This study was to examine the effects of microinjection of human recombinant interleukin 2 (IL-2) into locus coeruleus (LC) on spinal nociception. Following application of IL-2 (0.1 microl, 10 pM) into LC, the percentage of inhibition of nociceptive C responses of reflex at 3, 9, 15, 21 and 27 min after injection were 88.2 +/-9.4%, 84.0 +/- 11.8%, 89.7 +/- 10.5%, 57.1 +/- 8.7% and 26.3 +/- 12.2%, respectively. Also, the expression of Fos protein in superficial dorsal horn was reduced by 73.01 +/- 13.58% of control (P<0.0001). Naloxone (10 microg, i.p.) completely blocked the IL-2-induced inhibition of C responses. The results clearly show that IL-2 receptors present in LC mediate descending inhibition of the spinal nociception, which may couple with the activation of opioid receptors on LC neurons.

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Gender, technology change and globalization: the case of China.

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Asia↗

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Vascular dementia, with special reference to its vascular and immunological events.

Vascular dementia (VaD) is an poorly defined entity; it relates to different vascular mechanisms and different changes in the brain and has different clinical manifestations with different etiologies. From the pathogenetic and therapeutic point of view, we tried to find some practical events that could help identify VaD. We combined critical review with our own clinical and laboratory experience and found that some vascular, nonvascular, and immunological components are involved in the pathogenesis and treatment of VaD. We concluded that although the definition, etiology, clinical manifestation, laboratory data, and treatment are still controversial, it is useful to find some common, key points in the pathogenesis and treatment of VaD.

Dementia, Vascular↗

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Human tumors are methionine dependent in vivo.

Methionine-dependence is a tumor-specific biochemical defect expressed by the inability or decreased ability of tumors to grow under the condition of methionine-depletion. Many reports have shown that methionine-dependence occurs in human tumors of all types, including fresh surgical specimens in vitro. However, in vivo determinations of methionine-dependence have thus far been made only in rodent malignant tumors using methionine-deficient diets. We report here for the first time that human cancer xenografts in nude mice are methionine-dependent and when fed a methionine-free diet tumor growth is greatly inhibited. The body weight of mice on the methionine-free diet was found to be maintainable by once-per-week administration of methionine. The data presented here suggest that methionine-dependence can be an important target for human cancer treatment.

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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↗

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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.

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