Randomized phase II study of 5-fluorouracil hepatic arterial infusion with or without antineoplastons as an adjuvant therapy after hepatectomy for liver metastases from colorectal cancer.

BACKGROUND: Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplaston A10 and AS2-1 reportedly control neoplastic growth and do not significantly inhibit normal cell growth. Antineoplastons contain 3-phenylacetylamino-2, 6-piperidinedione (A10), phenylacetylglutamine plus phenylacetylisoglutamine (A10-I), and phenylacetylglutamine plus phenylacetate (AS2-1). This open label, non- blinded randomized phase II study compared the efficacy of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a postoperative therapy for colorectal metastasis to the liver. METHODS: Sixty-five patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998- 2004 in Kurume University Hospital. Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery. Primary endpoint was cancer-specific survival (CSS); secondary endpoints were relapse-free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity. FINDINGS: Overall survival was not statistically improved (p=0.105) in the AN arm (n=32). RFS was not significant (p=0.343). Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n=33) with a median survival time 67 months (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm. The limited extent of recurrent tumours in the AN arm meant more patients remained eligible for salvage surgery. Major adverse effects of antineoplastons were fullness of the stomach and phlebitis. No serious toxicity, including bone marrow suppression, liver or renal dysfunction, were found in the AN arm. INTERPRETATION: Antineoplastons (A10 Injection and AS2-1) might be useful as adjunctive therapy in addition to HAI after hepatectomy in colorectal metastases to the liver. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov UMIN000012099.

Demethylation effect of the antineoplaston AS2-1 on genes in colon cancer cells.

Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. antineoplastons have been shown to control neoplastic growth. In the present study, we investigated demethylation effect of the antineoplaston AS2-1 (a mixture of phenylacetylglutamine and phenylacetate in the ratio of 1:4) on various genes in colon cancer cells. An HpaII-MspI methylation microarray was used to investigate the methylation status of 51 genes at the promoter region in HCT116 and KM12SM human colon cancer cells before and after treatment of AS2-1. The expression of protein and mRNA of the demethylated genes by AS2-1 in HCT116 cells was evaluated. In 19 of the 34 methylated genes in HCT116 and in 7 of the 8 methylated genes in KM12SM, the methylation status was downregulated after treatment with 2 mg/ml of AS2-1 for 24 h. AS2-1 dramatically downregulated the methylation status of p15 and ESR1 in HCT116 cells and of MTHFR and MUC2 in KM12SM cells. Both mRNA and protein expression of p15 increased in a dose- and time-dependent manner after treatment with AS2-1. The antineoplaston AS2-1 may normalize the hypermethylation status at the promoter region in various genes including tumor suppressor genes, resulting in activation of the transcription and translation in colon cancer.

Antineoplaston induces G(1) arrest by PKCalpha and MAPK pathway in SKBR-3 breast cancer cells.

Antineoplastons such as A10 include naturally occurring peptides and amino acid derivatives that control the neoplastic growth of cells. The mechanism underlying this antitumor effect was investigated using the breast cancer cell line, SKRB-3. Cells treated with A10 were monitored for any changes in cell cycle, expression of protein kinase C (PKC), or intracellular signal transduction, particularly phos-phorylation of mitogen-activated protein kinase (MAPK). The A10 markedly inhibited SKBR-3 proliferation due to arrest in the G(1) phase. A10 down-regulated the expression of PKCalpha protein, resulting in inhibition of extracellular signal-regulated kinase (ERK) MAPK phosphorylation. This increased the expression of p16 and p21 protein, with resultant inhibition of Rb phosphorylation, leading to G(1) arrest. This study has defined a pathway in which A10 arrested SKBR-3 cells in the G(1) phase via PKCalpha and MAPK. Our findings indicate that the antineoplaston A10 antitumor effect could be utilized as an effective therapy for breast cancer patients.

Effects of antineoplaston AS2-1 against post-operative lung metastasis in orthotopically implanted colon cancer in nude rat.

We have investigated the efficacy and mechanisms of antineoplaston AS2-1 against post-operative lung metastasis following removal of implanted human colon cancer in nude rat. The influence of AS2-1 on in vitro KM12SM human colon carcinoma cell activities (growth, cell cycle, and apoptosis) was evaluated. AS2-1 was administered perorally after removal of the implanted KM12SM cecal cancer in nude rat. AS2-1 inhibited KM12SM cell proliferation through G1 cell arrest and, at a higher concentration, induction of apoptosis. AS2-1 showed significant reduction in lung metastasis at 5 weeks after cecal removal. The survival rate in the AS2-1 group was significantly higher than that in the control. TUNEL staining on the lung metastatic tumors revealed that the apoptosis index (AI) in the AS2-1 group was significantly higher. Antineoplaston AS2-1 showed an antimetastatic effect against post-operative lung metastases from colon cancer through G1 cell arrest and the subsequent induction of apoptosis.

Long-term survival following treatment with antineoplastons for colon cancer with unresectable multiple liver metastases: report of a case.

We report a case of survival for nearly 8 years after treatment of unresectable multiple liver metastases from colon cancer, using microwave ablation and the nontoxic antitumor agent, the antineoplastons. A 72-year-old man diagnosed with adenocarcinoma of the ascending colon and 14 bilateral liver metastases underwent a right hemicolectomy combined with microwave ablation of six metastatic liver tumors. We also decided to give antineoplastons to inhibit metastatic tumor growth and recurrence. Antineoplaston A10 was given intravenously, followed by oral antineoplaston AS2-1. Computed tomography scans done 1 and 4 years after the initial diagnosis showed recurrent tumors in S(4) and S(7), respectively. The patient underwent a second and a third microwave ablation of the recurrent tumors, and has survived for nearly 8 years without suffering any serious adverse effects. He is currently free from cancer. This case report demonstrates the potential effectiveness of the nontoxic antitumor agent, the antineoplastons, for controlling liver metastases from colon cancer.

[Citizen's understanding of anesthesia from a questionnaire survey].

BACKGROUND: In order to know general understanding or impression of anesthesia by citizens, we performed a questionnaire survey. MATERIALS AND METHODS: The participants for the survey were 218 citizens including 118 healthy persons with previous attendance to Kurume University Public Lecture for Citizens (group A) and 100 patients hospitalized in Kurume University Medical Center (group B). Their answers were collected prior to the lecture planned on the 39th Annual Meeting of Kyushu Society of Anesthesiologists. RESULTS: The recovery of the survey was 78.9%. The percentages of persons who wanted to know "How and by whom I am anesthetized" were 93.2% and 72.6% in groups A on B, respectively. The percentage of persons who wanted to know the name of surgeon was 91.7%. The answers to the question; "Which doctor do you think is responsible for the treatment of an intraoperative adverse event such as acute myocardial infarction?"; were in the order of an internist 37.5%, a surgeon 29.7% and an anesthesiologist 18.0%. CONCLUSION: We have realized through the questionnaire survey that the majority of citizens still consider an anesthesiologist as a technician merely putting patients into sleep for surgery. At the preoperative examination or round, we have to explain procedures and potential risks related to anesthesia to a patient and also have to answer patient's questions fully. We anesthesiologists should do more efforts to enlighten citizens at every opportunity so that citizens would understand our work fields and evaluate anesthesiologists correctly.

The preventive effect of antineoplaston AS2-1 on HCC recurrence.

Once hepatocellular carcinoma (HCC) develops, it repeats intrahepatic metastasis and has multicentric occurrence, which requires frequent treatment. We designed a phase II clinical trail to clarify whether antineoplaston AS2-1, a mixture of sodium salts of phenylacetylglutamine and phenylacetic acid at a ratio of 1:4, prolongs the recurrence-free interval of HCC patients who undergo frequent treatments for recurrence. Ten patients were enrolled in this trial, 2 in stage I, 6 in stage II, 1 in stage III, 1 in stage IV-B at initial diagnosis. Ten patients experienced 35 recurrence-free intervals. Recurrence-free intervals during antineoplaston AS2-1 administration were significantly longer than those without antineoplaston AS2-1 (16.19+/-15.916 versus 5.05+/-2.897 months: p<0.01). Patients who experienced recurrence-free intervals with and without antineoplaston AS2-1 showed longer intervals during antineoplaston AS2-1 administration than those before and after antineoplaston AS2-1 administration (14.47+/-13.821 versus 5.07+/-2.989 versus 5.02+/-3.009 months: p<0.05). Two patients in stage I showed longer recurrence-free intervals than those in more advanced stages. In conclusion, antineoplaston AS2-1 could not prevent recurrence of HCC but prolonged the recurrence-free interval between regional treatments and improved survival rate of these patients.

An increase in body temperature during radiofrequency ablation of liver tumors.

UNLABELLED: Radiofrequency ablation (RFA) therapy using an active needle electrode inserted into liver tumors has been used clinically. To avoid hyperthermia, we investigated the relationship between the total output energy of the applied radiofrequency wave and changes in body temperature (BT) in patients receiving RFA. Fifteen patients undergoing RFA of liver tumors with general anesthesia were enrolled. The total output energy of radiofrequency waves was calculated from the power and duration of RFA. Changes in rectal (T(rect)) and tympanic temperatures were measured throughout the study. The mean number of liver tumors per patient was 1.7 +/- 1.3. The mean RFA time was 30.0 +/- 26.3 min. The mean total output energy was 125,935 +/- 114,506 J. The mean value of T(rect) increased from 36.3 degrees C +/- 0.5 degrees C to 37.0 degrees C +/- 1.0 degrees C (P < 0.01). A linear correlation was obtained between the total output energy and the changes in T(rect), indicating that T(rect) increased approximately by 1 degrees C for every 3000 J/kg of total output energy. The increase in BT during RFA of liver tumors under general anesthesia is predictable. Close observation of total output energy delivered and BT are required, and preparation of cooling measures is important, in RFA of liver tumors. IMPLICATIONS: The increase in body temperature (BT) is predictable during radiofrequency ablation (RFA) of liver tumors under general anesthesia. Close observation of total output energy delivered and BT are required, and preparation of cooling measures is important, in RFA of liver tumors.