Resveratrol inhibits rhabdomyosarcoma cell proliferation.

Rhabdomysarcoma is the most common soft tissue tumour in children under the age of 15. Although the introduction of multimodal treatment programmes, including chemotherapy, radiation therapy and excision have increased the overall survival, the chemotherapeutic agents currently used for the treatment of rhabdomyosarcoma exhibit considerable toxicity. The aim of this study was to investigate the effects and possible mechanism(s) of action of resveratrol on human embryonal rhabdomyosarcoma (RD) cells. Resveratrol is a natural polyphenolic compound produced in a number of edible plants and has received considerable attention as a potential chemopreventive and/or chemotherapeutic agent against various types of cancers. In the present study, resveratrol was shown to inhibit cell proliferation of RD cells in a dose-dependent manner with an IC50 of 48.1 micromol/l and induce an arrest in the S/G2 phase of the cell cycle. As evident from immunocytochemical data, resveratrol treatment increased the size of the RD cells. Furthermore, resveratrol treatment resulted in a significant downregulation of cyclin B expression as demonstrated by western blot analyses. In conclusion, the present study shows that resveratrol exerts a strong inhibition of rhabdomyosarcoma cell proliferation in part by arresting cells in S/G2 phase of the cell cycle. These findings warrant further investigation to establish potential use of resveratrol as a relatively non-toxic chemotherapeutic agent for the treatment of rhabdomyosarcoma.

Genistein induces apoptosis and topoisomerase II-mediated DNA breakage in colon cancer cells.

The present study was undertaken to determine if (a) genistein induces topo II-mediated DNA damage in HT-29 colon cancer cells; and (b) if this damage is required to induce apoptosis. DNA damage was evaluated using the comet assay. Apoptosis was determined by the ethidium bromide/acridine orange staining technique. DNA breakage was noted within 1 h of treatment. Apoptosis was only induced with high concentrations (>/=60 microM) of genistein. Marked inhibition of HT-29 cell growth was evident at concentrations ranging from 60 to 150 microM. This was associated with a cell cycle arrest at G(2)/M. Similar findings were obtained in SW-620 and SW-1116 colon cancer cell lines. Aclarubicin, a topo II antagonist, reduced genistein-induced DNA breaks but did not reduce apoptosis. These data suggest that, in colon cancer cells, topo II serves as the enzymatic target of genistein. Furthermore, topo II-mediated DNA cleavage is not required for the induction of apoptosis.

Nitrogen mustard up-regulates Bcl-2 and GSH and increases NTP and PCr in HT-29 colon cancer cells.

We hypothesized that unexplained increases in nucleoside triphosphates (NTP) observed by 31P magnetic resonance spectroscopy (MRS) after treatment of tumours by DNA-damaging agents were related to chemotherapy-induced up-regulation of the bcl-2 gene and DNA damage prevention and repair processes. To test this hypothesis, we treated HT-29 cells with 10(-4) M nitrogen mustard (HN2) and performed sequential perchloric acid extractions in replicate over 0-18 h. By reference to an internal standard (methylene diphosphonic acid), absolute changes in 31P-detectable high-energy phosphates in these extracts were determined and correlated with changes in bcl-2 protein levels, cell viability, cell cycle, apoptosis and total cellular glutathione (GSH) (an important defence against DNA damage from alkylating agents). After HN2 administration, bcl-2 protein levels in the HT-29 cell line rose at 2 h. Cell viability declined to 25% within 18 h, but apoptosis measured using fluorescence techniques remained in the 1-4% range. Increased cell division was noted at 4 h. Two high-energy interconvertible phosphates, NTP (P < or = 0.006) and phosphocreatine (PCr) (P < or = 0.0002), increased at 2 h concurrently with increased levels of bcl-2 protein and glutathione. This study demonstrates that bcl-2 and glutathione are up-regulated by HN2 and links this to a previously unexplained 31P MRS phenomenon: increased NTP after chemotherapy.

Multimodal-therapy breast salvage in the urban poor with locally advanced cancer.

OBJECTIVES: To determine whether economically disadvantaged urban women with locally advanced breast cancer (American Joint Committee on Cancer stages IIB to IIIB) have rates of response to sequential neoadjuvant chemotherapy and radiation, breast salvage rates, overall survival rates, and disease-free survival rates comparable with those previously reported in other socioeconomic groups and to compare these variables in different ethnic groups within the study population. DESIGN: Prospective, nonrandomized, case series. SETTING: Urban county hospital. PATIENTS: Thirty-seven women with locally advanced breast cancer who came to the breast clinic at Cook County Hospital, Chicago, Ill, during a 3-year interval. INTERVENTION: Sequential chemoradiation followed by surgery in selected patients. MAIN OUTCOME MEASURES: Comparison of clinical response rates, disease-free survival rates, and breast salvage rates between different ethnic groups in the study population. RESULTS: In the entire group, the overall response rate to neoadjuvant chemotherapy was 73%, with a complete response rate of 32%. Twenty-five percent of patients whose tumors responded incompletely to chemotherapy had a complete response after subsequent radiation. With a mean follow-up of 18.7 months, 65% of patients had no evidence of disease, and breast salvage without evidence of recurrent disease was achieved in 38% of patients. No differences in overall response rates, breast salvage rates, or early disease-free survival rates were observed within different ethnic groups in the study population, and these results are generally comparable with previously reported results in other socioeconomic groups. CONCLUSION: These results do not show significant differences in responses to sequential chemotherapy and irradiation, in breast salvage rates, or in survival between different ethnic groups in this study population.

The role of lymphadenectomy in cancer, with particular reference to gastric cancer.

Lymphadenectomy has an acknowledged role in the staging of most solid tumors, however, its therapeutic role remains controversial. To date, several prospective, randomized, controlled trials comparing either extended vs. conventional lymphadenectomy (in breast cancer) or prophylactic lymphadenectomy vs observation (in N0 patients with breast cancer or melanoma) have failed to show survival differences between treatment arms. Gastrointestinal cancers, including gastric cancer, represent a special case of this general problem in that intra-abdominal nodes are not clinically accessible and accurate radiographic determination of nodal involvement continues to be problematic. Without question, staging and technical considerations dictate removal of at least some perigastric lymph nodes. However, the one prospective study testing survival benefit for R2 vs R1 lymphadenectomy in gastric cancer was negative. This study suffers from small sample size compounded by post operative pathologic upstaging resulting in entry of a moderate percentage of ineligible patients. Japanese surgeons have also been generally critical of the extent of R2 dissections in Western surgical studies. A second prospective trial, presently underway, addresses these concerns as well as other concerns about selection bias in older retrospective studies and should finally resolve the issue of the therapeutic efficacy of extensive lymphadenectomy in gastric cancer.

Long-term follow-up of patients with node-negative breast cancer treated only by regional therapy.

BACKGROUND: This study examines the potential impact of intercurrent diseases on survival after adjuvant chemotherapy for node-negative (N0) breast cancer in light of 30-year follow-up results in 136 patients with N0 disease receiving only regional therapy at the University of Texas M.D. Anderson Cancer Center between 1958 and 1960. METHODS: We made a retrospective review of treatment records. RESULTS: Thirty-nine women (28.6%) died of the initial breast cancer, including 12 (22%) of 54 premenopausal women, 15 (43%) of 35 perimenopausal women, and 12 (25%) of 47 postmenopausal women (p less than or equal to 0.09). Six (12%) of 49 patients with T1 disease died of the initial breast cancer versus 27 (38%) of 70 patients with T2 disease and 6 (35%) of 17 patients with T3 disease (p less than or equal to 0.006). Five of 10 women died of metachronous contralateral breast primary lesions. Deaths from other cancers occurred in 11%, 2.8%, and 6.4% of premenopausal, perimenopausal, and postmenopausal women, respectively. Deaths from nonmalignant conditions occurred in 22%, 20%, and 59% of premenopausal, perimenopausal, and postmenopausal women, respectively. Overall survival at 30 years was 35 (26%) of 136 patients. CONCLUSIONS: Given these statistics, if one postulates that adjuvant chemotherapy reduces the death rate from an initial breast cancer by 30% to 77% (estimates based on data from adjuvant chemotherapy trials in patients with N+ or N0 disease), a 5% to 12.9% increase in the 30-year survival would have resulted.

Isolated limb perfusion for localized melanoma of the extremity. A matched comparison of wide local excision with isolated limb perfusion and wide local excision alone.

The therapeutic efficacy of isolated limb perfusion in patients with localized melanoma of the extremity remains controversial. We compared patients treated at the University of Texas M.D. Anderson Cancer Center, Houston, with wide local excision and isolated limb perfusion using either melphalan or imidazole carboxamide with a group matched for prognostic factors from the University of Alabama at Birmingham and the University of Sydney (Australia) who were treated with wide local excision alone. No significant difference in disease-free or overall survival rates was found between patients treated with wide local excision with adjuvant isolated limb perfusion or wide local excision alone. However, a subset of patients with thicker lesions (greater than 2.0 mm) treated with wide local excision and isolated limb perfusion using melphalan had a significant improvement in both disease-free and overall survival rates. These data suggest that isolated limb perfusion using melphalan may improve survival rates in selected patients with localized melanoma of the extremity who are at increased risk for local and regional micrometastases, and justifies the continued study of this treatment approach in prospective clinical trials.

Isolated limb perfusion for stage I melanoma of the extremity: a comparison of melphalan and dacarbazine (DTIC).

Isolated limb perfusion (ILP) for melanoma of the extremity was first used clinically more than 30 years ago. Although ILP with chemotherapeutic agents has become routine practice in many oncologic centers, few studies have evaluated the therapeutic efficacy of particular agents. Two consecutive groups of 100 patients with stage I extremity melanoma of 1.5 mm thickness or greater were treated by ILP with either melphalan (L-PAM) or dacarbazine (DTIC). Demographics, clinical and pathologic stage, disease site, and complications were similar in both groups. No significant difference in the overall incidence of recurrent disease at two years was found between patients treated with either DTIC or L-PAM (22% vs 16%, respectively; P = .28). Patients who had perfusion with L-PAM, however, had a lower incidence of in-transit metastasis and recurrence at the scar than those having DTIC therapy (4% vs 12%, P = .06) at two years of follow-up. This preliminary report suggests that L-PAM may be more effective than DTIC in controlling scar recurrences and in-transit metastasis. Continued follow-up of this series of patients, with further analysis of patterns of recurrence and disease-free and overall survival at five years, will be necessary to better define the relative efficacy of L-PAM and DTIC in isolated limb perfusion.

Gastric cancer.

The overall cure rate for gastric cancer has changed relatively little in the United States over the past 30 years, largely because patients continue to present for treatment in advanced stages. The paucity of symptoms in early gastric cancer, the low incidence in the general United States population, and the lack of cost-effective screening methods suggest that improvements in early detection are unlikely. Hope for improved survival in late stage cases lies mostly in a better understanding of the pathophysiology and patterns of spread, in evolving techniques for more accurate perioperative staging, and in the gradually improving results of multimodality therapy for local-regional and systemic disease. A proposal is made for a new staging system integrating newer approaches to staging and for controlled trials of multimodality therapy in patients unlikely to be cured by surgery alone.

Application of MR spectroscopy to the study of tumor biology.

Though MR spectroscopy has long been used to analyze the structure of organic compounds in solution, interest in applying it to the study of biologic systems has been slow in evolving because of past problems with spectral resolution in solids and gels. Renewed interest in this area has been stimulated both by the rapid growth of MR imaging as a clinical tool as well as by improvements in MR spectrometer design and use of sophisticated pulse sequences which have greatly improved the analysis of molecular composition. This review specifically focuses on the application of MR spectroscopy to studying the biology of malignant cells. The bulk of MR studies in this area to date have involved either 1H or 31P spectroscopy. Several investigators have now demonstrated that 1H spectra can be used to distinguish both animal and human tumors of differing metastatic properties. Preliminary data suggest that these spectral differences result in part from differences in cell surface glycoproteins and/or glycolipids between cells of low and high metastatic potential. Many of these molecules can absorb cell water potentially affecting T1 of cell water by their relative concentrations. Prolonged T2 relaxation times have been associated with some spectral peaks which distinguish cells of differing metastatic potential. The findings may partly explain why tumors have the prolonged T1 and T2 relaxation times seen in proton MR imaging. Other 1H MR spectroscopic studies suggest that there are detectable differences in plasma lipids in patients with a variety of malignancies compared to normal controls, suggesting possible utility as a screening test.(ABSTRACT TRUNCATED AT 250 WORDS)

Three unresolved issues in the surgical treatment of melanoma.

The authors discuss the results of recent clinical trials on what constitutes an adequate resection margin in primary melanomas of varying thickness, concluding that it is still uncertain whether wider margins reduce the risk of regional cutaneous recurrences. Inherent in the issue of whether or not to perform elective node dissection is the difficulty of identifying patients who might benefit from the procedure. Proponents point to two recent studies, but actually the sample sizes were small. Isolated limb perfusion, while producing complete responses with long-term survival in some cases of regionally recurrent disease, is still questionable as a prophylactic treatment for high-risk primary disease.

Multivariate analysis of prognostic factors in regional cutaneous metastases of extremity melanoma.

In 135 patients with regional cutaneous recurrence of extremity melanoma, the prognostic significance of 12 clinical and pathologic variables was analyzed in four alternative Cox stepwise regression models and by single variable analysis. A highly significant fit of the regression (P less than 0.01) identified four factors that particularly influenced survival: the presence of intradermal or mixed (as opposed to purely subcutaneous) metastases (P less than 0.001), sex (P = 0.032), excision of regional cutaneous metastases with or without perfusion (P = 0.033), and the presence of subcutaneous metastases (P = 0.201). Not predictive of survival were age at diagnosis; site of primary; anatomic location, number, size, or distance from the primary of the regional cutaneous metastases; time since primary treatment; number of positive regional lymph nodes; and single- or triple-drug perfusion.

Proton magnetic resonance spectral patterns of metastasizing and nonmetastasizing human colon cancers.

The spectral features of surgically staged metastasizing (ie, modified Duke's stages C and D) and nonmetastasizing (ie, modified Duke's stages A and B1-2) human colon cancers were studied using 60-MHz continuous wave and 200-MHz pulse Fourier transform proton magnetic resonance spectroscopy. Twenty-one human colon cancers (four nonmetastasizing and 17 metastasizing tumors) collectively contained 24 spectral peaks. A peak at 6.7 to 6.87 parts per million cycles (ppm) was found in three nonmetastasizing tumors but only one metastasizing tumor; the mean area at this peak location was significantly higher in the nonmetastasizing tumors. Mean peak areas at 1.4 to 1.47 ppm, 2.0 to 2.33 ppm, and 8.3 to 8.6 ppm were significantly higher in metastasizing tumors; however, these peaks were observed with only marginally greater frequency in metastasizing vs nonmetastasizing tumors: seven of 17 vs zero of four, 11 of 17 vs one of four, and eight of 17 vs zero of four tumors, respectively. This study suggests that magnetic resonance spectral features may aid in staging human colon cancers and could be used to enhance magnetic resonance imaging of these lesions.

Adjuvant and neoadjuvant chemotherapy with dacarbazine in high-risk childhood melanoma.

Four of four children with clinical Stage II-IIIB childhood melanoma treated at The University of Texas System Cancer Center M.D. Anderson Hospital with surgical excision of gross disease and adjuvant or neoadjuvant chemotherapy with dimethyl triazeno-imidazole carboxamide (dacarbazine) were alive without evidence of disease at 2, 6, 9.5, and 10.5 years after treatment. In one of the four patients suspected pulmonary nodules developed shortly after the start of chemotherapy, but regressed completely with continued treatment. In another patient with a primary left wrist melanoma and palpable epitrochlear and axillary nodes, there was dramatic shrinkage of nodal disease during chemotherapy and subsequent biopsies were cytologically negative. The expected survival of children with this rare condition when diagnosed at a comparably advanced stage and treated primarily by surgery is 32% compared with the 100% survival in these four cases. Although dacarbazine has not been notably successful as adjuvant therapy in high-risk adult melanoma, data from this small series is suggestive of an adjuvant effect in high-risk childhood melanoma and merits further study although the rarity of this condition may make a controlled trial difficult.

Proton NMR examination of tumor cells of high or low metastatic potential.

Three rat 13762NF mammary adenocarcinoma clones and cell lines of different metastatic potentials (MTLn3, MTC, and MTPa) were studied for their proton nuclear magnetic resonance spectral characteristics as intact cells in vitro and after chloroform/methanol, neuraminidase, or ethanol treatments. The intact-cell spectral characteristics of the highly metastatic tumor cell clone MTLn3 were clearly distinguished from the less metastatic clone MTC or the parental MTPa cell line on the basis of spectral peaks in the range of 0.9 to 1.45 p.p.m. broad peaks near 2.0 p.p.m., and peaks in the range of 2.75 to 3.2 p.p.m. Glycoproteins are among the molecules known to have resonances in these upfield spectral regions, and these tumor cell subpopulations have previously been shown to possess characteristic quantitative differences in cell surface, metastasis-associated glycoproteins. Treatment of the cells with neuraminidase or ethanol, or extraction with chloroform/methanol increased spectral detail and also revealed characteristic differences in spectral peaks between the tumor cell subpopulations. The identity of the cellular components responsible for these spectral characteristics are unknown, but some clearly arise from differences in the extractable lipids present in the tumor cell subpopulations. Further study will be required to determine if the spectral differences described in this preliminary report are directly related to the known biochemical characteristics of the highly metastatic clone, and if the observations have general relevance to metastatic potential or are a singular feature of these cells. However, these initial results suggest that manipulation of factors which allow unmasking of spectral detail combined with the use of prescribed tumor cell subpopulations may aid in using proton NMR to identify and define biochemical or structural differences related to the metastatic potential of tumor cells.

Proton NMR of human breast tumors: correlation with clinical prognostic parameters.

Proton NMR spectroscopy and imaging of human breast tissue have provided new methods in studying breast carcinomas. Continuous wave proton NMR spectroscopy in this study is able to discriminate breast carcinomas from normal breast tissue on the basis of the integrated area under the water and lipid peaks, width at half height of the water peak, and chemical shift of the lipid peak. In addition, the NMR parameters were correlated with the following clinical and pathologic prognostic indices: TNM tumor stage, nuclear grade, and estrogen receptor status (ER). Width at half height of the lipid peak (1/2 delta lipid) correlated with tumor content and ER. Studies using higher resolution proton or phosphorus NMR spectra may separate signals that can correlate with biological information on breast neoplasms useful to the clinician. Chemical shift of the lipid peak may be used to sharpen contrast on MRI of breast tumors.

Adenocarcinoma of the stomach: are we making any progress?

We studied 2,062 patients with adenocarcinoma of the stomach seen at The University of Texas M. D. Anderson Hospital and Tumor Institute between 1944 and 1984. The distribution by site was cardia 33%, antrum 31%, and body 27%; 9% of the patients had linitis plastica. The raw five-year survival rate was 12.5%; surgically treated patients with negative nodes had a five-year survival rate of 75%, compared to 19% for those with positive nodes. Forty-one percent of patients had diagnostic procedures only, 35% had a Billroth I or II gastrectomy, and 24% had total gastrectomy or radical proximal gastrectomy. In the first decade fewer than one new patient per week was registered, but this has increased to more than two during the last decade. This apparent increase is due to the 65% of patients referred for palliative chemotherapy. Improved nutritional support has made operations safer and combined with chemotherapy has provided modest progress.