Purpose Because as many as 30% of cancer patients who receive chemotherapy of moderate or high emetogenic potential suffer from chemotherapy-induced nausea and vomiting (CINV), we undertook a multinational survey to identify healthcare providers’ perceived knowledge gaps, barriers, and educational interests relevant to CINV. Methods An Internet-based survey was developed and was electronically disseminated to members of Medscape, an international Internet-based continuing medical education provider. Results A total of 2388 healthcare providers responded to the survey. Although breakthrough nausea and vomiting was the most common CINV-related issue they managed in the preceding year, managing delayed nausea was the most problematic in that time period. Thirty-two percent of healthcare providers delayed or discontinued a patient's chemotherapy because of CINV. Cost of antiemetics, patients’ poor adherence to antiemetic regimens, and healthcare providers’ underestimation of risk for CINV were all barriers to effective management. Healthcare providers expressed a wide range of educational interests, including managing breakthrough CINV, keeping up with novel antiemetic agents, and learning about emerging approaches for CINV prevention/management. Conclusions This survey of healthcare providers uncovered key barriers and educational needs relevant to the management of CINV. The findings from this survey can be used to develop educational initiatives focused on improving the care of cancer patients at risk for or suffering from CINV.

Irofulven (6-hydroxymethylacylfulvene, HMAF, MGI 114) is one of a new class of anticancer agents that are semisynthetic derivatives of the mushroom toxin illudin S. Preclinical studies and clinical trials have demonstrated that irofulven is effective against several tumor types. Mechanisms of action studies indicate that irofulven induces DNA damage, MAPK activation, and apoptosis. In this study we found that in ovarian cancer cells, CHK2 kinase is activated by irofulven while CHK1 kinase is not activated even when treated at higher concentrations of the drug. By using GM00847 human fibroblast expressing tetracycline-controlled, FLAG-tagged kinase-dead ATR (ATR.kd), it was demonstrated that ATR kinase does not play a major role in irofulveninduced CHK2 activation. Results from human fibroblasts proficient or deficient in ATM function (GM00637 and GM05849) indicated that CHK2 activation by irofulven is mediated by the upstream ATM kinase. Phosphorylation of ATM on Ser 1981 , which is critical for kinase activation, was observed in ovarian cancer cell lines treated with irofulven. RNA interference results confirmed that CHK2 activation was inhibited after introducing siRNA for ATM. Finally, experiments done with human colon cancer cell line HCT116 and its isogenic CHK2 knockout derivative; and experiments done by expressing kinase-dead CHK2 in an ovarian cancer cell line demonstrated that CHK2 activation contributes to irofulven-induced S phase arrest. In addition, it was shown that NBS1, SMC1, and p53 were phosphorylated in an ATM-dependent manner, and p53 phosphorylation on serine 20 is dependent on CHK2 after irofulven treatment. In summary, we found that the anticancer agent, irofulven, activates the ATM-CHK2 DNA damage-signaling pathway, and CHK2 activation contributes to S phase cell cycle arrest induced by irofulven.Irofulven 1 (6-hydroxymethylacylfulvene, HMAF, MGI 114) is one of a new class of anticancer agents that are analogs of mushroom-derived illudin toxins. Preclinical studies and clinical trials have demonstrated that irofulven is effective against several tumor types (1-17). Studies of mechanisms of irofulven action suggest that it induces DNA damage, MAP kinase activation and apoptosis (18 -20). It is also suggested that irofulven-elicited DNA lesions are mainly repaired by transcriptioncoupled nucleotide excision repair (TC-NER) (21).In response to DNA damage, the cell evokes signal transduction pathways to arrest at G 1 /S, S, or G 2 /M checkpoints, allowing time to deal with the insult (22, 23). It has been well documented that DNA damage activates ATM (ataxia telangiectasia-mutated), and/or ATR (ATM-RAD3-related) kinases, two apical protein kinases of the DNA damage response pathways. ATM and ATR phosphorylate downstream effector kinases, CHK1 and CHK2. It is generally believed that ATM is the kinase mainly responding to ionizing radiation (IR)-induced DNA double strand breaks, while ATR responds to the formation of DNA adducts and stalled replication induced by UV, genotoxic drugs, and radia...

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.

Irofulven displays synergistic antiproliferative and pro-apoptotic effects when combined with oxaliplatin over a broad range of concentrations in human colon and breast cancer cells. Acquired resistance to irofulven has limited impact on the effects of cisplatin-irofulven and oxaliplatin-irofulven combinations. Based on these data, irofulven-oxaliplatin and cisplatin-irofulven combinations will be further explored in clinical trials, favoring the use schedules of oxaliplatin given prior to irofulven in patients with cancer.

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.