma cells, which indicates that NADPH is utilized during irradiation, either as a direct hydrogen donor or as a cofactor for enzymatic repair of radiation damage. To evaluate the role of the pentose cycle in radiation response, we treated A549 cells with 6-aminonicotinamide (6-AN), which blocks the oxidative limb of this pathway in some cell lines. We found 6-AN to be a very effective inhibitor of pentose cycle activity, as indicated both by accumulation of 6-phosphogluconate in A549 cells and by the inability of nitrofurazone or peroxide to stimulate release of 14CO2 from 14C-1-labeled glucose after 6-AN treatment. Effects of 6-AN were time and concentration dependent; it caused partial inhibition of glycolysis but had no effect on respiratory rate or on intracellular glutathione levels. Effects of 6-AN on radiation response were examined under two conditions: 1) after treatment with 0.3 mM drug for 5 hours, which inhibited pentose cycle activity by 50%, and 2) after treatment for 15 hours, which completely inhibited pentose cycle activity. Neither treatment affected aerobic radiation response, but both increased hypoxic sensitivity to a similar extent, with the oxygen enhancement ratio reduced from 3.0 to 2.0 at a 0.05 surviving fraction. Treatment of A549 cells with 6-AN caused an increase in hypoxic cell radiosensitization by misonidazole, but effects of the combined agents were not more than additive.(ABSTRACT TRUNCATED AT 250 WORDS)

We have evaluated the role of chemotherapy for the treatment of prostate carcinoma. The data of patients with endocrine-resistant stage D2 disease indicate that clinical benefits in such patients are at best marginal. Despite the controversies involved in the assessment of response in this disease, in this review we show that in over 3,000 patients eligible for evaluation, less than 10% had complete or partial responses to various treatment regimens. Survival evaluation on all prospective randomized clinical trials showed no advantages in favor of any treatment tested and, moreover, in 2 of such studies involving various single agents, survival was not better than a "no chemotherapy" control arm. Because of these data, we conclude that chemotherapy is not indicated as an adjuvant treatment for patients with localized prostate cancer. Although patients with prostate cancer frequently respond to androgen deprivation procedures, preclinical and clinical data strongly suggest the existence of endocrine-independent cell clones, which supports further testing with nonhormonal cytotoxic treatment. A close multidisciplinary interaction is a prerequisite for development of new effective systemic treatment in this disease.

A patient with locally advanced prostate cancer (stages C and D1) has a poor prognosis with a high risk of developing and dying of distant metastases. Hormonal therapy is the major form of systemic therapy for metastatic (stage D2) prostate cancer. The most commonly used forms of hormonal therapy are orchiectomy, diethylstilbestrol, and luteinizing hormone releasing hormone, agonists that prevent the stimulation of tumor cells by testosterone. They produce a 60%-80% symptomatic or objective response rate, but their ability to prolong overall survival remains uncertain. Surgical adrenalectomy, hypophysectomy, and pharmacologic adrenal suppression prevent the clinically less significant adrenal androgen stimulation of tumor cells. Antiandrogens competitively inhibit the interaction between androgens and cytosolic androgen receptors. Complete androgen blockade (luteinizing hormone releasing hormone agonist and antiandrogen) was initially espoused to be superior to single-agent hormonal therapy, but preliminary results from a multigroup randomized trial suggest that it has only a minimal advantage. The benefit of hormonal therapy in stages C and D1 prostate cancer at the time of diagnosis has not been clearly established. Available studies are few, and most often they are uncontrolled or include only small numbers of patients. However, they suggest that the early use of hormonal therapy prolongs disease-free survival but does not prevent ultimate disease progression or prolong overall survival. Hormone receptor assays may be helpful in the selection of patients who would benefit from early hormonal therapy.

To design protocols for exploitation of the potential for interaction among the platinum (Pt) chemotherapeutic agents cisplatin and paraplatin and radiation therapy, we measured levels of total platinum in a transplantable murine mammary adenocarcinoma (MTG-B) at different times after ip injection of platinum drugs and in various regimens. Cisplatin (20 mg/kg body weight) or paraplatin (60 or 120 mg/kg body weight) were injected ip in female C3H/HeJ mice bearing MTG-B of about 1 cm diameter. At various times after injection, tumors were removed and processed for acid digestion and total platinum analysis by atomic absorption spectrometry with a graphite furnace. The results of these experiments indicate that intratumoral Pt levels 15 minutes postinjection are higher than at 5 or 30 minutes. At 30 minutes, the Pt concentrations are of the magnitudes of 30 and 50 microM for cisplatin and paraplatin, respectively, that, when added to cells in vitro in combination with radiation therapy, produce the potentiation of cell killing. In addition, for paraplatin, intratumoral Pt levels at 30 minutes following an ip injection are approximately doubled if the tumors receive localized radiotherapy of 20 Gy immediately prior to injection of the drug. This apparent modification of paraplatin pharmacokinetics by radiotherapy might account for some of the supra-additive therapeutic potentiation in MTG-B reported for paraplatin added after irradiation.

We have combined cisplatin, 5-fluorouracil infusion, and radiation in an every-other-week schedule in a phase I-II study of 44 patients with head and neck cancer to assess toxicity and response. Ten patients were treated palliatively with 2 to 6 cycles of therapy, and 34 were treated curatively with a planned 7 cycles. Of 34 patients treated curatively, all were initially controlled. Three died during treatment (1 myocardial infarction, 1 bowel perforation, and 1 renal failure after amino-glycoside antibiotics). Four patients have had regional recurrences, 7 failed at distant sites (follow-up 2 to 5 yr). Thirty-three percent of 20 patients with complete clinical disappearance of all evidence of their cancer have had a recurrence, as have 38% of 14 (P greater than .1) with some residual abnormalities (partial responders) following treatment. All failures were in the 25 patients with T4 and/or N3 disease. None of the 9 patients with lesser stage IV or stage III disease who were followed for 24 months or more had recurrences. Eighteen patients (53%) survive with a projected 3-year survival of 63% (95% confidence interval 47% to 77%). Nine (27%) have died of disease, 1 (3%) died of a second primary in the head and neck, 3 (9%) of intercurrent disease at 15 to 45 months, and 3 (9%) during treatment. Of the 10 patients treated palliatively, 1 died during treatment with hepatic failure, 6 had complete responses, and 2 had partial responses.(ABSTRACT TRUNCATED AT 250 WORDS)

This trial of treatment for head and neck carcinoma was initiated in 1973 by the European Organization for Research and Treatment of Cancer. Its purpose was to investigate the value of single-agent chemotherapy with bleomycin (BLM) given during the course of a conventional treatment by external radiotherapy (RT) compared to treatment by external RT alone. In this randomized study, we compared treatment results in 2 groups of patients with squamous cell carcinoma of the oropharynx (T2, T3, and T4; International Union Against Cancer classification). One group of 92 patients was treated by RT at the prescribed dose of 70 Gy. The other group of 107 patients received radiation according to the same protocol and simultaneously received im injection of BLM at a dose of 15 mg twice a week, 2 hours prior to the session of RT, for a total dose of 150 mg in 5 weeks. The occurrence of local toxic effects (i.e., mucositis and epidermatitis) was significantly greater in the RT-BLM group (RT-BLM, 72%, vs. RT, 21%). Primary tumor response 6 weeks after completion of RT was the same in both arms of the study (RT, 68%, vs. RT-BLM, 67%). The 6-year survival rate was 24% (RT-BLM) versus 22% (RT). Long-term analysis (10 yr) is given.

The effect of the administration of bleomycin on repopulation in mouse lip mucosa during fractionated irradiation was studied. Two equal-sized irradiation fractions were delivered with 1-, 7-, or 10-day intervals, with and without simultaneous administration of 40 mg bleomycin/kg in a continuous sc infusion, given over 7 days. In the experiments with irradiation only, the prolongation of the interval from 1 day to 7 days resulted in a net increase of the isoeffective dose due to compensatory proliferation. This effect was even more pronounced with the 10-day treatment interval. The addition of bleomycin, however, nearly completely suppressed this proliferative activity.

In the early 1970s, a multicentered cooperative group effort was established by urologists and oncologists to examine the relative disease control provided by surgery, radiation therapy, or observation for patients with localized or regional disease. The data derived from this trial were controversial because they 1) did not support previous concepts regarding the relative impact of treatment and 2) raised provocative questions as to the interpretation of previous institutional reports that promoted a single treatment modality. The data from the randomized trial demonstrated that: 1) bipedal lymphangiography could not demonstrate accurately the presence or absence of microscopic involvement of pelvic lymphatic structures, 2) treatment selection should be based on the anatomic distribution of disease; 3) a clinician's use of first appearance of local or distant disease in a patient who was supposedly disease free after receiving the chosen therapy served as an accurate way to define the impact of the initial treatment; 4) radical surgery was more effective than radiation therapy in controlling disease that was clinically confined to the primary organ of origin; and 5) the apparent disease control produced by radiation on large-volume, localized disease might only reflect the natural history of the disease.