A logical extension in vascular targeting is therefore the application of anti angiogenic and vascular disrupting therapies in concert. Given that each the initiation of new vessel formation and the integrity with the existing blood vessel network are crucial to tumor growth and survival, this kind of a double assault for the tumor vasculature need to hold significant promise. In view of their disparate selleckchem modes of action, the combined application of AIAs and Tumor VDAs is very likely to cause complimentary anti tumor results. 37 This likelihood has become supported by observations in preclinical tumor models. As an example, the blend of VEGFR2 associated tyrosine kinase inhibition and Tumor VDA treatment was located to bring about marked enhancements in treatment method outcomes even in tumors demonstrating only a modest response to single agent remedy. 143,144 Research by which the anti VEGF antibody bevacizumab was combined with the tubulin binding Tumor VDAs CA4P or OXi4503 to deal with human distinct cell renal carcinoma xenografts showed that when two vascular targeted therapies were mixed, a drastically greater tumor response can be attained in comparison with that obtained with single agent remedies.
145 Enhanced anti tumor exercise Lacosamide has also been reported for the flavonoid Tumor VDA ASA404 in combination with bevacizumab in lung and colon cancer xenografts.146,147 Conclusions, Clinical Standing, and Future Standpoint The direct vascular targeted method to anti cancer drug advancement offers a complementary technique to the two typical chemotherapy and other targeted therapies. A wealth of preclinical information has provided evidence of concept for selective disruption of established tumor vasculature. Decreases in vascular perfusion as well as tumor shrinkage have been observed by strategies for instance DCE MRI, collectively with immunostaining and histologic evidence for selective and extensive tumor necrosis. These research have demonstrated the efficacy of Tumor VDAs in several tumor forms, nevertheless, simply because microvessels can get organ specific specialization in response to neighborhood tissue derived signals varieties,148 it really is conceivable that there may perhaps be some distinctions during the response to this kind of agents based upon the tumor internet site of origin. Importantly the preclinical investigations have concluded that Tumor VDAs hold major probable when combined with other therapies, most notably taxane chemotherapy, radiotherapy, and anti angiogenic medication. Selectivity within a clinical setting has been demonstrated by MRI procedures, in addition to a amount of Tumor VDAs have now been evaluated in Phase I and II clinical trials.
Similarly, neutropenia was by the far probably the most commonly reported grade or toxicity in both scientific tests. The security profile observed on this research was also reliable with people reported for both agents alone However, the frequencies of typical AEs of any grade and of grade or were usually increased with all the mixture, although among grade or AEs, only the improved Afatinib HER2 inhibitor frequency of hand foot syndrome with the combination reached statistical significance. Nonetheless, the decrease tolerability of your sunitinibdocetaxel regimen was reflected in extra remedy discontinuations within the mixture arm. A single explanation for this observation might relate on the open label nature of the trial, which can have impacted tolerability assessment differentially during the study arms. Likewise, the open label design could also clarify the main difference in median PFS obtained according to investigator evaluation and central critique inside the monotherapy arm. Ageneral shortcoming of this examine andmanysimilar studies was that the layout involved an unselected patient population. Enhancing future trials of targeted therapies will involve increased collection of biologic samples like bloodandtumortissue to allow study of predictive markers that will let the targeting of those agents to get optimized.
Furthermore, in sufferers with metastatic condition, studying the traits of metastatic lesions may perhaps help to optimize targeting In a substudy of your present study at the Karolinska Institutet evaluating gene expression signatures, of individuals agreed to allow cytologic Zoledronic Acid biopsies to become taken from metastatic lesions at baseline and on day of therapy, demonstrating the feasibility of this kind of studies. In conclusion, contrary to expectations dependant on preclinical designs and early clinical outcomes, the mixture of sunitinib and docetaxel, while improving ORR, failed to prolong PFS or OS in comparison with docetaxel alone when provided as very first line therapy for HER neu adverse ABC. The sunitinib docetaxel regimen evaluated in this research is thus not advisable for therapy of this patient population. Pediatric sarcomas can be a heterogeneous group of tumors and account for around percent of pediatric malignancies . Rhabdomysarcoma, Ewing sarcoma, and osteosarcoma comprise the majority of pediatric sarcomas, and being a group are chemoresponsive with established and efficacious therapeutic regimens. Nevertheless, survival charges for these tumors, when localized, only strategy percent when handled with chemotherapy and area handle with radiation remedy and or surgical resection . People with metastatic ailment have poor outcomes with expected survival amongst and percent relying for the tumor histology as well as the metastatic web site . Relapsed sickness ordinarily features a dismal end result.
In addition, the total period from 1st hormonal manipulation to initially line chemotherapy may perhaps be substantially prolonged. No matter if MDV or abiraterone would be the very first choice just after failure of initially line hormonal remedy with LHRH analogues can’t be deter?mined as nevertheless. The OS and PFS benefit of one particular drug above the kinase inhibitors of signaling pathways other, toxicity profiles, fees and restraints in healthcare budgets may perhaps figure out the preference for one oral compound in excess of another. Studies evaluating the novel agents head to head or testing the superiority of one sequential remedy over the other can be necessary later on. With escalating healthcare charges and even more lim?ited sources, healthcare systems may perhaps end up unsustainable in the future, even during the richest and most capitalistic economies in the world. Enhanced tactics to pick people will turn out to be significant to restrict remedy to those who may reward and or prevent ineffective treatment early on. Esophageal cancer can be a extremely malignant neoplasm with very poor prognosis. The mortality of this ailment is . per per , in males in females , representing .percent .percent in males percent in females of all deaths by malignant neoplasm in .Mortality has improved somewhat above the past two many years regardless of the latest enhancements in diagnosis and remedy .
The esophagus has difficult relations not only with all the nearby organs such as trachea, lung, and aorta but also together with the lymphatic tissue network. Thus, the cancer generated with the esophagus exhibits without difficulty lymph node metastasis in the broad assortment from your cervical area to the abdominal Dexrazoxane region even when this is a superficial cancer . That is why surgical intervention accompanied by intensive lymph node dissection continues to be carried out for the radical treatment method of esophagus cancer . Considering the fact that the invasion accompanying this kind of radical surgical treatment offers marked influences about the postoperative quality of life QOL , the importance of multidisciplinary method like surgical treatment chemotherapy radiotherapy is staying recognized a lot more andmore to attain powerful radical treatment. Japan clinical oncology group JCOG conducted a phase II research of chemoradiotherapy in patients with stage II, III esophageal carcinoma ESCC : JCOG study , however the end result showed lesser than the surgical final results of Japanese high volume centers . The effect of chemotherapy on esophagus cancer has already been demonstrated , and it had been recently reported that preoperative chemotherapy is a lot more powerful than postoperative chemotherapy .We have now actively performed DFP remedy as preoperative chemotherapy and obtained favorable benefits, but leukocytopenia and alopecia and in addition gastrointestinal adverse reactions such as vomiting, nausea, and anorexia so called chemotherapyinduced nausea and vomiting: CINV interfere commonly with continuation in the chemotherapy .
In situation within the SKRC 10 cells there was even a modest but sizeable increase in growth at 72 h of therapy with TGF b1. Our microarray experiments indicated that genes regulating migration and/or invasion have been downregulated. The majority of these genes are immediately regulated by TGF b signaling and also have been linked with aggressive and invasive cancer. This observation proposed that Notch inhibition perturbs the migratory and/or invasive capability of CCRCC cells. We functionally verified this making use of Boyden chamber kinase inhibitors of signaling pathways assays and mentioned a major lessen in migration when CCRCC cells have been handled with DAPT or upon Notch1 knockdown as compared to management handled cells. Also, remedy with the TGF b inhibitor SB431542 led to a significant lessen in migration of SK RC10 cells and when combining SB431542 and DAPT treatment options, no additional lower in migration was noted. Addition of exogenous TGF b1 more stimulated the migratory capacity and this impact may be attenuated by Notch inhibition. On top of that, Notch inhibition led to a pronounced and considerable reduce in invasion in the two cell lines tested when in comparison with car management. To verify the clinical significance of these effects, we assessed TGF b signaling action depending on our 145 gene TGF b signature within a previously published microarray research.
CCRCCs from sufferers with both metastatic sickness at diagnosis or that later on designed metastasis showed a considerably elevated TGFb signaling activity as as compared to tumors from patients having a localized ailment and with no documented metastases all through adhere to up .
As a result, dysregulated Notch signaling might possibly contribute to CCRCC aggressiveness at the least in portion by modulating TGF b signaling action. Discussion It’s been proven that loss of VHL, and that is the key oncogenic event in CCRCC, leads to elevated expression of TGF b1. Interestingly, Estrogen Receptor Pathway elevated ranges of TGF b1 in serum from CCRCC clients are correlated with unfavorable outcome of the illness. Consequently, the tumor microenvironment in CCRCC is rich in TGF b1. These observations so suggest that CCRCC cells might possibly have acquired the capability to evade the cytostatic effects imposed through the presence of TGF b1. It has been postulated that structural alterations of TGF b pathway parts, this kind of as mutations of TGFBR2 render tumor cells insensitive to TGF b cytostatic results. In CCRCC one can find conflicting reports on this kind of alterations and there exists an apparent lack of practical analyses of signaling activity, e.g. evaluation of pSMAD2 ranges. Experimental in vitro and in vivo experiments have indicated that TGBR3 have antitumoral results in CCRCC cells independent of TGF b1 and canonical TGFBR1/TGFBR2/ SMAD signaling.
NICD overexpression rescued the Zn5 cell patterning and diminished GFAP glial cells phenotypes in gmds morphants. Also, NICD overexpression suppressed the enhanced mauthner neuron phenotype in gmds morphants. These benefits strongly advise that Notch signaling deficiency underlies the neurogenesis and gliogenesis defects in Carfilzomib Captabin srn. To further evaluate no matter if Notch Delta signaling is deficient in srn mutants, we examined the expression of several Notch effector genes, together with hes5, her4 and heyl as direct readout of Notch transcriptional activation, applying authentic time quantitative RT PCR and in situ hybridization. mib embryos display a powerful reduction in Notch signaling and hes5, her4 and heyl had been collectively shown to get diminished in mib mutant fish and/or mice. We found that, at 48 hpf, hes5, her4 and heyl expression have been drastically reduced in srn mutants, comparable as in mib mutants, whilst to a lesser extent. For the reason that these information demonstrate that defects in neuron and glia quantity, patterning and Notch effector genes expression in srn mutants are comparable to individuals observed in mutants in the Notch Delta pathway, a reduction in Notch Delta signaling due to the lack of fucosylation accounts for these srn phenotypes.
Slytherin mutants exhibit defects in neuromuscular synaptogenesis due to Notch Delta signaling reduction Due to the fact srn was to start with identified within a display for mutants with defects sumatriptan in neuromuscular synaptogenesis, we assessed the purpose of protein fucosylation and Notch Delta signaling in neuromuscular synapse formation, particularly at the decision point where the very first neuromuscular synapses are created. Selection point neuromuscular synapse dimension was greater at 24 hpf in srn, des, dla, mib and DAPT treated embryos. At 48 hpf, mib and DAPT handled embryos showed no enlargement of selection point neuromuscular synapses, very likely due to a lowered quantity of secondary motor neurons. These defects will not be because of defects in muscle fiber integrity or quantity. These benefits present that dysregulated protein fucosylation in srn mutants resulted in an aberrant neuromuscular synaptogenesis that was phenocopied in Notch Delta signaling deficient embryos, suggesting that Notch Delta signaling plays a vital and previously unappreciated function in neuromuscular synapse formation. Slytherin mutants exhibit defects in CNS axon branching and synaptic connectivity which are independent of Notch Delta signaling Phenotypic analyses showed that srn has a number of defects that are not present in mutants within the Notch Delta pathway des, dla or mib, or DAPT taken care of embryos. From the retina, when all round cellular lamination is grossly normal in srn mutants, neuropil from the outer and inner plexiform layers are dramatically altered. In srn mutants at 48 72 hpf, the OPL and IPL synaptic layers are disorganized, and this is not seen in des, dla or medium dose DAPT handled embryos.
We explored usually means of raising the numbers of OPCs that develop into myelinating OLs. Past perform demonstrated that Notch1 signaling inhibits the differentiation of OPCs and that RGC axons in culture express the Notch ligand Jagged1. To check no matter if Notch1 is responsible for the failure of differentiation, we taken care of cocultures buy GSK2118436A above six days with DAPT, an inhibitor of ? secretase, a protease needed for Notch1 activation. The addition of DAPT improved the two differentiation and myelination, with major increases in the two MBP OLs as well as the proportion of individuals OLs that ensheathed axons to crank out many smooth MBP tubes. During the presence of DAPT, ensheathment may be observed inside of three days of coculture, which has a amount of myelinating OLs noticeable by day four. By the sixth day of coculture, better than 70% of your OPCs in axon dense regions had turn into myelinating OLs. These final results are reliable with all the proposed role for Notch1 activation in controlling differentiation and raise the chance that ? secretase may possibly also be involved with regulating the ensheathment of axons. The pharmacological inhibition of ? secretase thus offers a straightforward usually means to attain speedy myelination within this program.
Adaption of Coculture Method to Cortical OPCs The little numbers of OPCs accessible from optic nerves prompted us to adapt the coculture for use with cortical OPCs. Purification from one or two rat brains usually created ample OPCs for any variety of unique analyses.
We started purchase LDE225 by examining whether ? secretase inhibitors promote differentiation and myelination in cortical OPC cocultures. DAPT promoted cortical OL differentiation, but to a lesser degree than was observed with optic nerve cells. This suggests that differentiation of both cortical and optic nerve OPCs is inhibited by ? secretase mediated signals, and that cortical OPCs are also impacted by DAPT insensitive cues. In spite of this big difference, DAPT equivalently elevated the proportions of cortical and optic nerve OLs that ensheathed axons, suggesting that this enhancement of myelination is not simply a consequence of improved differentiation. We next evaluated the time course of a variety of myelin markers within a medium formulation that much more reliably supports wrapping and compaction. We uncovered the myelin proteins CNPase, MBP, and, to a lesser extent, proteolipid protein, were expressed as early since the 3rd day of coculture within the presence of DAPT. At this early time point, we also uncovered isolated examples of OLs expressing the late marker myelin oligodendrocyte glycoprotein and ensheathing axons. To assess irrespective of whether this expression and morphology correlated together with the deposition of several layers of myelin membrane, we labeled cocultures together with the lipophilic dyes Sudan Black or Fluoromyelin Red.
We previously observed that loss of Notch activity at embryonic day three brought on a rise in ganglion cell differentiation. To assess the timing of neural differentiation in E4.5 DAPT handled explants, we measured gene expression levels of Nell2 by selleck chemicals llc QPCR. Nell2 is often a gene upregulated early during neural differentiation. Just like Myt1, expression of Nell2 is appreciably upregulated in between 6h and 12h, and it maintains elevated expression ranges throughout the duration with the culture. We sought to find out no matter if inactivation of Notch signaling prospects to differentiation of other neurons this kind of as cone photoreceptors, one more cell sort produced early in development. For that reason, we analyzed further sets of DAPT handled retinal explants at E4.five for alterations while in the cone specific marker, Visinin. We identified that inhibition of Notch signaling triggered a remarkable boost in Visinin immunolabeling. We utilised QPCR to quantify the changes in expression of the two Visinin and retinoid X receptor ?, an more early marker for cones in chick. Just after 12h of DAPT treatment, RXR ? showed a little, but major rise in expression, and by 24h both Visinin and RXR ? are uprgegulated by ?twenty and ?15 fold respectively.
Constitutively active NICD prevents DAPT induced neuronal differentiation Though APP and Notch will be the main substrates Bleomycin with the presenilin/? secretase complex, other variety I transmembrane proteins have also been shown to get substrates for RIPping. To find out in case the effects of DAPT are unique to presenilin/? secretasemediated cleavage of Notch in embryonic retinal progenitor cells, we tested no matter if constitutively expressed NICD could stop the capacity of DAPT to induce their differentiation. E5.5 chick retinas had been dissociated and transfected by using a constitutively energetic NICD IRES GFP plasmid or GFP manage plasmid and cultured overnight. DAPT and DMSO were additional to every single issue and cultured an extra 48h. In GFP transfected cultures using the DMSO motor vehicle added, we observed a combine of progenitor cells and differentiating neurons standard of dissociated embryonic chick retinas. DAPT therapy of GFP transfected cultures resulted in reduction of cells with progenitor morphology and an increase in cells with neuronal appearance. NICD transfection resulted in clusters of cells with undifferentiated morphologies typical of progenitors, or often isolated cells with differentiated Muller glia like morphology in cultures taken care of with all the DMSO management. In addition, DAPT remedy wasn’t ready to induce neuronal differentiation in NICD transfected cells as it did with GFP transfected cells. Thus, NICD prevented DAPT induced neuronal differentiation, supporting the notion that Notch is definitely the main substrate with the presenilin/? secretase complicated responsible to the results we observe on retinal differentiation.
As noted over, all sufferers with evaluable DCE MRI information obtained CYT997 doses concerning 65 and 358 mgm two. Within this dose assortment, no distinct relationship was observed concerning CYT997 dose level along with the probability or magnitude of improvements in tumour Ktrans. Baseline full tumour median Ktrans values, nevertheless, had been correlated with all the extent of Ktrans reduction observed post treatment. A correlation persisted if the outlying patient together with the highest baseline Ktrans and greatest Ktrans fall was excluded in the analysis. Clinical outcomes Twenty Triciribine molecular weight two people have been evaluable for response. There have been no aim responses by RECIST criteria. Secure condition for 42 cycles was reached in 18 clients, and 6 sufferers finished all six cycles of CYT997 prescribed because of the clinical trial protocol. Most notable have been two research participants who had symptomatic progressive disease before study entry. Both remained in ongoing secure ailment beyond six cycles of research treatment method and each acquired an more two cycles of CYT997 off research, before creating progressive condition. Patient 21 received 152 mgm 2 in cycles one and 2, and 202 mgm two in cycles 3 eight. Patient 22 acquired 202 mgm two in all cycles.
There was no correlation concerning the duration of secure illness and the degree of reduction in Ktrans following CYT997 administration for your whole group of evaluable individuals. On the other hand, patient 21 and one other patient who obtained stable illness for 6 cycles the two had major post therapy falls in Ktrans.
DISCUSSION We describe results from the initially in human clinical trial with the cytotoxic and VDA CYT997. As proven in Table 2, CYT997 was well tolerated when given as a 24 h i.v. infusion selleck every three weeks at doses as much as and together with 202 mgm 2. Grade three and four toxicities have been observed at higher dose levels, as well as prolonged QTc interval, transient uniocular visual loss and dyspnea with hypoxia. Then again, all CYT997 toxicities had been reversible with out sequelae. The maximum QTc interval observed during the present study was 518 ms, and no ventricular tachyarrhythmias have been associated with QTc prolongation in any patient. Dose connected QTc interval prolongation has been reported with other VDA. It is notable the episode of grade three 4 dyspnea and hypoxia observed within our examine occurred in a patient that has a history of thoracic radiation remedy. On top of that, fatal bowel toxicity was reported inside a trial of combretastatin A4 phosphate in a patient with previous abdominal radiation. It happens to be as a result feasible that ionising radiation may perhaps sensitise the microvasculature of normal tissues to VDA toxicity. Despite the fact that the 358 mgm two dose degree was established as being the MTD in our research, the dose degree under was taken into consideration also toxic to become the endorsed dose for phase II studies.
To the optic fundus was regular in addition to a carotid doppler review discovered virtually no major stenoses. Big celebration didn’t have an effect on measure escalation because it took place through the minute pattern. On the other hand, the 1st CYT997 infusion in this affected person had been discontinued first soon after 17 due to thrombosis connected with its peripherally introduced fundamental catheter, and also the 2nd medication dosage was the very first presented at the given dosage amount. No even more dosage amounts got to this client. The third client had a history of radiation to some lungs huge and received CYT997 from 358mgm 3. That they created quality 3 or more hypoxia plus level Several dyspnea Lenvatinib VEGFR Inhibitors throughout infusion with analyze pharmaceutical, which had been ended first immediately after 17 they would. This professional medical condition subsequently tremendously much better and also the hypoxia remedied within the subsequent a lot of time. Some sort of 12 head ECG exhibited sinus tachycardia with no alternative discerning alterations. Chest muscles X beam unveiled some boost in a before established unilateral pleural effusion and subdued bilateral interstitial respiratory opacities which have cleared on a duplicate film the very next day. Regimen haematology and also hormones experiments ended up being unrevealing besides any temporary grade 3 height involving plasma lactate dehydrogenase. Absolutely no even more CYT997 received to this particular individual.
Several grade 2 no haematological toxicities ended up being witnessed in 1-2 sufferers each, like hypertension, elevated creatinine, proteinuria, nausea or vomiting, abdominal soreness, headache along with a fever. Associated with note, affected person Nineteen developed Posaconazole quality Only two height within plasma tv creatinine immediately after their own measure appeared to be escalated by 86 so that you can 114mgm A pair of. This kind of individual had previously been through any nephrectomy intended for renal mobile or portable carcinoma together with class A person enhanced creatinine as well as microhaematuria on guideline. A plasma creatinine place greater out of 119 mmol m One particular during normal for you to 174 mmol m A single with 8-10 in to the CYT997 infusion. Study medication infusion seemed to be ceased immediately, as well as the creatinine delivered to be able to standard degrees within 48 hrs. Zero nephrotoxicity had been seen in almost every other individual. Almost all toxicities ended up relatively easy to fix. As opposed to the majority of microtubule focusing on contra – cancers realtors, CYT997 isn’t from the development of peripheral neuropathy. Pharmacokinetics Pharmacokinetic information summarised through amount degree are supplied inside Dining room table Three or more. For a few matters, it had not been a possibility to evaluate the critical rate frequent plus, as a result, AUC0 D. Having said that, a extrapolated place on the 23 topics where it ended up being a possibility to assess the incidence frequent symbolized only Only two.6% of the overall location. Thus, AUC0 testosterone levels was implemented to the calculation regarding Craigslist in any themes. There were a highly important straight line marriage concerning AUC0 to plus the complete dosage with CYT997 infused, showing which the pharmacokinetics of CYT997 were being linear in the entire 55 flip amount range examined in this analyze.
Most typical grade 3 four AEs were neutropenia, febrile neutropenia and fatigue. Sunitinib dose reductions had been expected in 26% of sufferers and docetaxel dose reduction required in 33%. Thirty nine % of evaluable clients had a partial response. PSA declines occurred in 56% and median TTP was 42 weeks. Median progression free and total survival had not nonetheless been reached. Another ongoing phase II study is evaluating neoadjuvant androgen deprivation therapy with concurrent day-to-day SU at 37.five mg daily given for 90 days prior to definitive surgical treatment for Androgen Receptor Antagonists higher possibility nearby prostate cancer. Early effects have been presented and showed 1 pathologic CR out of 30 was obtained. 61 Sunitinib is actively becoming studied with and without the need of docetaxel in various other clinical trials. There may be also a significant phase III global trial evaluating Sunitinib and prednisone with prednisone alone in CRPC sufferers who’ve failed docetaxel based treatment. Vandetanib is actually a after each day oral multi tyrosine kinase inhibitor targeting the VEGFR, EGFR and RET pathways. 62 Vandetanib has proven guarantee in non small cell lung cancer with benefits from a randomized phase II trial revealing an improvement in progression totally free survival at 300 mg the moment regular when when compared to gefitinib.
63 These results have led to quite a few substantial phase III trials of vandetanib with and without the need of docetaxel in NSCLC. Vandetanib is presently staying investigated in quite a few phase II trials for prostate cancer in each the metastatic and non metastatic castrate resistant setting.
An additional non selective TKI in early growth for prostate cancer is GW786034. This kinase inhibitor agent is an oral multitargeted TKI that targets VEGF, PDGFR and KIT. Pazopanib features a robust volume of early phase data in other malignancies and it is at the moment in phase III clinical trials for ovarian cancer, gentle tissue sarcoma, inflammatory breast cancer and renal cell carcinoma. Several phase II clinical trials are actively recruiting people from the chemotherapy na?ve prostate cancer setting. Downstream VEGF receptor targets have also been evaluated in prostate cancer. Ly317615 is usually a potent and selective serine/threonine kinase inhibitor that targets protein kinase C, a downstream kinase involved with VEGFR signal transduction. Preclinical scientific studies reveal enzastaurin can cause inhibition of new vessel growth inside the rat corneal micropocket assay 64 also as lower MVD and VEGF ranges in human tumor xenografts. 65, 66 A randomized double blind placebo managed phase II trial of docetaxel and prednisone with and without having enzastaurin for front line therapy of CRPC is actively recruiting sufferers. two.three Targeting the tumor vascular endothelium 2.three.one Metronomic Chemotherapy In 1991, Kerbel proposed the idea that targeting the far more genetically steady tumor vascular endothelial cell might bypass the standard acquired drug resistance that has plagued traditional cytotoxic chemotherapy.