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Biomedical subjects

Hon-Wah Man

Publications and source records attributed to Hon-Wah Man.

6 recordsLinked to original sources
PubMed2003

Selective cytokine inhibitory drugs with enhanced antiangiogenic activity control tumor growth through vascular inhibition.

Selective cytokine inhibitory drugs (SelCIDs) are a novel class of phosphodiesterase 4 inhibitors discovered during a thalidomide analog discovery program. These analogs were evaluated for their ability to inhibit tumor angiogenesis, vascularity, and growth. Two analogs (CC-7034 and CC-9088) were identified that had enhanced antiangiogenic activity in Matrigel assays compared with parental thalidomide. These analogs also inhibited the growth of established K1735 and RENCA murine tumors. Tumors whose growth was suppressed by SelCID treatment exhibited decreased vessel density together with increased tumor cell hypoxia and death. The decrease in vascularity produced by SelCID treatment is attributed to a selective loss of vessels devoid of pericyte coverage, suggesting that these agents target immature tumor vessels. That tumor cell death was localized to relatively avascular or hypoxic areas, coupled with the fact that none of the analogs was cytotoxic in vitro against the tumor cells, demonstrates that these analogs are novel antivascular agents with potent antitumor activity.

Angiogenesis Inhibitors↗
PubMed2003

Alpha-fluoro-substituted thalidomide analogues.

Thalidomide, (1), has made a remarkable comeback from its days of a sedative with teratogenic properties due to its ability to selectively inhibit TNF-alpha, a key pro-inflammatory cytokine and its clinical benefit in the treatment of cancer. Thalidomide contains one chiral center and is known to be chirally unstable under in vitro and in vivo conditions. It has been hypothesized that different biological properties are associated with each isomer. Thus, chirally stable analogues of thalidomide, alpha-fluorothalidomide, (3) and alpha-fluoro-4-aminothalidomide (4) were prepared by electrophilic fluorination. Analogue 3 was found to be cytotoxic and did not inhibit TNF-alpha production in LPS stimulated hPBMC below toxic concentrations. On the other hand, 4 was non-cytotoxic at the tested concentrations and was found to be 830-fold more potent than thalidomide as TNF-alpha inhibitor.

Cells, Cultured↗
PubMed2003

Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs.

CC-4047 (Actimid) and CC-5013 (Revimid) belong to a class of thalidomide analogs collectively known as the immunomodulatory drugs (IMiDs), which are currently being assessed in the treatment of patients with multiple myeloma and other cancers. IMiDs potently enhance T cell and natural killer cell responses and inhibit tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-12 production from LPS-stimulated peripheral blood mononuclear cells. However, the molecular mechanism of action for these compounds is unknown. Herein, we report on the ability of the IMiDs to up-regulate production of IL-2 from activated human CD4+ and CD8+ peripheral blood T cells, production of IL-2 and IFN-gamma from T helper (Th)1-type cells, and production of IL-5 and IL-10 from Th2-type cells. Elevation of IL-2 production from Jurkat T cells was observed as early as 6 h poststimulation and correlated with an increase in IL-2 promoter activity that was dependent upon the proximal but not the distal AP-1 binding site. The IMiDs enhanced AP-1-driven transcriptional activity 2- to 4-fold after 6 h of T cell stimulation, and their relative potencies for AP-1 activation correlated with their potencies for increased IL-2 production in Jurkat T cells and in CD4+ or CD8+ human peripheral blood T cells. The most potent of these IMiDs, CC-4047, had no effect on nuclear factor of activated T cells transcriptional activity, calcium signaling, or phosphorylation of extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase 1/2, p38 mitogen-activated protein kinase, or c-Jun/Jun D in Jurkat T cells. These data suggest that IMiDs increase T cell cytokine production by potentiating AP-1 transcriptional activity.

Adjuvants, Immunologic↗
PubMed2003

A novel subclass of thalidomide analogue with anti-solid tumor activity in which caspase-dependent apoptosis is associated with altered expression of bcl-2 family proteins.

Thalidomide is clinically useful in a number of cancers. Antitumor activity may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-alpha and T-cell costimulatory and antiangiogenic activities. However, it may also involve direct antitumor effects. A series of second generation thalidomide analogues have been separated into two distinct groups of compounds, each with enhanced therapeutic potential, i.e., SelCIDs, which are phosphodiesterase (PDE) type IV inhibitors, and IMiDs, which have unknown mechanism(s) of action. We report here our efforts to determine direct antitumor effects of thalidomide and compounds from both groups. We found that one of the SelCID analogues (SelCID-3) was consistently effective at reducing tumor cell viability in a variety of solid tumor lines but had no effect on non-neoplastic cells. The antitumor activity was independent of known PDE4 inhibitory activity and did not involve cAMP elevation. Growth arrest was preceded by the early induction of G(2)-M cell cycle arrest, which led to caspase 3 mediated apoptosis. This was associated with increased expression of pro-apoptotic proteins and decreased expression of antiapoptotic bcl-2. Furthermore, extensive apoptosis in vivo was detected during SelCID-3-mediated inhibition of tumor growth in a murine xenotransplantation cancer model. Our results suggest that SelCID-3 represents a novel antitumor agent distinct from thalidomide and from previously characterized analogues with therapeutic potential against a range of solid tumors. This effect appears to be mediated via alterations in the expression of bcl-2 family proteins.

Animals↗
PubMed2003

Effect of 3-fluorothalidomide and 3-methylthalidomide enantiomers on tumor necrosis factor production and antitumor responses to the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).

5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is an antivascular drug that induces tumor necrosis factor (TNF) in mice. Thalidomide inhibits TNF induction by DMXAA and also potentiates its antitumor activity. We investigated whether these effects were enantiomer specific, using the R- or S-enantiomers of two nonracemizable thalidomide analogues. Racemic 3-fluorothalidomide (3FThal) and racemic 3-methylthalidomide (3MeThal) were separated into enantiomers of greater than 98% optical purity using preparative chiral column chromatography. C57Bl/6 mice implanted with subcutaneous Colon 38 tumors were treated with DMXAA (25 mg/kg) alone or together with the pure R- or S-enantiomers by a single i.p. injection. TNF levels in the serum or tumor tissues 3 h after treatment were measured using ELISAs and tumor growth was also measured. 3FThal and 3MeThal, at their respective single maximum tolerated doses (MTD) of 15 and 50 mg/kg, were more toxic in mice than thalidomide (100 mg/kg). The R- and S-enantiomers of either 3FThal or 3MeThal, at their respective MTD, inhibited DMXAA-induced TNF activity in serum and tumor tissue, but no significant differences were observed between the enantiomers. Coadministration of racemic or enantiomers of 3FThal or 3MeThal at their respective MTD did not potentiate the antitumor responses above that obtained with DMXAA alone, and no enantioselectivity was apparent. We conclude that there is no advantage in using the nonracemizable thalidomide analogues to improve the antitumor activity of DMXAA.

Angiogenesis Inhibitors↗