Compact Cr:ZnS channel waveguide laser operating at 2,333 nm.

A compact mid-infrared channel waveguide laser is demonstrated in Cr:ZnS with a view to power scaling chromium laser technology utilizing the thermo-mechanical advantages of Cr:ZnS over alternative transition metal doped II-VI semiconductor laser materials. The laser provided a maximum power of 101 mW of CW output at 2333 nm limited only by the available pump power. A maximum slope efficiency of 20% was demonstrated.

Self-Q-switched waveguide laser based on femtosecond laser inscribed Nd:Cr:YVO(4) crystal.

We report on the self-Q-switched laser operation of a monolithic Nd:Cr:YVO(4) channel waveguide cavity. Femtosecond laser inscription was used to fabricate a buried channel waveguide in the substrate. The Nd:Cr:YVO(4) crystal works as both the gain medium and the saturable absorber, which enables the realization of a self-Q-switched waveguide laser pumped at 808 nm and emitting at 1064 nm. The compact waveguide cavity achieved maximum output powers up to 57 mW, corresponding to a single-pulse energy of 22.8 nJ, at 2.3 MHz repetition rate with a pulse duration of 85 ns.

Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer.

Previously, we reported on the anti-tumor activities of two designed calix[4]arene-based topomimetics (PTX008 and PTX009) of the amphipathic, angiostatic peptide Anginex. Here, we chemically modified the hydrophobic and hydrophilic faces of PTX008 and PTX009, and discovered new calixarene compounds that are more potent, cytotoxic anti-tumor agents. One of them, PTX013, is particularly effective at inhibiting the growth of several human cancer cell lines, as well as drug resistant cancer cells. Mechanistically, PTX013 induces cell cycle arrest in sub-G1 and G0/G1 phases of e.g. SQ20B cells, a radio-resistant human head and neck carcinoma model. In the syngeneic B16F10 melanoma tumor mouse model, PTX013 (0.5 mg/Kg) inhibits tumor growth by about 50-fold better than parent PTX008. A preliminary pharmacodynamics study strongly suggests that PTX013 exhibits good in vivo exposure and a relatively long half-life. Overall, this research contributes to the discovery of novel therapeutics as potentially useful agents against cancer in the clinic.

Efficient mid-infrared Cr:ZnSe channel waveguide laser operating at 2486 nm.

We report a Cr:ZnSe channel waveguide laser operating at 2486 nm. A maximum power output of 285 mW is achieved and slope efficiencies as high as 45% are demonstrated. Ultrafast laser inscription is used to fabricate the depressed cladding waveguide in a polycrystalline Cr:ZnSe sample. Waveguide structures are proposed as a compact and robust solution to the thermal lensing problem that has so far limited power scaling of transition metal doped II-VI lasers.

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

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.

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

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.

Discovery of a rare and striking new pierid butterfly from Panama (Lepidoptera: Pieridae).

We here describe and name a distinctive new pierid species in the subfamily Pierinae, Catasticta sibyllae Nakahara, Padrón MacDonald, n. sp. from western Panama. Catasticta. sibyllae n. sp. is known from only two male specimens collected at two sites which are approximately 130 km apart in western Panama. This new species is the only species in the genus without markings in the median area of both surfaces of forewing and hindwing, and our molecular data suggest that the Peruvian species C. lisa Baumann Reissinger, 1969 is its sister species.

Characterization and multiparameter analysis of visual adverse events in irofulven single-agent phase I and II trials.

PURPOSE: Irofulven (6-hydroxymethylacylfulvene) is a novel agent, derived from illudin S, with potent apoptotic effects in preclinical models. In the Phase I trial evaluating intermittent weekly schedules, visual symptoms were dose limiting. The aim of this analysis was to better characterize the visual adverse events of irofulven and provide treatment guidelines. EXPERIMENTAL DESIGN: Clinical data from 277 patients entered in single-agent Phase I to II clinical trials who received irofulven on days 1 and 15 every 4 weeks; days 1, 8, and 15 every 4 weeks; or days 1 and 8 every 3 weeks were included in this multiparameter analysis. RESULTS: Overall, 74 patients (27%) experienced visual symptoms. The most frequently reported symptoms were flashing lights (12% of patients), blurred vision (9%), and photosensitivity (8%). Grade 3 toxicity was observed in 12 patients (4%). The incidence and severity of visual events were dose dependent, with no grade 3 visual events occurring at doses < or =0.50 mg/kg and grade 1 to 2 events in only 12% and 8% of patients, at doses of < or =0.50 mg/kg and < or =20 mg/m2, respectively. Grade 1 to 2 toxicity was reversible in most patients. Abnormal electroretinogram and abnormal visual fields were noted after irofulven treatment in 24 of 39 patients (62%) and 15 of 26 patients (58%), respectively. All but 1 patient who had electroretinogram assessment received doses >0.50 mg/kg. Clinical examination and visual field assessment were found to be better correlated with symptoms and appear to be more appropriate for surveillance of irofulven retinal symptoms than electroretinograms. CONCLUSIONS: On the basis of retained antitumor activity and reversibility of grade 1 and 2 visual symptoms at lower doses, it appears that an irofulven dose of < or =0.50 mg/kg or < or =20 mg/m2, not to exceed 50 mg in a single dose, given as a 30-minute infusion on days 1 and 8 every 3 weeks or days 1 and 15 every 4 weeks minimizes the frequency and severity of visual symptoms.

Phase I and pharmacokinetic study of irofulven administered weekly or biweekly in advanced solid tumor patients.

PURPOSE: We performed a Phase I and pharmacokinetic study to determine the maximum tolerated dose of irofulven (6-hydroxymethylacylfulvene; MGI-114, MGI PHARMA, Inc.), administered in intermittent weekly schedules in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Three schedules were tested: A, days 1, 8, and 15 every 4 weeks; B, days 1 and 8 every 3 weeks; C, days 1 and 15 every 4 weeks. Drugs were administered as 5- and 30-min (schedules B and C) infusions. Dose levels of 10, 12, and 14 mg/m(2)/week were explored. RESULTS: Ninety-nine patients received 256 cycles. Fifteen of 74 patients evaluable for maximum tolerated dose experienced 16 dose-limiting toxicities (5 of 17 patients on schedule A, 2 of 25 on schedule B, and 8 of 32 on schedule C), principally treatment delay for thrombocytopenia. Schedule A was considered unsuitable because of frequent thrombocytopenia and treatment discontinuations. Twenty-three percent of the overall population (22 patients with grade 1-2, and 1 patient with grade 3), including 37% of patients on dose level 3, experienced unexpected dose-limiting visual toxicity, which included color perception and visual field alterations linked to retinal cone cell toxicity; the visual toxicity had an early onset, was mostly reversible, and was related to higher dose per infusion. Safety profiles were similar for 5- and 30-min infusions. The relationships between dose and area under the plasma concentration-time curve and maximum plasma concentration were linear for both 5- and 30-min infusions in the 78 patients evaluated for pharmacokinetics. The area under the plasma concentration-time curve and clearance were comparable between infusion durations. Responses included one complete (ovarian), one partial (renal), and seven disease stabilizations lasting >4 months. CONCLUSIONS: We recommend doses of 18 mg/m(2)/infusion for schedule B and 24 mg/m(2)/infusion for schedule C, limited to 0.55 mg/kg and a total dose of 50 mg/infusion, administered over 30-min.

Evaluation of 111In-labeled Anginex as Potential SPECT Tracer for Imaging of Tumor Angiogenesis.

Angiogenesis is a prerequisite for solid tumors to grow and metastasize, providing oxygen and nutrients to the tumor site. The protein galectin-1 has been identified to be overexpressed on tumor vasculature and represents an interesting target for anti-angiogenic therapy, as well as in molecular imaging. Therefore, the galectin-1-binding peptide Anginex was modified for radiolabeling using (111)In. In vitro, (111)In-Ax showed significantly more binding to galectin-1-positive EC-RF24 and MDA-MB-231-LITG cells than to galectin-1-negative LS174T cells and association with EC-RF24 cells was reduced in the presence of excess native Anginex. However, ex vivo biodistribution profiles showed little tumor uptake of (111)In-Ax and extensive accumulation in non-target organs. Although this study shows the ease of modification of the therapeutic peptide Anginex and favorable characteristics in vitro, in vivo assessment of the tracer revealed negligible tumor targeting. Hence, the strategy we employed lends little support for successful non-invasive imaging of tumor angiogenesis using this peptide.

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

Unlike postmitotic cell death, direct premitotic apoptosis diminishes the risk of clonal selection and allows for the elimination of slowly growing cancer cells. This study characterized the ability to induce premitotic apoptosis by irofulven (hydroxymethylacylfulvene), a novel alkylating drug which targets cellular DNA and proteins. Irofulven effects were examined in HeLa-derived BH2 cancer cells with conditional overexpression of antiapoptotic Bcl-2. Cells were synchronized in either early S or in G(1). Following 12 h exposure to irofulven, cells that were originally in early S accumulated in late S or remained in early S phase (at 0.5 and 2.5 muM drug, respectively). Drug treatment of cells in the G(1) cohort prevented their entry into the S phase. Significant apoptosis was detected based on the appearance of sub-G(1) particles and cells with DNA strand breaks in both G(1) and S cohorts. Apoptotic cells were mostly recruited from the G(1)/S border ("G(1)" cohort) and from the S phase ("early S" cohort). All the cell cycle and apoptotic effects were only marginally affected by Bcl-2 overexpression. Similar results were obtained with irofulven-treated synchronized cultures of leukemic CEM cells. Collectively, these observations indicate that irofulven-treated cells become committed to death early. Neither active DNA replication nor traverse through mitosis are necessary for irofulven-induced cell death. The ability to promote direct premitotic apoptosis is likely to play a role in the consistently potent apoptotic effects of irofulven and its ability to cause tumor regression in vivo.

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

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.

Activity of irofulven against human pancreatic carcinoma cell lines in vitro and in vivo.

BACKGROUND: Irofulven (MGI 114), a novel antitumor agent synthesized from the natural product illudin S, has a unique mechanism of action involving macromolecule adduct formation, S-phase arrest and induction of apoptosis. MATERIALS AND METHODS: This study utilized MiaPaCa pancreatic xenografts to demonstrate irofulven antitumor activity using either a daily or intermittent dosing schedule. Additionally, irofulven and gemcitabine were tested in vitro and in vivo to assess the anticancer activity of the combination. RESULTS: Both dosing regimens of irofulven demonstrated curative activity against the MiaPaCa xenografts. Similar activity of irofulven on the intermittent schedule was observed at lower total doses compared to the daily dosing schedule. Furthermore, enhanced antitumor activity was observed when irofulven and gemcitabine were combined compared to single agent activity. CONCLUSION: These results support further clinical characterization of intermittent irofulven dosing schedules and suggest that irofulven combined with gemcitabine may have activity in patients with pancreatic tumors.

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

BACKGROUND: Pancreatic carcinoma resists chemotherapeutic mediation of apoptosis. Irofulven (MGI 114, 6-hydroxymethylacylfulvene) is a novel illudin S analogue that we have shown to induce caspase-mediated apoptosis in pancreatic carcinoma cell lines. MATERIALS AND METHODS: Westem blot analysis and kinase assays were used to demonstrate the activation of Erk 1/2 and JNK1 kinases following Irofulven administration in the presence and absence of selective kinase inhibitors. RESULTS: Irofulven activates JNK1 and Erk1/2, but not p38. The addition of the MAPK inhibitors, SB202190 and PD98059 (targeting JNK1 and Erk1/2 activation, respectively), prevents kinase activation and blocks Irofulven-induced activation of caspases -3, -7, -8 and -9. Blockade of either JNK1 or Erk1/2 results in a 50% decrease in apoptosis in MiaPaCa-2 cells treated with Irofulven. CONCLUSION: Our data demonstrated that JNK1 and Erk1/2 are activated by Irofulven treatment and that blockade of either MAPK subfamily decreases apoptosis by rendering Irofulven incapable of inducing caspase activation.

A phase I and pharmacokinetic study of irofulven and capecitabine administered every 2 weeks in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD), recommended dose, dose limiting toxicities (DLT), safety and pharmacokinetics of irofulven combined with capecitabine in advanced solid tumor patients. EXPERIMENTAL DESIGN: Irofulven was given i.v. over 30 min on days 1 and 15 every 4 weeks; capecitabine was given orally twice daily, day 1 to 15. Dose levels (DL) were: irofulven (mg/kg)/capecitabine (mg/m2/day): DL1: 0.3/1,700; DL2: 0.4/1,700; DL3: 0.4/2,000; DL4: 0.5/2,000. RESULTS: Between May 2002 and March 2004, 37 patients were treated and 36 evaluable for MTD. DLT occurred in 1/6 evaluable patients in DL1 (grade 3 thrombocytopenia); 1/6 in DL3 (grade 3 thrombocytopenia); 2/7 in DL4 (grade 3 febrile neutropenia, grade 3 thrombocytopenia). DL4 was defined as the MTD and DL3 was established as the recommended dose (RD). DLTs occurred in 1 of 14 additional patients treated at DL3. No treatment-related deaths or grade 4 non-hematological toxicity occurred, and grade 3 toxicities were infrequent. Antitumor activity was observed; two partial responses were noted in thyroid carcinoma (DL1, DL4); one unconfirmed partial response was observed in a patient with nasopharyngeal carcinoma, (DL3); 12 patients had disease stabilization >3 months; of eight patients with hormone refractory prostate cancer (HRPC), one patient had PSA normalization and four short-term stabilizations of PSA occurred. Capecitabine and irofulven pharmacokinetics results did not suggest drug-drug interactions. CONCLUSIONS: Irofulven with capecitabine was adequately tolerated and evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and capecitabine 2,000 mg/m2/day.

A phase I and pharmacokinetic study of irofulven and cisplatin administered in a 30-min infusion every two weeks to patients with advanced solid tumors.

BACKGROUND: To determine maximum tolerated dose (MTD), recommended dose, safety and pharmacokinetics of irofulven combined with cisplatin in advanced solid tumor patients. PATIENTS AND METHODS: Cisplatin and irofulven were given sequentially i.v. over 30 min on day 1 and 15 every 4 weeks. Four dose levels (DL) were explored: irofulven (mg/kg)/cisplatin (mg/m2): DL1: 0.3/30; DL2: 0.4/30; DL3: 0.4/40; DL4: 0.5/40. Dose-limiting toxicity (DLT) included dosing omission and delay > 1 week. MTD was the DL with DLT in 2/2 or > or = 2/6 patients during cycle 1-2. RESULTS: Between March 2002 and April 2003, 33 patients were treated. DLT occurred in 1/6 patients in DL1 (hypomagnesemia, hypocalcemia); 1/6 in DL2 (thrombocytopenia); 2 heavily pretreated patients out of 6 patients in DL3 (neutropenic infection, thrombocytopenia, stomatitis); 2/3 in DL4 (asthenia, blurred vision). Three DLT occurred in 12 additional patients treated at DL2. No toxic deaths occurred; grade 4 toxicity and grade 3 non-hematological toxicity were infrequent. Six patients reported grade 1-2 visual events. Antitumor activity was observed over a broad spectrum of tumor types in all DLs: 1 partial response in bulky sarcoma (DL1); 1 clinical response in endometrial carcinoma (DL1); 2 partial responses not confirmed due to discontinuation (ovarian DL2, renal DL4); 8 stabilizations > 3 months; PSA response: 3/9 prostate cancer patients. Irofulven showed rapid elimination and high interpatient variability. Platinum and irofulven pharmacokinetics did not suggest drug-drug interactions. CONCLUSION: Irofulven with cisplatin was adequately tolerated and substantial evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and cisplatin 30 mg/m2.

Irofulven demonstrates clinical activity against metastatic hormone-refractory prostate cancer in a phase 2 single-agent trial.

BACKGROUND: The primary objective of this study was to assess the antitumor activity of irofulven in patients with hormone-refractory prostate cancer by measuring a sustained decrease of 50% or greater in serum prostate-specific antigen (PSA) levels. PATIENTS AND METHODS: Forty-two patients (median age, 73 years) received at least 1 dose of 10.6 mg/m2 irofulven per day on days 1-5 of a 28-day course. Eligible patients had pathologically confirmed metastatic hormone-refractory adenocarcinoma of the prostate and had not received prior cytotoxic chemotherapy. RESULTS: Forty-two patients received a median of 3 courses of irofulven. Thirty-two patients received at least 2 courses of therapy and were evaluable for efficacy. Four patients (13%) achieved partial response, with a median duration of 2.9 months (range, 2.6-5.8 months). Twenty-seven patients (84%) had disease stabilization and 1 patient (3%) progressed on study. Median progression-free survival was 3.2 months (95% confidence interval, 2.3-4.2 months), with a median progression-free survival of 4.2 months (range, 3.5-6.9 months) for responders. Grade 4 toxicities consisted of thrombocytopenia, anemia, and neutropenia, occurring in 1 patient each. The most common treatment-related grade 3 nonhematologic toxicities included asthenia (19% of patients), vomiting (14%), nausea (12%), and infection without grade 3/4 neutropenia (10%). CONCLUSION: Irofulven shows activity in hormone-refractory prostate cancer and has an acceptable safety profile, warranting further investigation of this drug, particularly in combination therapies.

Antitumor activity of irofulven monotherapy and in combination with mitoxantrone or docetaxel against human prostate cancer models.

BACKGROUND: Irofulven (6-hydroxymethylacylfulvene, HMAF, MGI 114) is a novel antitumor agent currently undergoing clinical trials in hormone-refractory prostate cancer. This report examines the efficacy of irofulven alone or in combination with mitoxantrone or docetaxel against androgen-independent prostate cancer cell lines. METHODS: To elucidate the activity of irofulven monotherapy and in combination, PC-3 and DU-145 cell lines were utilized in cellular viability assessments and tumor growth inhibition studies. RESULTS: Viability assays with irofulven and mitoxantrone show additive to synergistic activity. Furthermore, irofulven and mitoxantrone in combination exhibit enhanced antitumor activity against PC-3 and DU-145 xenografts. Additive combination effects are also observed when irofulven and docetaxel were tested against PC-3 xenografts and curative activity (8/10 CR) is observed in DU-145 xenografts. CONCLUSIONS: These studies demonstrate that irofulven displays strong activity as monotherapy and in combination with mitoxantrone or docetaxel against androgen-independent prostate cancer in vitro and in vivo; thus, supporting the clinical investigation of irofulven against hormone-refractory prostate cancer.