The antioxidant effect of lovastatin on phagocyte-induced DNA damage: implications for cancer prevention.

Lovastatin is one of a series of HMG-CoA reductase inhibitors used in the treatment of hypercholesterolemia. It may also inhibit atheroma formation by inhibiting the oxidation of low density lipoproteins (LDLs). We investigated the antioxidant properties of lovastatin and its effect on phagocyte-induced genotoxicity in mammalian cells. In a cytochrome c reduction assay using 106 phorbol ester-induced phagocytes as a positive control, lovastatin (10 microM) in its naturally occurring lactone form, had no effect. When converted to its acid form, however, superoxide anion formation was inhibted by 36%. Similarly, lovastatin in its acid form completely inhibited H2O2 formation by stimulated phagocytes. Using the fluorometric analysis of DNA unwinding, single-strand breakage was assayed in MRC-5 lung cells exposed to 106 human phagocytes +/- lovastatin (10 microM, 5 min. incubation). Stimulated phagocytes induced a decrease in double-stranded DNA to 48% of control values which, in the presence of lovastatin, reverted to 91% of control values. Lovastatin acts as an antioxidant by decreasing oxygen radical production by human phagocytes and may be important in abrogating the carcinogenic effect of chronic inflammation.

Twelve-year follow-up of trimodality therapy for stage IIIA non-small cell lung cancer.

Non-small cell carcinoma of the lung (NSCLC) remains a formidable problem with a poor 5 year survival for stage III patients. Between 1985-1991, 53 patients with biopsy proven Stage IIIA NSCLC were treated with a trimodality treatment program. Chemotherapy, consisting of two cycles of continuous infusion cisplatinum and bolus etoposide, was started on days 1 and 28 of radiation therapy (54 Gy + 5.4 Gy boost in 6 1/2 weeks) directed to the lung primary and mediastinum. Four to six weeks after radiation therapy, patients underwent thoracotomy for radical pulmonary resection. Three weeks post surgery, the same chemotherapy was repeated for two cycles every 28 days. Forty-seven out of 53 patients (89%) achieved a clinical response after induction chemoradiation. Of these 47 patients, 33 underwent thoracotomy and 27 of them completed surgical resection. Treatment was well-tolerated. All surviving patients have no or minimal respiratory toxicities. With a median follow up of 9 1/2 years, surgically treated patients have a disease specific survival of 42% at 12 years. One patient survived beyond 9 years without surgery. Concurrent chemoradiation plus surgery is well tolerated and offers patients with Stage IIIA NSCLC significant long term survival benefit and warrants further assessment in a randomized trial.

The effect of epigallocatechin galleate and sarcophytol A on DNA strand breakage induced by tobacco-specific nitrosamines and stimulated human phagocytes.

The tobacco-specific nitrosamines (TSNAs) are metabolites of nicotine and are major carcinogens in cigarette smoke. Chronic inflammation may promote the carcinogenic effect of these nitrosamines through the generation of oxygen radicals as evidenced by an increase in DNA strand breakage in cultured human lung cells treated with stimulated human phagocytes and TSNAs. Sarcophytol A (SaA), a simple monohydroxycembratetraene isolated from marine soft coral, and (-)-epigallocatechin galleate (EGCG), one of the main constituents of green tea, both inhibit tumor promotion. To evaluate their effect on TSNA-induced genetic damage, cultured human lung cells were pretreated with SaA or EGCG and then exposed to the TSNA 4-(N-methyl-N-n-trosamino)-1-(3-pyridyl)-1-butanone (NNK) and stimulated human phagocytes and then assayed for single-strand DNA breaks. Both SaA and EGCG provided significant protection against the induction of genetic damage in these cells and may prove useful in the chemoprevention of tobacco-induced carcinogenesis.

Effect of vitamin E and beta-carotene on DNA strand breakage induced by tobacco-specific nitrosamines and stimulated human phagocytes.

The tobacco-specific nitrosamines (TSNAs), nitrosonornicotine (NNN) and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are metabolites of nicotine and are major carcinogens in cigarette smoke. Chronic inflammation may promote the carcinogenic effect of these nitrosamines through the generation of oxygen radicals. To evaluate the effect of oxygen radicals on TSNA-induced genetic damage, cultured human lung cells treated with NNN or NNK were exposed to stimulated human phagocytes and assayed for single-strand DNA breaks. TSNAs or stimulated phagocytes alone cause a significant increase in strand breakage which is augmented in an additive fashion when the two are combined. Pretreating the cells with vitamin E or beta carotene provided significant protection against the induction of DNA damage but vitamin E was significantly more effective than beta carotene. These data suggest a possible approach to the chemoprevention of tobacco-induced carcinogenesis.

Nonionizing electromagnetic fields and cancer: a review.

Low-frequency electromagnetic radiation had previously been thought to cause human injury only by generation of excess heat or by shock from direct contact with electric current. Information accumulating over the past few decades, however, suggests that nonionizing electric and magnetic fields associated with this radiation may be an environmental etiology in human disease. Human beings are affected not only by natural background nonionizing electromagnetic fields produced by the Earth, but also by a host of manmade sources. Of the diseases believed related to these fields, cancer and participation of these fields in the carcinogenic process have received considerable attention. This paper is a review of the basic science that points to this possible association.

Phase II study of 5-fluoruracil leucovorin and azidothymidine in patients with metastatic colorectal cancer.

The primary objective of this study was to determine the response rate of patients with metastatic colorectal cancer to combined therapy with 5-fluorouracil (5-FU), leucovorin, and intravenous azidothymidine (AZT), a thymidine nucleoside analog. By itself, AZT has limited antineoplastic efficacy. However, experimental studies indicate that 5-FU enhances the antitumor activity of AZT by inhibiting synthesis of normal thymidine nucleotides with which AZT competes for incorporation into nucleic acids. A phase I study defined the maximum tolerated dose of AZT as 7 g/m2 with hypotension during the infusion being the dose-limiting toxicity. A phase II study was performed with oral leucovorin (100 mg p.o. hourly for 4 h prior to 5-FU and 4 h and 8 h after 5-FU), bolus 5-FU (400 mg/m2) followed 1 h later by a 2-h infusion of AZT (7 g/m2). Treatment was given weekly for 4 weeks followed by a 1-week break, which constituted a cycle of therapy. Responses were evaluated after every two cycles. Patients continued on therapy as long as they tolerated treatment and did not have progressive disease. Of 15 evaluable patients who had received no chemotherapy there was 1 complete response and 4 partial responses (a 33% response rate), whereas only 1 of 6 patients who had received prior adjuvant chemotherapy had a partial response (17%). An additional 10 patients had stable disease lasting 2-14 months. Therapy was well tolerated with the only one instance each of grade 3 nausea and vomiting, diarrhea, anemia, and hypotension. Approximately 50% of treatments were accompanied by mild hypotension, which was easily corrected by increasing the rate of normal saline infusion. There was no difficulty administering this regimen in the outpatient setting. While the overall response rate (29%) is comparable to that seen with combinations of 5-FU and leucovorin alone, in most reported series a considerably higher dose of 5-FU was utilized than in this study. Since patients in the present study experienced relatively little 5-FU toxicity, increasing the dose of 5-FU in this regimen would appear to be feasible and might result in a higher response rate.

Phase I trial of high-dose infused zidovudine combined with leucovorin plus fluorouracil.

This phase I trial evaluated a high-dose, short-term infusion of zidovudine (AZT) following oral leucovorin (LV) and bolus 5-fluorouracil (FUra). Thirteen patients with metastatic cancer received 30 cycles of therapy. Plasma monitoring demonstrated a dose-dependent increase in peak plasma levels of AZT through the range of dose levels, from 104.3 +/- 8.7 microM at the 1.5 g/m2 dose of AZT to 1312.6 +/- 165.9 microM at the 11.0 g/m2 dose. While AZT did not potentiate the usual clinical toxicities of LV plus FUra, an unexpected finding of symptomatic hypotension during the AZT infusion was the dose-limiting toxicity in this trial. One partial response was observed in a previously untreated patient with metastatic colorectal cancer. The maximal tolerated dose of AZT, 7.0 g/m2 over 2 hr, is recommended for future phase II evaluation of this novel combination.

Ataxia without telangiectasia.

Ataxia telangiectasia (AT) is an autosomal recessive hereditary disorder characterized by onset in infancy or childhood of a cerebellar and later extrapyramidal disorder associated with telangiectasias and an immune deficit. Only a handful of cases have been described in which the features were not stereotypic. This report describes a case that is classic except for the absence of telangiectasias through age 17. This and other cases suggest that a new, more inclusive term be used to describe the syndrome of ataxia with immune deficit until the genetic abnormalities in these disorders become identifiable.

Oxygen radicals potentiate the genetic toxicity of tobacco-specific nitrosamines.

Tobacco-specific nitrosamines (TSNAs), nitrosonornicotine (NNN) and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are metabolites of nicotine and the major carcinogens in cigarette smoke. To evaluate the effect of oxygen radicals on TSNA-induced genetic damage, MRC-5 fetal human lung cells were exposed to NNN and NNK (5 mM) and DNA single-strand breaks measured. Both NNN and NNK produced a dose-dependent increase in strand breaks up to 10 mM which was cytotoxic. In combination with enzymatically-generated oxygen radicals, strand breakage increased by approximately 50% for both NNN and NNK. Oxygen radical scavengers (superoxide dismutase, catalase, mannitol) significantly reduced the DNA damage caused by both the TSNAs and TSNAs plus oxygen radicals, suggesting that the genotoxicity is radical-mediated. Because both superoxide dismutase and catalase were protective, the hydroxyl radical may be playing an important role in the mediation of the DNA damage observed.

Combined modality therapy for stage IIIA non-small cell carcinoma of the lung.

53 patients with stage IIIA non-small cell carcinoma of the lung (NSCCL) were treated with multimodality therapy consisting of induction radiotherapy (55.8 Gy) and two cycles of concurrent chemotherapy with cisplatin, 25 mg/m2 for 4 days by continuous infusion and bolus etoposide, 100 mg/m2 on days 2 and 4 of each cycle followed by surgery and adjuvant chemotherapy. Of 53 evaluable patients, 47 achieved clinical responses (9 complete response, 38 partial response) after induction therapy for a response rate of 89%. 47 patients were resectable after induction therapy, but 8 patients refused surgery and 6 patients were not eligible for surgery based on poor pulmonary function (medical contraindications). 33 patients underwent thoracotomy and in 6 patients, resection was technically unfeasible. Thus complete surgical resection was accomplished in 27 patients. After all therapy, 28 patients achieved a complete response (53%) and 19 patients a partial response (36%). Toxicities were mild. At a maximum of 75 months (median, 28 months) of follow-up, the median survival of the entire group is 24 months. The median survival of resected patients has not been reached; their 6-year survival rate is 55%. Unresected patients survived for a median of 11 months. This multimodality regimen is well-tolerated, induces a high response and resectability rate and prolongs survival in resected patients.

High-dose intravenous zidovudine with 5-fluorouracil and leucovorin. A phase I trial.

BACKGROUND: The inhibition of pyrimidine metabolism by 5-fluorouracil (5-FU) enhances the anti-cancer effects of zidovudine (formerly called AZT) in in vitro and in vivo model systems without additive toxicity. Zidovudine-induced DNA damage correlates with cytotoxicity. METHODS: A Phase I trial of high-dose continuous-infusion intravenous zidovudine therapy in combination with 5-FU and leucovorin therapy was performed. Eighteen patients with advanced malignant tumors were treated with 43 courses of oral leucovorin (50 mg every 4 hours); continuous-infusion 5-FU (800 mg/M2/day) for 72 hours (3 days); and zidovudine, begun 24 hours after the start of 5-FU and leucovorin, for 48 hours, and terminating with the end of the 5-FU infusion. Zidovudine plasma levels and zidovudine-induced DNA damage were assessed. RESULTS: Zidovudine administered in doses of 2-20 g/M2/day, added no obvious toxicity to the basic chemotherapeutic treatment with 5-FU and leucovorin but resulted in a dose-dependent biologic effect manifested by an increase in DNA strand breaks in peripheral blood cells. At doses greater than 15 g/M2/day, altered plasma kinetics of zidovudine were observed; plasma zidovudine levels increased dramatically in relation to the dose of zidovudine. Limitations in drug administration restricted administration of higher intravenous doses without achieving a maximally tolerated dose. No responses were seen in this heavily pretreated population. CONCLUSIONS: Based on the results of preclinical studies, plasma zidovudine levels greater than those achieved at the maximal dose (133 microns) are required for increased anti-cancer activity with 5-FU. Additional studies using a bolus or rapid infusion as a method of achieving higher peak levels are indicated.

Preoperative chemotherapy and radiation therapy for stage IIIa carcinoma of the lung.

Thirty-six patients with stage IIIa histologically proven non-small cell carcinoma (T3 N2 or T2 N2) underwent concomitant radiation therapy and chemotherapy before pulmonary resection. The therapy consisted of two cycles of continuous infusion of cis-platinum, 25 mg.m-2.day-1 (days 1 through 4) every 4 weeks and concomitant irradiation, 55 Gy, of the tumor and mediastinum. Two to 3 weeks after treatment, the patients were reevaluated for thoracotomy and pulmonary resection. Five patients were found to have unresectable lesions. Thirty-one patients had complete resection, 27 by radical pneumonectomy and 4 by radical lobectomy, giving a resectability rate of 86%. Complete sterilization of lung tumor and mediastinal nodes proven histologically was achieved in 10 patients (28%) and 17 patients (47%). The 3-year survival rate is 61.7% for patients who had resection. Median follow-up is 27 months (range, 6 to 61 months). The preliminary study indicates that preoperative cis-platinum and concomitant radiation therapy is tolerated, appears to increase resectability, and may improve survival in patients with stage IIIa lung cancer.

Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia.

The purpose of this study was to determine the relative merits of idarubicin and daunorubicin in acute myeloid leukemia (AML) therapy. Thirty-two sites provided 214 previously untreated adults with AML aged 15 years or more who were randomized to receive for induction therapy cytarabine 100 mg/m2/d as a continuous 7-day infusion plus either daunorubicin 45 mg/m2/d (A + D) or idarubicin 13 mg/m2/d (A + I), daily on the first three days of treatment. Postremission therapy consisted of two courses of the induction regimen at the same daily doses, with the anthracycline administered for 2 days and cytarabine for 5. The complete response (CR) rates for evaluable patients were 70% (A + I) and 59% (A + D) (P = .08). The difference in CR rates was significant in patients aged 18 to 50 years (88% for A + I, 70% for A + D, P = .035). Resistant disease was a significantly more frequent cause of induction therapy failure with A + D than with A + I. Hyperleukocytosis (white blood cell count greater than 50,000/microL) unfavorably affected the attainment of CR with A + D but not with A + I. CR duration was significantly greater after A + I. CR duration was significantly greater after A + I treatment, and the survival of all randomized patients treated with A + I was significantly better than that observed after A + D treatment (median 12.9 months v 8.7 months, respectively, P = .038). Toxicity of the two treatments was similar, although A + I patients experienced more prolonged myelosuppression during consolidation therapy, and a greater incidence of mild chemical hepatitis was observed in the A + I group. It is concluded that, at the doses and schedule used in this study, A + I is superior to A + D for induction therapy of AML in adults.

A phase I-II trial of continuous-infusion cisplatin, continuous-infusion 5-fluorouracil, and VP-16 in colorectal carcinoma.

Twenty-nine evaluable patients with colorectal adenocarcinoma were treated in a phase I-II trial of combination chemotherapy with a 72-h continuous infusion of cisplatin (CDDP) and 5-fluorouracil (5-FU) with an infusion of VP-16 given at 24 and 48 h after the start of therapy. There were five (17 +/- 14%) partial responses lasting 2-6 months (median, 3). Three of these responses occurred among the 10 previously untreated patients. The toxicity of this regimen was pronounced. Four of eight patients with severe neutropenia required hospitalization for infections, two of which were life-threatening; one of six patients with severe thrombocytopenia had a life-threatening hemorrhagic complication; and four patients experienced severe, dose-limiting fatigue. These complications occurred principally with CDDP and VP-16 at doses above 27.5 mg/m2/day and 110 mg/m2/dose, respectively. Mucositis occurred in six patients and limited the dose of 5-FU to 1,300 mg/m2/day. Although the response rate appeared to be high in previously untreated patients, the minimal palliative benefit of treatment and the brief duration of the responses do not compensate for the toxicity observed.

The influence of patient age on the diagnosis and treatment of lung and colorectal cancer.

We examined the relationship between patient age and medical care received by patients diagnosed with the following two common cancers: non-small-cell lung cancer and colorectal cancer. Controlling for the influence of sex, marital status, presence of comorbid disease, and socioeconomic status, we found that age was not related to the diagnostic tests ordered for either cancer type. However, lung cancer patients with local disease who were older than age 74 years underwent definitive surgical treatment less often than did younger patients. Few patients at any age (less than 9%) with colorectal cancer did not undergo definitive surgical treatment. Patients with regional colorectal disease who were older than 74 years of age underwent radiation therapy to the abdomen less often than did younger patients. These results add to the growing body of literature suggesting that older cancer patients are less likely to undergo the same type of care received by younger patients.

Translocation of chromosomes 16 and 18 in oxygen radical-transformed human lung fibroblasts.

Human lung fibroblasts (MRC5) were treated chronically with the oxygen radical-generating system hypoxanthine plus xanthine oxidase and assayed for malignant transformation in the soft agar colony assay. After a thrice weekly exposure to oxygen radicals for 4 and 5 weeks, there was a significant number of transformants compared to controls. In 4 separate experiments, karyotypes of the malignant transformants were examined. 22/75 metaphases exhibited karyotypic abnormalities and in 13/22 of the abnormal karyotypes, a t16:18 (p13.3,q21) translocation was observed. This genetic lesion may represent a marker for oxygen radical-induced malignant transformation in mammalian cells.