Biomedical subjects

Y Tan

Publications and source records attributed to Y Tan.

221 records · Page 13Linked to original sources

PubMedDate not supplied

Methionine depletion modulates the antitumor and antimetastatic efficacy of ethionine.

The elevated methionine requirement for the growth of tumors, termed methionine dependence, is a potentially highly effective therapeutic target. To attack this target we are developing anti-methionine chemotherapy. In this study of anti-methionine chemotherapy we have observed that the methionine analog ethionine is synergistic with methionine depletion in arresting the growth of the Yoshida sarcoma both in vitro and when transplanted to nude mice. In contrast, ethionine in vitro in a methionine-containing medium is not effective against Yoshida sarcoma cells. Similarly, ethionine administered along with a methionine-containing diet is ineffective against the Yoshida sarcoma growing in nude mice. A methionine-depleted diet alone is only partially effective against tumor growth. The Yoshida sarcoma gave rise to metastases in 75% of the- organs observed in the mice on the methionine-containing diet, and 43 % of the organs in the mice on the methionine-free diet. In striking contrast, no metastases were observed in the ethionine-treated animals on the methionine-free diet. Anti-methionine chemotherapy consisting of dietary methionine depletion and ethionine administration caused an initial weight loss but the animals weight stabilized resulting in no animal deaths. The synergism of ethionine and methionine depletion is markedly similar in vitro and in vivo suggesting the observed efficacy is due to the specific anti-methionine targeting. Thus methionine depletion highly potentiates the anti-tumor and anti-metastatic effectiveness of ethionine suggesting that anti-methionine chemotherapy consisting of methionine depletion as a modulator of methionine analogs holds great promise as a new, tumor-selective therapeutic approach.

Animals↗

PubMedDate not supplied

Anticancer efficacy of methioninase in vivo.

Therapeutics that are selective for cancer would have a high potential for efficacy. We have previously shown that the metabolic defect of enhanced methionine dependence is a broad cancer-selective target. Methionine depletion can completely arrest the growth of methionine-dependent tumor cells in vivo with a reversible pre-mitosis cell-cycle block. Dietary methionine depletion can partially arrest the growth of methionine-dependent rodent tumors in vivo. This report demonstrates that methioninase isolated from Pseudomonas putida can arrest rodent and human tumors in nude mice with no apparent toxic side effects. Methioninase injected i.p. arrested the growth of the Yoshida sarcoma in nude mice and greatly slowed the growth of the H460 human non-small-cell-lung carcinoma in nude mice. The effectiveness of methioninase against H460 was in contrast to 5-fluorouracil and vincristine, which were inactive against this tumor. The activity of the administered methioninase did not cause weight loss for up to 10 days treatment at 40-120 units/day indicating the possibility of low toxicity. In contrast, vincristine was highly toxic despite its ineffectiveness. Methioninase also induced a tumor-specific late cell-cycle block. The tumor-selective late cell-cycle block induced by methioninase should be able to be exploited to enhance the tumor specificity of antimitotic drugs and other agents in future experiments. Thus methioninase is a highly effective antitumor agent with a new tumor-selective mode of action with minimal toxicity, demonstrating potential clinical effectiveness against solid tumors.

Animals↗

PubMedDate not supplied

Serum methionine depletion without side effects by methioninase in metastatic breast cancer patients.

The growth dependence of human tumors on elevated levels of methionine has been shown in preclinical in vitro and in vivo studies to be a frequently occurring, highly effective, tumor-selective therapeutic target. High purity endotoxin-free methioninase was produced from Pseudomonas putida in order to develop anti-methionine chemotherapy targeting of human tumors. A pilot Phase I clinical trial has been initiated in order to determine methioninase toxicity, the pharmacokinetics of methioninase and methionine-depletion and maximum tolerated dose. A two hour i.v. infusion of 5,000 units (0.4 g) and 10,000 units (0.8 g) and a ten hour i.v. infusion of 20,000 units (1.6 g) of methioninase was administered to patient-1, patient-2, and patient-3, respectively. All patients had advanced breast cancer. Blood and urine samples were obtained at frequent intervals between 0 and 24 hours. The toxicity evaluations were carried out according to FDA criteria. Pharmacokinetics data were obtained for both methioninase and methionine levels in the serum. No acute clinical toxicity was observed for all the toxicity criteria measured in patient-1, patient-2 and patient-3. The depletion of serum methionine started within 30 minutes of the infusion, and was maintained for 4 hours after the infusion was completed in patient-1 and patient-2. The lowest serum methionine levels were 35% and 19% of the pretreatment level, respectively, in patient-1 and patient-2. Patient-3 received a ten hour i.v. infusion of 20,000 units of methioninase without any signs of side effects. Patient-3 maintained serum levels of methioninase as high as 50% of the maximum level for a subsequent 6 hours after infusion. Methionine was depleted over 200-fold from 23.1 microM to 0.1 microM by the 10-hour infusion of patient-3. No clinical toxicity was observed whatsoever in all the toxicity criteria measured in patient-3. The results of the methioninase pilot Phase 1 clinical trial suggested that i.v. infusion of the methioninase is safe and effectively depletes serum methionine without any signs of side effects. Clinical studies are continuing to determine the maximum length of time complete serum methionine depletion can be tolerated.

Antimetabolites, Antineoplastic↗

PubMedDate not supplied

Visualization of the metastatic process by green fluorescent protein expression.

We demonstrate here the visualization of the cancer metastatic process in live tissue in vivo by green fluorescent protein (GFP) expression. The human lung adenocarcinoma cell-line Anip 973 was transfected with the humanized GFP-S65T cDNA and stable high-level GFP-expressing transfectants were established. GFP transfectants were initially inoculated subcutaneously in nude mice. Five weeks after transplantation, when the tumor had reached 1.2 cm in diameter, fragments of subcutaneously tumor were implanted onto the visceral pleura of nude mice by surgical orthtopic implantation (SOI) as a spontenous metastatic model. GFP expressing cells were injected intravenously in nude mice as an experimental hematogenous metastasis model. Mice were sacrificed four and eight weeks after treatment. At eight weeks, SOI-treated mice had lymphogenous (3/4 mice) and direct seeding (3/4) metastasis in the pulmonary hilum, cervical lymph nodes, the mediastinum and contralateral pleural cavity as detected by GFP expression in live tissue. All intravenously injected mice had metastases in the lung (4/4) and some of them had metastases in the brain (2/4) and other organs (1/4) as detected by GFP expression in fresh tissue. Some of the lung metastases produced by intravenous injection remained as dormant small colonies even eight weeks after treatment. These different metastatic patterns after SOI and intravenous injection visualized by GFP expression indicates that initial steps of the metastatic cascade influence the subsequent progression of metastasis.

Animals↗

PubMedDate not supplied

Recombinant methioninase infusion reduces the biochemical endpoint of serum methionine with minimal toxicity in high-stage cancer patients.

The tumor-specific increased minimal requirement for methionine has been shown to be a highly promising therapeutic target. To attack this target we have previously cloned the methioninase gene from Pseudomonas putida and produced recombinant methioninase (rMETase). A pilot Phase I clinical trial has been carried out to determine rMETase toxicity, rMETase pharmacokinetics, and serum MET-depletion in cancer patients. Patients with advanced breast cancer, lung cancer, renal cancer and lymphoma were given a single rMETase treatment at doses ranging from 5,000 to 20,000 units by i.v. infusion over 6-24 hours. No clinical toxicity was observed in any patient after rMETase treatment. rMETase levels reached 0.1 to 0.4 units per ml of serum in the patients which correspond to therapeutic levels in vitro. The lowest serum methionine levels in rMETase-treated patients were 0.1% of the pre-treatment levels corresponding to approximately 0.1 microM, which also correlates to therapeutic levels in vitro. The results of the rMETase pilot Phase I clinical trial therefore indicate that i.v. infusion of rMETase is safe and effectively depletes its biochemical target of serum methionine suggesting potential efficacy in future clinical trials.

Antimetabolites, Antineoplastic↗