Pic Of The Day
Posted by rob on October 31, 2004 under Uncategorized | 
Be the First to Comment
Relatives of the victims of the Beslan hostage siege light candles during a memorial service in Beslan, North Ossetia
Pic Of The Day
Posted by rob on October 30, 2004 under Uncategorized | Be the First to Comment
A man walks along the canon of a tank in front of the Motherland monument and WW II museum in Kiev during festivities marking the 60th anniversary of the liberation of Ukraine from the Nazi occupation.
Hendrick knows pain
Posted by rob on October 29, 2004 under Uncategorized | Be the First to Comment
Hendrick knows pain
|
By Ed Hinton
STAFF WRITER
October 29, 2004
Regarding Rick Hendrick, the NASCAR team owner who lost his only son, only brother, twin nieces and most of the top management of his racing empire in a plane crash last Sunday, longtime friends have no doubts.
He has turned too much personal tragedy and suffering into too many triumphs, over too many years, for those who know him to question his resilience now.
Hendrick, at 55 a familiar face at the Daytona International Speedway, has been in seclusion since this latest and worst ordeal, but …
“If anybody can stand it, he can,” said H.A. Wheeler, president of Lowe’s Motor Speedway, which lies less than a mile from the massive Hendrick Motorsports compound near Charlotte, N.C.
In 1996-97, Hendrick fought a two-front personal war for survival, against a rare form of leukemia and against federal prosecutors who wanted him sentenced to 210 years in prison — this while doctors couldn’t guarantee he had 210 hours left.
“I never saw him cry about it. I never saw him throw up his hands. There was no `Why me?’ or, `I can’t take this anymore,’” said Max Muhleman, the Charlotte-based marketing executive who 21 years ago got Hendrick his first NASCAR sponsors. They’ve been close ever since.
“Life is a series of tests, and they get harder as we get older,” said John Bickford, stepfather and mentor of Hendrick’s star driver, Jeff Gordon. “Rick Hendrick passes all the tests.”
Legendary driver Bobby Allison for more than a decade has been roundly considered NASCAR’s own version of the biblical figure Job. Allison lost both his racing sons, Clifford in a track accident in 1992 and Davey in a helicopter crash in ‘93. He still suffers debilitating effects of life-threatening injuries that ended his own career in 1988.
“This tragedy over the weekend is, by far, the most monumental thing that any of us [in NASCAR] have ever looked at,” Allison said.
“What we went through was the most horrible thing you can imagine. And we had to do it twice.
“But Rick’s lost 10 people who were members of several families — 10 sets of agonies, all part of the same package.”
Ricky Hendrick, 24, was heir-apparent not only to the most successful team in recent NASCAR history (128 wins and five championships in the elite Nextel Cup series) but the $2 billion a year retail car dealership empire, with more than 60 showrooms nationwide, his father controls.
John Hendrick, 53, stepped in to run both organizations while his brother was fighting the leukemia and the federal rap in the ’90s. Kimberly and Jennifer Hendrick, 22, were John’s daughters.
Jeff Turner was the team’s vice president and general manager. Joe Jackson was a liaison from Gordon’s primary sponsor, DuPont. Scott Lathram, 38, was a helicopter pilot for another team’s driver, Tony Stewart, and a guest of the Hendrick entourage last Sunday.
Richard Tracy, 51, and Elizabeth Morrison, 31, were staff pilots in the Hendrick fleet that includes private jets, but were flying the turboprop Beech King Air that crashed into a Virginia mountainside minutes before the start of the Subway 500 at nearby Martinsville Speedway.
Hendrick is grieving for every one of them as a family member lost, say those who know his mind, his sense of personal responsibility for 460 employees of his racing team and the thousands who work at his dealerships.
“How much can the human psyche deal with in a short period of time?” Wheeler wondered. “If you look at his trial, his leukemia, his father dying [in July, devastating an extraordinary bond] and now this, they’re all in a fairly short period of time, as far as a lifetime is concerned.”
In the holiday season of ‘96, Hendrick was given a diagnosis of chronic myelogenous leukemia, an especially deadly and difficult to treat form of the disease … and then a multi-count federal indictment, the major charge being money laundering in relation to the American Honda bribery scandal, where dealers paid corporate executives kickbacks in exchange for more of the highly demanded cars to sell.
Hendrick’s friends were privately outraged, certain he was a mostly innocent victim of grandstanding politics by prosecutors.
“Those guys have a special appetite for nailing big targets,” Muhleman said. “Rick sounded like a big target. One of the guys at American Honda had asked Rick for some loans to help him with a home mortgage. Rick loaned him money, but stopped when they kept asking for it. He didn’t go to them and say, `How about some money in order for me to get some more cars?’”
Hendrick entered a plea-bargain in order to finish the case and get on with his cancer treatments, and received a sentence of one year in home detention, during which he was forbidden from contact with his racing team.
Hendrick was fully pardoned by President Clinton in 2000, so that ordeal is over. But the leukemia is only in remission, not considered cured.
“It’s the kind of cancer that many, many people don’t beat,” Muhleman said. “It’s still serious. But the longer the remission, the better the chance.”
During the worst of Hendrick’s illness, Muhleman sent a public-relations representative to meet with Hendrick and his lawyers regularly during the legal battle.
“He would come back from those meetings and say, `Man, he looks awful today.’ Or, `He’s in such bad shape he can hardly walk.’
“But at the same time he was suffering, Rick got his marrow program started.”
Hendrick raised more than $4 million, helped expand the national bone marrow transplant match network, and gave it unprecedented publicity through his race team on national television.
“Rick was a prodigy,” Muhleman said. “He was still in his 20s, selling cars down in South Carolina, when City Chevrolet came up for sale here in Charlotte. George Shinn [controversial owner of the NBA Hornets] loaned him the money to buy it.
“That’s the dealership that was featured in the Tom Cruise movie, Days of Thunder,” Muhleman said.
The film was conceived after Hendrick invited friend Cruise to take a drive in one of his race cars.
“That was Rick’s first dealership,” Muhleman said.
Now there are more than 60, nationwide, in the Hendrick Automotive Group. His current Nextel Cup team includes drivers Gordon, Jimmie Johnson (who won the Martinsville race last Sunday before he was told the plane had crashed), Terry Labonte and Brian Vickers.
“Once again, he’s put to the test,” said Bickford, who can predict the outcome. “You look at the situation he had with the government, and out of it came a stronger organization. He delegated responsibilities. He took a negative and turned it into a positive.
“He battled leukemia. Look at all the bone marrow recipients and all the attention that’s been brought, all the money raised, all the great things.
“So constantly, these life tests are given to Rick, and he passes the tests, and out of it come stronger things.”
“I don’t think he’s likely to walk away, although many would,” Muhleman said, “and they would not only walk away, but they would get as far away as possible.”
“I have to believe that in the next couple of years the organization will be stronger, and that the whole world will benefit from things that are learned from this catastrophe,” Bickford said. “Rick will see to it that that happens.”
Ed Hinton can be reached at ehinton@tribune.com.
Copyright © 2004, South Florida Sun-Sentinel
http://www.sun-sentinel.com/sports/sfl-hendrick29oct29,0,6024739.story?coll=sfla-sports-headlines
Pic Of The Day
Posted by rob on under Uncategorized | Be the First to Comment
The moon is engulfed in the Earth’s shadow during a total lunar eclipse over Mexico City
KIT Gene Deletions at the Intron 10-Exon 11 Boundary in GI Stromal Tumors.
Posted by rob on under Uncategorized | Be the First to Comment
J Mol Diagn. 2004 Nov ; 6(4): 366-70
Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in the KIT gene, and the majority of these mutations affect the juxtamembrane domain of the kinase encoded by exon 11. Screening GISTs for KIT gene mutations is important for translational research studies and for providing prognostic information on the likelihood of tumor response to treatment with the kinase inhibitor imatinib mesylate (Gleevec). In a series of GISTs analyzed in our laboratory by a combination of denaturing HPLC and direct DNA sequencing, we identified 19 cases with KIT exon 11 deletions that included from 1 to 14 bp of intron 10 sequence and resulted in loss of the normal splice acceptor site at the beginning of exon 11. Predicted use of the next potential splice-acceptor site was confirmed by cDNA sequencing in 4 cases. Thus, the resulting mutant isoform, deletion KPMYEVQWK 550-558, was the same in all 19 cases. Only two other examples of deletions across the intron 10-exon 11 boundary have been reported, yet among 722 GISTs analyzed in our laboratories these deletions were not uncommon, accounting for 3.9% of exon 11 mutations and 2.6% of all tumors. Loss of KIT intron 10 sequences may be under-recognized if the forward primer is too close to exon 11, or if cases are examined exclusively at the cDNA level. Laboratories that offer clinical screening for KIT mutations in GI stromal tumors should be aware of this class of mutations.
http://www.hubmed.org/display.cgi?issn=15251578&uids=15507676
A novel mode of gleevec (STI-571, Imatinib) binding is revealed by the structure of spleen tyrosine kinase (Syk).
Posted by rob on under Uncategorized | Be the First to Comment
Atwell S, Adams JM, Badger J, Buchanan MD, Feil IK, Froning KJ, Gao X, Hendle J, Keegan K, Leon BC, Müller-Dieckmann HJ, Nienaber VL, Noland BW, Post K, Rajashankar KR, Ramos A, Russell M, Burley SK, Buchanan SG
J Biol Chem. 2004 10 26;
Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase required for signaling from immunoreceptors in various hematopoietic cells. Phosphorylation of two tyrosine residues in the activation loop of the Syk kinase catalytic domain is necessary for signaling, a phenomenon typical of tyrosine kinase family members. Syk in vitro enzyme activity, however, does not depend on phosphorylation (activation loop tyrosine to phenylalanine mutants retain catalytic activity). We have determined the X-ray structure of the unphosphorylated form of the kinase catalytic domain of Syk. The enzyme adopts a conformation of the activation loop typically seen only in activated, phosphorylated tyrosine kinases, explaining why Syk does not require phosphorylation for activation. We also demonstrate that Gleevec (STI-571, Imatinib) inhibits the isolated kinase domains of both unphosphorylated Syk and phosphorylated Abl with comparable potency. Gleevec binds Syk in a novel, compact cis conformation that differs dramatically from the binding mode observed with unphosphorylated Abl, the more Gleevec-sensitive form of Abl. This finding suggests the existence of two distinct Gleevec binding modes: an extended, trans conformation characteristic of tight binding to the inactive conformation of a protein kinase and a second compact, cis conformation characteristic of weaker binding to the active conformation, characteristic of activated protein kinases. Finally, the Syk-bound cis conformation of Gleevec bears a striking resemblance to rigid structure of the non-specific, natural product kinase inhibitor Staurosporine.
http://www.hubmed.org/display.cgi?issn=00219258&uids=15507431
JunB Deficiency Leads to a Myeloproliferative Disorder Arising from Hematopoietic Stem Cells.
Posted by rob on under Uncategorized | Be the First to Comment
|
Cell. 2004 Oct 29; 119(3): 431-43 The AP-1 transcription factor JunB is a transcriptional regulator of myelopoiesis. Inactivation of JunB in postnatal mice results in a myeloproliferative disorder (MPD) resembling early human chronic myelogenous leukemia (CML). Here, we show that JunB regulates the numbers of hematopoietic stem cells (HSC). JunB overexpression decreases the frequency of long-term HSC (LT-HSC), while JunB inactivation specifically expands the numbers of LT-HSC and granulocyte/macrophage progenitors (GMP) resulting in chronic MPD. Further, we demonstrate that junB inactivation must take place in LT-HSC, and not at later stages of myelopoiesis, to induce MPD and that only junB-deficient LT-HSC are capable of transplanting the MPD to recipient mice. These results demonstrate a stem cell-specific role for JunB in normal and leukemic hematopoiesis and provide experimental evidence that leukemic stem cells (LSC) can reside at the LT-HSC stage of development in a mouse model of MPD. |
http://www.hubmed.org/display.cgi?issn=00928674&uids=15507213
Personalized Medicine in Cancer: Matching Patients and Drugs
Posted by rob on under Uncategorized | Be the First to Comment
Posted: October 28, 2004
For the first time in quite a while, physicians who treat cancer are genuinely excited about the possibility that â??personalized medicineâ? may soon become a reality for some lung cancer patients.
It has been a year and a half since the drug Iressa came on the market, which works spectacularly in about ten percent of lung cancers patients and fails to help the rest. No one could figure out why.
Last spring, two groups of researchers figured out that most people who respond to Iressa have similar genetic mutations in their tumors. A later study extended the findings to a related drug, Tarceva, which is awaiting approval by the U.S. Food and Drug Administration.
Now that scientists can explain the drugsâ?? effectiveness in some cases, there is hope that they can better predict who will respond to them in the future and that lessons from Iressa and Tarceva can be applied to other cancers.
Just a few months ago, two research hospital laboratories began offering a test to detect the mutations, which occur in a gene called EGFR. The tests have been used in fewer than 200 patients so far, but scientists speculate they could become widely available in three to six months.
â??The simple fact is itâ??s all about matching the right patient with the right drug,â? says Brian Druker of Oregon Health and Science University in Portland, who was a pioneer in developing another drug, Gleevec.
â??Weâ??re in a transition phase where we donâ??t know all the options,â? says Druker, â??but the era of matching patients and drugs is not far away.â?
One of the problems is that all of the patients donâ??t fit into neat boxes, and perhaps they never will. For example, some people without the mutations also respond to Iressa for reasons that are not known, but scientists are expanding their search for key mutations that could explain this.
â??We are looking for mutations in other genes that could explain why some tumors respond to Iressa in the absence of EGFR mutations, and also looking at how and why tumors may eventually become resistant to Iressa,â? says Daniel Haber of Massachusetts General Hospital in Boston.
Haberâ??s colleague at Mass General Thomas Lynch is doing work on Iressa too. He has a clinical trial that is testing patients for the mutations as a predictor of their response to Iressa as an initial treatment. Iressa isnâ??t usually the first option; itâ??s typically given to lung cancer patients who havenâ??t responded to chemotherapy.
Iressa and Tarceva are part of a relatively new class of drugs known as targeted drugs, which are different from traditional chemotherapy drugs because they are designed to specifically hit cancer cells. Unlike chemotherapy drugs which kill healthy and cancerous cells, targeted drugs are supposed to kill only cancer cells.
The vision for these types of drugs was that they would be â??magic bulletsâ? against cancer, but theyâ??ve had their ups and downs.
Iressa didnâ??t work in most people in clinical trials, but it had marvelous, undeniable benefit for a small percentage of people, and for this reason the U.S. Food and Drug Administration approved it in May 2003.
Itâ??s approved for patients with the most common type of lung cancer, non-small-cell lung cancer, which is also the biggest killer among cancers in the United States with 140,000 new cases each year. AstraZeneca makes Iressa.
It took a year for researchers to begin to unravel the reasons behind Iressaâ??s erratic success.
Two groups of Harvard researchers painstakingly sequenced the EGFR gene, for Epidermal Growth Factor Receptor, in lung tumors from patients who responded to Iressa and those who did not. Most responders had the mutations. Non-responders did not.
Both Haber and Lynch were researchers on the study from Mass General. The other study was done by scientists at Dana-Farber Cancer Institute.
â??The studies generated significant buzz,â? says Daniela Gerhard of the Office of Cancer Genomics at the National Cancer Institute. â??It was very important and encouraging for everyone who was trying to use genomics to develop new targets for cancer treatments.â?
It was a buzz for some patients too. After the studies were published, the scientists received calls from patients trying to find out if their tumors had mutations and whether Iressa would work for them.
The problem was the scientists did not have the time or the facilities to do the sequencing.
Thatâ??s when Harvard Partners stepped in. Harvard Medical School-Partners Healthcare Center for Genetics and Genomics (HPCGG) is a Harvard-affiliated institute with DNA sequencers, and they developed a genetic test that could be done â??at costâ? for doctors at Massachusetts General and Dana-Farber.
The test was up and running in August, and the center now screens up to 50 tumors a month for roughly $850 per sample.
â??The discovery [of the EGFR mutations] was made and in a relatively short time we had turned it around into a clinical test,â? says Randall Mason of HPCGG.
At the same time, scientists at City of Hope National Medical Center in Duarte, California, saw the two Harvard studies and set to work on a genetic test for Iressa. It also had a test ready in August and has done fourteen tests to date, mostly for doctors at City of Hope Hospital. Their turnaround is about two weeks.
â??We were pretty excited by the papers and we thought the data was significant, so we immediately started to develop a test to detect the mutations,â? says Juan-Sebastian Saldivar, co-director of the laboratory at City of Hope.
He says that some of the requests for tests have been patient-driven. For example, two patients asked their doctors at City of Hope for the test because they were concerned about a side effect of Iressa, a sometimes fatal kind of pneumonia called interstitial lung disease.
â??Weâ??re not advocating that someone should be tested before they receive Iressa,â? says Saldivar. â??Itâ??s one tool that can be used in decision-making about treatments, but itâ??s not the absolute deal breaker,â? he says.
These tests raise more questions than answers right now, and theyâ??re not even widely available yet. Who should get the test? How should the information be used?
The other question that remains is why certain groups of patients such as nonsmokers and women are more likely to have the mutations and respond to Iressa and Tarceva. While most lung cancer patients are smokers, a small percent of lung tumors occur in people who have never smokedâ??and they tend to respond to Iressa.
It could take a long time to answer these and other questions about why drugs work for some people and not others. But doing so will be critical if medicine is to reach the goal of matching the right drugs with the right patients.
| Paez, J. G. et al. EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy. Science (Published online April 29, 2004). |
| Lynch, T. J. et al. Specific Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib. The New England Journal of Medicine (Published online April 29, 2004). |
| Pao, W. et al. EGF receptor gene mutations are common in lung cancers from â??never smokersâ? and are associated with sensitivity of tumors to gefitinib and erlotinib. Published online in Proceedings of the National Academy of Sciences on August 23, 2004. |
http://www.genomenewsnetwork.org/articles/2004/10/28/matchingpatients.php
Pic Of The Day
Posted by rob on October 28, 2004 under Uncategorized | Be the First to Comment
A man looks at Spanish painter Pablo Picasso’s “Woman in a Hat” at the museum Palazzo Ruspoli in Rome as part of an exhibit called “Picasso and His Epoch.”
Recent developments in the discovery of protein kinase inhibitors from the urea class.
Posted by rob on under Uncategorized | Be the First to Comment
Curr Opin Drug Discov Devel. 2004 Sep; 7(5): 600-16
Dumas J, Smith RA, Lowinger TB
With two compounds on the market (Gleevec and Iressa), and a number of drug candidates in late-stage clinical trials, small-molecule kinase inhibitors hold great potential as novel therapies for cancer and inflammatory disorders. Inhibitors from the urea class were first reported in 1996 and have emerged as an important compound class for medicinal chemists due to their unique binding mode and kinase inhibition profile. Currently, five members of this class are undergoing clinical trials, BIRB-796 (Boehringer Ingelheim Pharmaceuticals Inc), BAY-43-9006 (Bayer AG/Onyx Pharmaceuticals Inc), CP-547632 (Pfizer Inc), MLN-518 (Millennium Pharmaceuticals Inc) and KRN-951 (Kirin Brewery Co Ltd). This review focuses on the most recent developments in the discovery of urea-based protein kinase inhibitors.
http://www.hubmed.org/display.cgi?issn=13676733&uids=15503863
[Therapy of chronic myelogenous leukemia in 2004]
Posted by rob on under Uncategorized | Be the First to Comment
Dtsch Med Wochenschr. 2004 Oct 1; 129(40): 2122-7
Hochhaus A, Berger U, Hehlmann R
Chronic myelogenous leukemia constitutes a clinical model for other neoplastic diseases. The cytogenetic hallmark of CML, the Ph chromosome with the molecular juxtaposition of BCR and ABL genes and the multistep pathogenesis with the stable chronic phase, the accelerated phase and the terminal blast crisis provide the background for the translation of molecular-cytogenetic findings into clinical practice. The systematic development of the selective BCR-ABL inhibitor imatinib was based on the discovery of the molecular pathogenesis of CML. Promising preclinical data were confirmed in phase I-III trials. Concerning hematologic and cytogenetic response and adverse effects imatinib is superior to interferon alpha. Open questions are treatment duration in patients with good response, long term side effects, persistence of minimal residual disease in almost all patients, development of resistance after long term therapy, and the efficacy of combination treatments. Prospective clinical trials, e. g. CML study IV of the German CML Study Group, should answer these questions. The impact of the various treatment modalities (imatinib, interferon alpha, ara-C, allogeneic stem cell transplantation) will be elucidated. The recruitment of newly diagnosed CML patients into CML-study IV is recommended.
http://www.hubmed.org/display.cgi?issn=00120472&uids=15455305
[Complete remission of an idiopathic hypereosinophilic syndrome while using imatinib]
Posted by rob on under Uncategorized | Be the First to Comment
Dtsch Med Wochenschr. 2004 Oct 1; 129(40): 2104-6
Wolf D, Gastl G, Rumpold H
HISTORY AND ADMISSION FINDINGS: A 47-year-old man with a hypereosinophilic syndrome (HES), which has been known for 20 years, was admitted to our department due to insufficient therapeutic response to hydroxyurea. In general, the patient felt well, but reported increasing neurological problems, such as ataxia, memory deficits and dysarthria. INVESTIGATIONS: Bone marrow assessments corroborated the diagnosis of a HES. However, we were not able to detect the insertional deletion 4q12 with concomitant fusion of the FIP1L1 to the PDGFRA locus. Magnetic resonance imaging (MRI) indicated a granulomatous vasculitis, which was most likely due to the hematologic malignancy. TREATMENT AND COURSE:: Despite negativity for the FIP1L1-PDGFRA fusion gene, therapy was started with the tyrosine kinase inhibitor Imatinib. This led to a rapid normalization of eosinophilic granulocytes in the peripheral blood as well as in the bone marrow. In addition, the neurologic symptoms substantially improved. CONCLUSION: Imatinib provides a potent therapeutic option in FIP1L1-PDGFRA negative patients suffering from HES.
http://www.hubmed.org/display.cgi?issn=00120472&uids=15455302
[An alternative Abl-kinase inhibitor overcomes imatinib resistance mutations of Bcr-Abl oncogenes]
Posted by rob on under Uncategorized | Be the First to Comment
Dtsch Med Wochenschr. 2004 Oct 1; 129(40): 2100-3
Von Bubnoff N, Peschel C, Duyster J
BACKGROUND AND OBJECTIVE: The tyrosinkinase inhibitor Imatinib is active in Philadelphia-positive (Ph+) leukemia. Mutations within the Bcr-Abl kinase domain represent the major cause for clinical resistance toward imatinib. We aimed to examine, whether the alternative Abl Kinaseinhibitor SKI-DV 2 – 43 may be capable of suppressing the growth of cells expressing mutant forms of Bcr-Abl. METHODS: The proliferation of cells expressing wild-type and mutant forms of Bcr-Abl was measured in the presence of imatinib or the pyrido-pyrimidine SKI-DV 2 – 43. RESULTS: The growth of a cell line expressing wild-type Bcr-Abl was suppressed with higher potency in the presence of SKI-DV 2 – 43 when compared to imatinib. Moreover, SKI-DV 2 – 43 effectively suppressed mutant forms of Bcr-Abl that cause imatinib resistance in patients. CONCLUSION: Therefore, alternative Abl kinase inhibitors might play an important role in the future therapy of Philadelphia-positive leukemias.
http://www.hubmed.org/display.cgi?issn=00120472&uids=15455301
Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations.
Posted by rob on under Uncategorized | Be the First to Comment
Proc Natl Acad Sci U S A. 2004 10 25;
Wong S, McLaughlin J, Cheng D, Zhang C, Shokat KM, Witte ON
Protein kinase inhibitors can be effective in treating selected cancers, but most suppress several kinases. Imatinib mesylate has been useful in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and B cell acute lymphoblastic leukemia through the inhibition of BCR-ABL tyrosine kinase activity. Imatinib mesylate has also been shown to inhibit KIT, ARG, and platelet-derived growth factor receptors alpha and beta, and potentially other tyrosine kinases. We have produced a mutant allele of BCR-ABL (T315A) that is uniquely inhibitable by the small molecule 4-amino-1-tert-butyl-3-(1-naphthyl)pyrazolo[3,4-D]pyrimidine and used it to demonstrate that sole suppression of BCR-ABL activity was insufficient to eliminate BCR-ABL(+) KIT(+)-expressing immature murine myeloid leukemic cells. In contrast, imatinib mesylate effectively eliminated BCR-ABL(+) KIT(+)-expressing leukemic cells. In the cellular context of mature myeloid cells and Pro/Pre B cells that do not express KIT, monospecific BCR-ABL inhibition was quantitatively as effective as imatinib mesylate in suppressing cell growth and inducing apoptosis. These results suggest that the therapeutic effectiveness of small molecule drugs such as imatinib mesylate could be due to the inhibitor’s ability to suppress protein kinases in addition to the dominant target.
http://www.hubmed.org/display.cgi?issn=00278424&uids=15505216
Structural insights into the conformational selectivity of STI-571 and related kinase inhibitors
Posted by rob on under Uncategorized | Be the First to Comment
Curr Opin Drug Discov Devel. 2004 Sep; 7(5): 639-48
Mol CD, Fabbro D, Hosfield DJ
STI-571 (Gleevec) is a highly successful cancer drug due to its activity as an inhibitor of the Abelson cytoplasmic tyrosine kinase (Abl), which is constitutively active in a majority of patients with chronic myelogenous leukemia. STI-571 also inhibits two type III receptor tyrosine kinases, c-Kit and platelet-derived growth factor receptor, and functions by targeting inactive conformations of these kinases. This review focuses on recent developments in X-ray co-crystal structure analyses of STI-571 bound to Abl and the c-Kit receptor tyrosine kinase domain, and also three other relevant kinase inhibitor co-crystal structures. The similar structural features of these inactive kinases suggest they will be useful for the successful drug discovery and development of specific and targeted gene-based cancer drugs.
http://www.hubmed.org/display.cgi?issn=13676733&uids=15503866
Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells.
Posted by rob on under Uncategorized | Be the First to Comment
Nat Med. 2004 10 24;
Ptasznik A, Nakata Y, Kalota A, Emerson SG, Gewirtz AM
We studied the effects of Lyn ablation on the survival of drug-resistant chronic myelogenous leukemia (CML) blast crisis cells using siRNA. Lyn siRNA reduced Lyn protein in both normal hematopoietic cells and BCR-ABL1-expressing (BCR-ABL1(+)) blasts by 80-95%. Within 48 h, siRNA-treated BCR-ABL1(+) blasts underwent apoptosis, whereas normal cells remained viable. This increased dependence on Lyn signaling for BCR-ABL1(+) blast survival provides the basis for rational treatment of drug-resistant CML blast crisis, particularly when lymphoid in nature.
http://www.hubmed.org/display.cgi?issn=10788956&uids=15502840
A phase I and pharmacodynamic study of fludarabine, carboplatin, and topotecan in patients with relapsed, refractory, or high-risk acute leukemia.
Posted by rob on under Uncategorized | Be the First to Comment
Clin Cancer Res. 2004 Oct 15; 10(20): 6830-9
Cooper BW, Veal GJ, Radivoyevitch T, Tilby MJ, Meyerson HJ, Lazarus HM, Koc ON, Creger RJ, Pearson G, Nowell GM, Gosky D, Ingalls ST, Hoppel CL, Gerson SL
PURPOSE: A novel regimen designed to maximize antileukemia activity of carboplatin through inhibiting repair of platinum-DNA adducts was conducted in poor prognosis, acute leukemia patients. EXPERIMENTAL DESIGN: Patients received fludarabine (10 to 15 mg/m(2) x 5 days), carboplatin (area under the curve 10 to 12 by continuous infusion over 5 days), followed by escalated doses of topotecan infused over 72 hours (fludarabine, carboplatin, topotecan regimen). Twenty-eight patients had acute myelogenous leukemia (7 untreated secondary acute myelogenous leukemia, 11 in first relapse, and 10 in second relapse or refractory), 1 patient had refractory/relapsed acute lymphoblastic leukemia, and 2 patients had untreated chronic myelogenous leukemia blast crisis. Six patients had failed an autologous stem cell transplant. Patients ranged from 19 to 76 (median 54) years. Measurement of platinum-DNA adducts were done in serial bone marrow specimens. RESULTS: Fifteen of 31 patients achieved bone marrow aplasia. Clinical responses included 2 complete response, 4 complete response with persistent thrombocytopenia, and 2 partial response. Prolonged myelosuppression was observed with median time to blood neutrophils >/=200/microl of 28 (0 to 43) days and time to platelets >/=20,000/microl (untransfused) of 40 (24 to 120) days. Grade 3 or greater infections occurred in all of the patients, and there were 2 infection-related deaths. The nonhematologic toxicity profile was acceptable. Five patients subsequently received allografts without early transplant-related mortality. Maximum tolerated dose of fludarabine, carboplatin, topotecan regimen was fludarabine 15 mg/m(2) x 5, carboplatin area under the curve 12, and topotecan 2.55 mg/m(2) over 72 hours. An increase in bone marrow, platinum-DNA adduct formation between the end of carboplatin infusion and 48 hours after the infusion correlated with bone marrow response. CONCLUSIONS: Fludarabine, carboplatin, topotecan regimen is a promising treatment based on potential pharmacodynamic interactions, which merits additional study in poor prognosis, acute leukemia patients.
http://www.hubmed.org/display.cgi?issn=10780432&uids=15501959
Urea derivatives of STI571 as inhibitors of Bcr-Abl and PDGFR kinases.
Posted by rob on under Uncategorized | Be the First to Comment
Bioorg Med Chem Lett. 2004 Dec 6; 14(23): 5793-7
Manley PW, Breitenstein W, Brüggen J, Cowan-Jacob SW, Furet P, Mestan J, Meyer T
The constitutively active Abl kinase activity of the Bcr-Abl oncoprotein is causative for chronic myelogenous leukemia. Urea derivatives, structurally related to the therapeutic agent STI571, have been identified, which potently inhibit the tyrosine kinase activity of recombinant Abl. In particular a dimethylamino-aniline derivative (18) inhibited c-Abl transphosphorylation with an IC(50) value of 56nM. Although this activity was not translated into cellular activity against the constitutively activated oncogenic Bcr-Abl, a number of compounds from this series potently inhibited cellular PDGFR autophosphorylation. It was also possible to differentiate between c-Abl and PDGFR kinase inhibition, with compound 22 being selective towards Abl and 23 selective for PDGFR.
http://www.hubmed.org/display.cgi?issn=0960894X&uids=15501042
Pic Of Day
Posted by rob on October 27, 2004 under Uncategorized | Be the First to Comment
This image taken Tuesday, Oct. 26, 2004, by the spacecraft Cassini, is one of the closest ever of Saturn’s hazy moon Titan. The image was captured by the spacecraft’s imaging science subsystem as it flew by Titan. At its closest, Cassini was 1,200 kilometers (745 miles) above the moon, 300 times closer than during its first flyby on July 3, 2004.
Orphan Drug Designation Granted to Kosan’s 17-AAG for the Treatment of Chronic Myelogenous Leukemia (CML)
Posted by rob on under Uncategorized | Be the First to Comment
Orphan Drug Designation Granted to Kosan’s 17-AAG for the Treatment of Chronic Myelogenous Leukemia (CML)
Tuesday October 26, 7:30 am ET
HAYWARD, Calif., Oct. 26 /PRNewswire-FirstCall/ — Kosan Biosciences Incorporated (Nasdaq: KOSN – News) today announced that the U.S. Food and Drug Administration has granted its anticancer compound 17-allylamino-17-demethoxy- geldanamycin, or 17-AAG, an analog of the polyketide geldanamycin, orphan drug status for the treatment of Chronic Myelogenous Leukemia (CML). 17-AAG is being evaluated for the treatment of multiple cancer indications in Phase II, Phase I, and Phase Ib clinical trials, including a Phase Ib trial with Gleevec(TM) as a combination therapy in CML. These trials are being conducted in collaboration with the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement (CRADA) between Kosan and the NCI Cancer Therapy Evaluation Program (CTEP).
“This is the second orphan drug designation granted in the U.S. to Kosan and the NCI, and is a significant achievement for the collaborative geldanamycin analog clinical program,” said Robert G. Johnson, Jr., M.D., Ph.D., Executive Vice President, Development and Chief Medical Officer, Kosan Biosciences. “This designation strengthens Kosan’s position in this highly visible area of clinical development and can afford important marketing advantages to Kosan in the future.”
17-AAG inhibits Hsp90 (heat shock protein 90), a protein chaperone that binds to signaling proteins, known as “client proteins.” These client proteins include a “who’s who” list of cancer-relevant targets such as mutated p53, Bcr-Abl, Her2, Akt, Raf-1, B-Raf, and others. When 17-AAG binds to Hsp90, it disrupts the Hsp90-client protein complexes, leading to degradation of the client proteins.
Chronic myelogenous leukemia, or CML, often referred to as chronic myeloid leukemia is a cancer of the blood system in which too many white blood cells (WBCs) are produced in the bone marrow. CML has three distinct phases. The chronic phase can be insidious in onset and last several years. This is followed by an accelerated phase, accompanied by a more rapid growth rate of the malignant WBCs. Finally, CML patients enter into a “blast crisis” stage associated with a rapid rate of cell growth and a survival of only a few months on average. The American Cancer Society estimates that 4,300 new cases of chronic myelogenous leukemia will be diagnosed this year in the United States. CML usually occurs in people in their 40s and beyond, although it can occur in younger patients.
About Orphan Drug Designation
Orphan drug designation is granted by the U.S. Food and Drug Administration to products that treat rare diseases or conditions that affect fewer than 200,000 people in the United States. The designation provides eligibility for a special seven-year period of market exclusivity after marketing approval, potential tax credits for research, grant funding for research and development, possibly reduced filing fees for marketing applications, and assistance with the review of clinical trial protocols.
About Kosan
Kosan Biosciences has two first-in-class anticancer agents in Phase II clinical trials. KOS-862 (Epothilone D) is in Phase II and Phase Ib clinical trials and is partnered with Roche in a global development and commercialization agreement. 17-AAG, Kosan’s lead geldanamycin analog, is in Phase II and Phase Ib clinical trials, and DMAG, its second-generation geldanamycin analog, is in Phase I. Both compounds are being developed in collaboration with the National Cancer Institute. Kosan’s proprietary formulation of 17-AAG, designated KOS-953, is in Phase I. 17-AAG and DMAG are polyketide inhibitors of Hsp90 and interrupt several biological processes implicated in cancer cell growth and survival. Kosan’s focus is on an important class of natural products known as polyketides. Polyketides are a class of natural products that have yielded numerous important pharmaceuticals for the treatment of cancer, infectious diseases, high cholesterol, transplant rejection and other diseases. Kosan applies its expertise and proprietary technologies to generate polyketide analogs and increase the production yields of polyketides, resulting in a robust pipeline of potentially significant products for cancer, as well as for infectious disease and other therapeutic areas. For additional information on Kosan Biosciences, please visit the Company’s website at www.kosan.com.
This press release contains “forward-looking” statements, including statements relating to the ongoing and further development and potential efficacy and commercialization of 17-AAG and KOS-953 in the treatment of cancer. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. There are a number of important factors that could cause the results of Kosan to differ materially from those indicated by these forward-looking statements, including, among others, risks related to the clinical advancement of 17-AAG, KOS-953 and other geldanamycin analogs and Kosan’s dependence on the collaboration with the NCI and other risks detailed from time to time in the Company’s SEC reports, including its Quarterly Report on Form 10-Q for the quarter ended June 30, 2004, and other periodic filings with the SEC. Kosan does not undertake any obligation to update forward-looking statements.
Source: Kosan Biosciences Incorporated