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Dive into the research topics where Stephen J. Waters is active.

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Featured researches published by Stephen J. Waters.


Bioconjugate Chemistry | 2010

Inhibiting tumor growth by targeting tumor vasculature with galectin-1 antagonist anginex conjugated to the cytotoxic acylfulvene, 6-hydroxylpropylacylfulvene.

Ruud P.M. Dings; Emily S. Van Laar; Melissa Loren; Jeremy Webber; Yan Zhang; Stephen J. Waters; John R. MacDonald; Kevin H. Mayo

Targeted delivery of therapeutic drugs promises to become the norm to treat cancer. Here, we conjugated the cytotoxic agent 6-hydroxypropylacylfulvene (HPAF) to anginex, a peptide that targets galectin-1, which is highly expressed in endothelial cells of tumor vessels. In a human ovarian cancer model in mice, the conjugate inhibited tumor growth better than equivalent doses of either compound alone. Immunofluorescence on tumor tissue demonstrated that the conjugate, like parent anginex, selectively targeted tumor vasculature and inhibited tumor angiogenesis. Increased activity from the conjugate further suggests that HPAF retains at least some of its normal cytotoxic activity when linked to anginex. More importantly perhaps is the observation that the conjugate abrogates apparent systemic toxicity from treatment with HPAF. This work contributes to the development of tumor vascular targeting agents against cancer in the clinic.


Cancer Letters | 2008

Ovarian tumor growth regression using a combination of vascular targeting agents anginex or topomimetic 0118 and the chemotherapeutic irofulven

Ruud P.M. Dings; Emily S. Van Laar; Jeremy Webber; Yan Zhang; Robert J. Griffin; Stephen J. Waters; John R. MacDonald; Kevin H. Mayo

Combination of chemotherapeutic agents and angiogenesis inhibitors is now commonly employed in the clinic to treat cancer. Here, we used angiostatic agents anginex and 0118, in combination with the chemotherapeutic irofulven, to treat human ovarian tumor xenografts in mice. General linear mixed models were used to statistically analyze tumor growth curves. Overall, combination of a low, non-toxic dose of irofulven with either angiogenesis inhibitor was more effective at inhibiting tumor growth than any of the single agent therapies. For example, the anginex/irofulven and 0118/irofulven combinations inhibited tumor growth relative to controls by 92% (p<0.0001) and 96% (p<0.0001), respectively, with the 0118/irofulven combinations yielding 100% complete responses. This study suggests that combination therapy of 0118 or anginex and irofulven may be highly effective in the clinical setting.


Biochemical Pharmacology | 2003

Apoptosis induction by the dual-action DNA- and protein-reactive antitumor drug irofulven is largely Bcl-2-independent

Maryanne C. Herzig; Alex V. Trevino; Huiyun Liang; Richard Salinas; Stephen J. Waters; John R. MacDonald; Barbara A. Woynarowska; Jan M. Woynarowski

The overexpression of Bcl-2 is implicated in the resistance of cancer cells to apoptosis. This study explored the potential of irofulven (hydroxymethylacylfulvene, HMAF, MGI 114, NSC 683863), a novel DNA- and protein-reactive anticancer drug, to overcome the anti-apoptotic properties of Bcl-2 in HeLa cells with controlled Bcl-2 overexpression. Irofulven treatment resulted in rapid (12hr) dissipation of the mitochondrial membrane potential, phosphatidylserine externalization, and apoptotic DNA fragmentation, with progressive changes after 24hr. Bcl-2 overexpression caused marginal or partial inhibition of these effects after treatment times ranging from 12 to 48hr. Both Bcl-2-dependent and -independent responses to irofulven were abrogated by a broad-spectrum caspase inhibitor. Despite the somewhat decreased apoptotic indices, cell growth inhibition by irofulven was unaffected by Bcl-2 status. In comparison, Bcl-2 overexpression drastically reduced apoptotic DNA fragmentation by etoposide, acting via topoisomerase II-mediated DNA damage, but had no effect on apoptotic DNA fragmentation by helenalin A, which reacts with proteins but not DNA. Irofulven retains its pro-apoptotic and growth inhibitory potential in cell lines that have naturally high Bcl-2 expression. Collectively, the results implicate multiple mechanisms of apoptosis induction by irofulven, which may differ in time course and Bcl-2 dependence. It is possible that the sustained ability of irofulven to induce profound apoptosis and to block cell growth despite Bcl-2 overexpression may be related to its dual reactivity with both DNA and proteins.


Journal of Pediatric Hematology Oncology | 2000

MGI 114 : Augmentation of antitumor activity when combined with topotecan

Steve Weitman; H. Barrera; Rodney V. Moore; C. Gonzalez; Jennifer Marty; Susan G. Hilsenbeck; John R. MacDonald; Stephen J. Waters; D. D. Von Hoff

PURPOSE 6-Hydroxymethylacylfulvene (HMAF; MGI 114; Irofulven) is a semisynthetic analogue of the mushroom toxin illudin S that has been shown to be a potent cytotoxic agent with an improved therapeutic index compared with its parent compound. The studies were conducted to evaluate the antitumor activity of MGI 114 as a single agent and in combination with topotecan against pediatric solid tumor cell lines and xenograft models. MATERIALS AND METHODS In vitro studies were designed to determine the cytotoxic potential of MGI 114 using the MTT assay and 13 pediatric tumor cell lines. In addition, combination in vitro studies were performed with MGI 114 and topotecan to generate isoeffect plots. Single agent and combination in vivo studies were also performed using MGI 114 against rhabdomyosarcoma and neuroblastoma xenograft models. RESULTS After a 1-hour exposure to MGI 114, the mean IC50 (+/-standard error of mean) for medulloblastoma, neuroblastoma, Ewing sarcoma/primitive neuroectodermal tumor, and rhabdomyosarcoma cell lines were 1.58+/-0.51, 1.60+/-0.82, 1.18+/-0.08, and 3.99+/-1.69 microg/mL, respectively. When tumor cells were exposed concurrently to MGI 114 and topotecan, evidence of synergy was observed in 10 of 12 (83%) cell lines. Single agent and combination in vivo studies with MGI 114 showed that this agent had substantial, and at times curative, antitumor activity against rhabdomyosarcoma and neuroblastoma xenograft tumors. CONCLUSIONS These data suggest that MGI 114 has significant efficacy as a single agent in preclinical studies against pediatric tumors. In addition, based on previous reports and the results presented here, combining MGI 114 with topotecan appears to be an attractive approach to the treatment of pediatric malignancies. After completion of the pediatric phase I studies of MGI 114, consideration should be given to phase II single agent and phase I combination studies with a topoisomerase I inhibitor such as topotecan or irinotecan.


Investigational New Drugs | 2001

Changes in Prostate-Specific Antigen (PSA) Level Correlate with Growth Inhibition of Prostate Cancer Cells Treated in Vitro with a Novel Anticancer Drug, Irofulven

Barbara A. Woynarowska; Arlene L. Higdon; Ruben M. Muñoz; Perry Bushong; Stephen J. Waters

Irofulven (hydroxymethylacylfulvene,HMAF, MGI 114) is a novel agent withalkylating activity and a potent inducer ofapoptosis. It is currently undergoing PhaseII clinical trials for several tumor types,including hormone-refractory prostatecancer. Reduction of serumprostate-specific antigen (PSA) levels hasbeen proposed as a generally usefulendpoint for evaluating the antitumorefficacy of treatments for prostate cancer.However, the utility of PSA as a marker oftumor cell burden could be compromised, ifdrugs directly affected PSA secretionand/or expression. In these studies, weevaluated the effects of irofulven on PSAprotein and mRNA levels during the courseof treatment of prostate tumor cells in vitro. Therate of PSA secretion(normalized per equal cell number) bycontrol and drug treated cells was similar,as determined by a solid phase, two-siteimmunoradiometric assay. Consistent withthe lack of effect of irofulven on PSAprotein level, the drug does not appear toaffect the expression of PSA mRNA (on a percell basis) as assessed by RT-PCR. Thus,changes in PSA secretion and expressionappear to reflect irofulven-induced cellgrowth inhibition rather than reflecting adirect effect of the drug on PSA. Theseresults suggest that PSA should be areasonable marker of tumor burden inirofulven-treated prostate cancerpatients.


Journal of Biological Chemistry | 2004

ATM-dependent CHK2 activation induced by anticancer agent, irofulven

Jian Wang; Timothy D. Wiltshire; Yutian Wang; Carmenza Mikell; Julian Burks; Cynthia Cunningham; Emily S. Van Laar; Stephen J. Waters; Eddie Reed; Weixin Wang


Cancer Chemotherapy and Pharmacology | 2006

Characterizations of irofulven cytotoxicity in combination with cisplatin and oxaliplatin in human colon, breast, and ovarian cancer cells

Maria Serova; Fabien Calvo; François Lokiec; Florence Koeppel; Virginie Poindessous; A.K. Larsen; Emily S. Van Laar; Stephen J. Waters; Esteban Cvitkovic; Eric Raymond


Molecular Cancer Therapeutics | 2004

Caspase-mediated apoptosis and caspase-independent cell death induced by irofulven in prostate cancer cells.

Huiyun Liang; Richard Salinas; Belinda Z. Leal; Teresa Kosakowska-Cholody; Christopher J. Michejda; Stephen J. Waters; Terence S. Herman; Jan M. Woynarowski; Barbara A. Woynarowska


Cancer Biology & Therapy | 2004

Cell cycle effects and induction of premitotic apoptosis by irofulven in synchronized cancer cells

Jan M. Woynarowski; Barbara A. Woynarowska; Alex V. Trevino; Richard Salinas; Terence S. Herman; Stephen J. Waters; John R. MacDonald


Anticancer Research | 2002

Irofulven (6-hydroxymethylacylfulvene, MGI 114)-induced apoptosis in human pancreatic cancer cells is mediated by ERK and JNK kinases.

Weixin Wang; Stephen J. Waters; John R. MacDonald; Caleb C. Roth; Shujun Shentu; James W. Freeman; Daniel D. Von Hoff; Alexander R. Miller

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John R. MacDonald

University of Texas Health Science Center at San Antonio

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Barbara A. Woynarowska

University of Texas Health Science Center at San Antonio

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Jan M. Woynarowski

University of Texas Health Science Center at San Antonio

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Huiyun Liang

University of Texas Health Science Center at San Antonio

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Richard Salinas

University of Texas Health Science Center at San Antonio

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Steven Weitman

University of Texas Health Science Center at San Antonio

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A.K. Larsen

École Normale Supérieure

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Florence Koeppel

École Normale Supérieure

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