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Chapter 2
Metastasis and Drug Resistance

Dominic Fan, Sun-Jin Kim, Robert L. Langley, and Isaiah J. Fidler
Multidrug resistance (MDR) phenotype emerging from chemotherapy is a major problem in managing patients with metastatic cancers. The discovery thata cardiovascular drug, verapamil, can bind to P-glycoprotein and reverse MDR ini-tiated serious research efforts in MDR-reversal by various compounds and modesof pharmacological modifiers. Those include major calcium channel blockers suchas bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine and nimodip-ine, verapamil and analogs; calmodulin antagonists; antibiotics and analogs; indolealkaloids; cyclosporins and analogs; hormones and antihormones; pharmaceuticalemulsifying surfactants; liposomal encapsulation; etc. The majority of the studiestargeted one of the MDR mechanisms, P-glycoprotein. These studies have beensuccessful under in vitro and limited in vivo animal conditions; the correlations forclinical trails are still lacking. Therefore, an effective MDR-reversing chemother-apy is not available. It is the purpose of this chapter to review the past and currentexperimental reversal of MDR and, in particular, the importance in targeting drugresistance in relevant cancer metastasis models.
Keywords Metastasis · MDR · Apoptosis · Animal models
Despite improvements in diagnosis, surgical techniques, patient care, and adjuvanttherapies, most deaths from cancer are due to metastases that are resistant to conven-tional therapies (Fidler 1990). The major obstacle to effective treatment is tumor cellbiologic heterogeneity. Moreover, the metastases can be located in different organs,and the specific organ environment can influence the biologic behavior of metastatic D. Fan (B)Department of Cancer Biology, Cancer Metastasis Research Center, Unit 854, The University ofTexas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USAe-mail: dfan@mdanderson.org K. Mehta, Z.H. Siddik (eds.), Drug Resistance in Cancer Cells, DOI 10.1007/978-0-387-89445-4 2, C  Springer Science+Business Media, LLC 2009 D. Fan et al.
cells, including their response to systemic therapy. Only a better understanding ofthe molecular mechanisms that regulate the process of metastasis and the interac-tions between the metastatic cells with the organ microenvironment can provide afoundation for the design of more effective therapy.
The Pathogenesis of Metastasis
The process of metastasis is highly selective and consists of a series of sequential,interrelated steps. To produce clinically relevant lesions, metastatic cells must com-plete all steps of this process. After the initial transformation and growth of cells,vascularization must occur if a tumor mass is to exceed 1 mm in diameter. The syn-thesis and secretion of several proangiogenic factors by tumor and host cells and theabsence of antiangiogenic factors play a key role in establishing a capillary networkfrom the surrounding host tissues. Next, local invasion of the host stroma occursas a consequence of the enhanced expression of a series of enzymes (e.g., collage-nase). Once tumor cells penetrate lymphatic or vascular channels, they may growat the invasion site or detach and be transported within the circulatory system. Thetumor emboli must survive immune and nonimmune defenses and the turbulenceof the circulation, then arrest in the capillary bed of receptive organs, extravasateinto the organ parenchyma, proliferate, and establish a micrometastasis. Growth ofthese microscopic lesions requires development of a vascular supply and evasion ofhost defense cells. When the metastases grow, they can shed tumor cells into thecirculation to produce metastasis of metastases (Fidler 1990).
The outcome of the metastatic process depends on multiple and complex interac- tions of metastatic cells with host homeostatic mechanisms (Fidler 1997). More thana century ago, Stephen Paget researched the mechanisms that regulate organ-specificmetastasis, i.e., pattern of metastasis by different cancers, and questioned whetherthe organ distribution of metastases produced by different human neoplasms wasdue to chance and analyzed more than 700 autopsy records of women with breastcancer. His research documented a nonrandom pattern of visceral (and bone) metas-tasis. This finding suggested to Paget that the process was not due to chance but,rather, that certain tumor cells (the "seed") had a specific affinity for the milieu ofcertain organs (the "soil"). Metastases resulted only when the seed and soil werecompatible (Paget 1889).
A current definition of the "seed and soil" hypothesis consists of three principles.
First, neoplasms are biologically heterogeneous and contain subpopulations of cellswith different angiogenic, invasive, and metastatic properties (Fidler 2003; Lang-ley and Fidler 2007). Second, the process of metastasis is selective for cells thatsucceed in invasion, embolization, survival in the circulation, arrest in a distant cap-illary bed, and extravasation into and multiplication within the organ parenchyma.
Although some of the steps in this process contain stochastic elements, as a whole,metastasis favors the survival and growth of a few subpopulations of cells that pre-exist within the parent neoplasm (Fidler and Kripke 1977; Talmadge et al. 1982).
2 Metastasis and Drug Resistance Thus, metastases can have a clonal origin, and different metastases can originatefrom the proliferation of different single cells (Fidler and Talmadge 1986; Hu et al.
1987; Talmadge et al. 1982).
Third, and perhaps the most important principle for the design of new can- cer therapies, is that the outcome of metastasis depends on multiple interactions("cross-talk") of metastatic cells with homeostatic mechanisms, which the tumorcells can usurp (Fidler 1995). Therapy of metastasis, therefore, can be targeted notonly against tumor cells but also against the homeostatic factors that promote tumorcell growth, survival, angiogenesis, invasion, and metastasis.
One of the most depressing and predictable facts of cancer management is the devel-opment of the multidrug resistance (MDR) phenotype in patients treated chronicallywith certain natural chemotherapeutic drugs. This clinical phenomenon accounts forthe unsatisfactory low incidence of response rate for the majority of solid tumors tochemotherapy – one of the few conventional treatments for metastatic diseases inpast few decades.
Since the heterogeneous nature of tumor and cancer metastasis was conceptu- alized (Paget 1889; Fidler 1973; Fidler and Kripke 1977; Fidler 1978; Poste andFidler 1979; Fidler and Poste 1985; Fidler 2001), it is clear that MDR is a resul-tant clinical outcome manifested by successful cancer cells endowed with multi-ple mechanisms for survival. Like other vital traits of metastatic cancer cells, MDRshould be conceived as a phenotype marked by a collection of independent or collat-eral modifications, overexpressions, and/or amplifications of endogenous moleculesthat interplay with distinct normal cellular pathways (Fig. 2.1) that include ABC Transporters Tubulin Mutation Episomes Amplification Topoisomerase II Mutation Altered Cellular Calcium Levels Enhanced Sodium Pump Activity Altered Reduction-Oxidation Pathways Formation of Double Minute Chromosomes Overexpression of Cytoplasmic 22 kDa Sorcin Fig. 2.1 MDR-associated mechanisms
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P-glycoprotein (Juliano and Ling 1976; Kartner et al. 1983), protein kinase-C (PKC)overexpression (Fan et al. 1992a, b; Aftab et al. 1994), ABC transporters (Adachiet al. 2007), tubulin mutation (Inaba et al. 1987), episomes amplification (Ruiz et al.
1989), formation of double minute chromosomes (Von Hoff et al. 1990), alteredcellular calcium levels (Nair et al. 1986), topoisomerase II mutation and alteredreduction–oxidation (Deffie et al. 1988), and the overexpression of cytoplasmic 22-kDa sorcin (Hamada et al. 1988). Those cancer cells employing single and espe-cially unique oncogenic mechanism, presumably exist, would likely be eliminatedby the host defense mechanisms during the progression of cancer or by conventionalcancer therapy and would be without further clinical manifestation. Therefore, ini-tial treatment with chemotherapeutic drugs and subsequent reversal of MDR shouldbe combined as a standard protocol for effective chemotherapy at the onset of cancermanagement, rather than resolving to salvage therapies – when the patients returnwith compromised performance status and growth of refractory tumors.
Unfortunately, an effective MDR-reversing chemotherapy is not available. Since the inception of an organized drug-screening program (DeVita et al. 1979), researchefforts have been largely compound-oriented (sensitive drug-screens) (Frei 1982;Venditti 1981) rather than disease-oriented (tumor panels) (Alley et al. 1988),metastasis-oriented (orthotopic animal models) (Wilmanns et al. 1992; Singh et al.
1994; Killion et al. 1999; Langley and Fidler 2007) or MDR-oriented (relevant resis-tant drug-screens) (Mickisch et al. 1991a, b, Dong et al. 1994). In the followingsections, we review the past and current experimental reversal of MDR and, in par-ticular, the importance in targeting drug resistance in cancer metastasis.
Reversal of Experimental MDR
The majority of the MDR-reversing studies were in vitro assays that cannot addressthe complexity of physiology and pathology in cancer patients, and in particularmetastasis of the cancer. It is physiology and pathology that modulate the progres-sion of cancer and metastasis and the pharmacokinetics (what the host and cells doto the drugs) and pharmacodynamics (what the drugs do to the host and cells) (Fordand Hait 1990). Decisively, the validity of an in vitro assay is governed by its abil-ity to derive an acceptable level of sensitivity (the prediction of true positives) andspecificity (the prediction of true negatives) (Fan et al. 1985).
Calcium Channel Blockers
Verapamil and Other Clinically Approved Agents
As the elements of time and costs stacking up against the development of newanticancer drugs, the initial observation of Tsuruo et al. (1981) of a reversal byverapamil (a coronary vasodilator) on an MDR phenotype in P388 leukemia cells(Tsuruo et al. 1981, 1982) inscribed the beginning of an explosive search for 2 Metastasis and Drug Resistance MDR-reversing anticancer therapeutics. Several major calcium channel blockersapproved for clinical use in the United States were candidates for such a search:bepridil (a pyrrolidylamine), diltiazem (a benzothiazepine), felodipine, isradipine,nicardipine, nifedipine and nimodipine (dihydropyridines), and verapamil (a ben-zeneacetonitrile). Although one of the major biological effects of verapamil is theblockage of the slow-channel-mediated calcium entry into cardiac cells (Kohlhardtet al. 1972) and drug-resistant cancer cells (Bucana et al. 1990), its MDR-reversingmechanism is not clearly understood and may be quite apart from its physiologicaction, in which a trial depolarization plays an important role and is related tothe fast-channel effect for sodium influx (Rougier et al. 1969). Verapamil-mediatedenhancement of intracellular accumulation of MDR-linked anticancer drugs is uni-versally observed and attributed to an effect on P-glycoprotein-mediated efflux ina variety of cancer cell lines (Tsuruo et al. 1982; Inaba et al. 1979; Harker et al.
1986). Extensive efforts were made to identifying and translating the unique MDR-reversing properties of verapamil and other calcium channel blockers into clini-cal terms (Slater et al. 1982; Tsuruo et al. 1983a, b; Fojo et al. 1985; Fine et al.
1987; Ford et al. 1990; Fan et al. 1994a, b). Unfortunately, the adverse hemato-dynamic effects of verapamil have limited its clinical potential for routine use inadjunct chemotherapy (Ozols et al. 1987). In addition to verapamil, many clinicallyapproved calcium channel blocker were shown to affect intracellular accumulationof MDR-linked anticancer drugs and to reverse MDR phenotype in vitro (Tsuruoet al. 1983a, b; Schuurhuis et al. 1987; Hollt et al. 1992; Fan et al. 1994a, b). How-ever, with the exception of the bepridil studies, most preclinical studies employedconcentrations of calcium channel blockers much higher (to achieve experimentalMDR-reversing activity) than the peak plasma levels derived from patients whoseperformance status was less compromised than those of cancer patients enteringclinical trials with advanced disease. Therefore, it was not surprising that difficultieswere encountered in clinical trials using verapamil (Ozols et al. 1987) and with othercalcium channel blockers for reversing drug resistance to standard chemotherapeu-tics in advanced cancer patients. At a micromolar dose range of verapamil, the cyto-toxic effects to normal cells are remarkably severe (Lampidis et al. 1986). Further-more, the high-dose requirement for reversal of MDR in vitro suggested additionaleffects (mechanisms of action) other than a simple physiologic blockage of the cal-cium channels (Huet and Robert 1988). Several groups have shown that verapamilcan bind to P-glycoprotein and compete for binding sites for MDR-related agentsto P-glycoprotein (Cornwell et al. 1987; Safa et al. 1987; Akiyama et al. 1988;Beck et al. 1988). It was shown that in the process of reversing an MDR pheno-type, verapamil also stimulated marked ultrastructural changes (an MDR-associatedtwofold increase in the number of intramembrane particles) of drug-resistant P388cells (Garcia-Segura et al. 1992). Moreover, under certain experimental conditions,treatments of the drug-resistant human colon LS 180 with verapamil, nifedipine,nicardipine, or diltiazem could increase mdr-1 mRNA expression and induce celldifferentiation (Herzog et al. 1993).
If one examines the bulk of in vitro literature and the clinical pharmacoki- netic information, one finds in general a lack of consideration for controlled D. Fan et al.
pharmacokinetic parameters (e.g., plasma elimination half-life of chemosensitizersand of standard anticancer drugs) to simulate relevant pharmacodynamic effects invitro. As nonphysiologic as in vitro assays are, chemical–cell interactions do fol-low the law of concentration and time; this kind of pharmacologic considerationmay help in reducing the frequency and costs in deriving false-positive experimen-tal new drugs and MDR-reversing agents. Therefore, while it may be feasible toseek enhancement for the efficacy of standard anticancer drugs by verapamil andother calcium channel blockers, the selectivity, scheduling, and dose intensity of thechemosensitizers must be taken into consideration inasmuch as these parametersmay influence MDR, tumor spread, and clinical outcome of therapy.
Verapamil Derivatives and Other Experimental Calcium Channel Blockers
The disappointment of the initial clinical trials with verapamil (Ozols et al. 1987)stimulated an intense effort to develop chemosensitizers that were less cytotoxic tonormal cells: one of the critical parameters in systemic cancer therapeutics (Lam-pidis et al. 1986; Fan et al. 1988). A number of structural analogs to verapamil(e.g., devapamil, emopamil, gallopamil, D528, D595, D792) have been implicatedin the reversal of MDR in vitro (Pirker et al. 1990) with marginal toxicity inanimal models (Nawrath and Raschack 1987; Pirker et al. 1989). The less cal-cium antagonistic and less cardiotoxic R-enantiomer of verapamil (versus that ofclinically approved racemic verapamil) could reverse an MDR phenotype in vitro(Mickisch et al. 1990a, b). R-enantiomer of verapamil decreased the expression ofP-glycoprotein, resistance to tamoxifen, and experimental pulmonary metastases ofthe R3230AC rat mammary adenocarcinoma in vivo (Kellen et al. 1991). Therefore,the potential for clinical enhancement of standard chemotherapeutic drugs medi-ated by verapamil and its derivatives remains on the horizon (Chatterjee et al. 1990;Mickisch et al. 1991a; Hollt et al. 1992; Kroemer et al. 1992; Teodori et al. 2005;Shen et al. 2008).
Calmodulin is an intracellular calcium-binding protein that plays critical roles in awide range of cellular activities (Ramakrishnan et al. 1989). Although the lack ofdown-regulation of calmodulin was found to produce higher levels of this proteinin transformed cells (Jaffr´ezou and Laurent 1993), such difference was not foundbetween the drug-sensitive and MDR P388 leukemia cells (Nair et al. 1986). How-ever, its calcium-sequestrating regulatory roles prompted investigation on the MDR-reversing effects of the potent calmodulin antagonist trifluoperazine (Tsuruo et al.
1982, 1983b; Klohs et al. 1986), and many antipsychotic phenothiazines marketedin the United States for clinical use and investigational compounds were found toreverse experimental MDR (Ganapathi et al. 1984; Ford et al. 1989; Ford et al. 1990;Fan et al. 1994b; Zhu et al. 2005).
2 Metastasis and Drug Resistance Antibiotics and Analogs
New drug development is time consuming and costly, hindering the availabilityof effective anticancer drug for the treatment of metastatic cancer. Similar to thecircumvention of clinical side effects of anticancer drugs (Tsuruo et al. 1983a, b),one approach to overcome drug resistance of cancer cells would be the developmentof derivatives amongst clinically proven chemotherapeutic compounds. Severalantibiotics such as the third-generation broad-spectrum cephalosporins (cefopera-zone and ceftriaxone) (Gosland et al. 1989), protein synthesis inhibitor antibacterialerythromycin (Hofsli and Nissen-Meyer 1989), veterinary antimicrobial monensin(Ling et al. 1995), a variety of vinca alkaloid derivatives (Ruiz et al. 1989; Nasioulaset al. 1990) were found to reverse experimental MDR phenotypes. Of particularinterest is the MDR-reversing effect of an anticancer benzylisoquinoline plant alka-loid thaliblastine that binds to P-glycoprotein and reverses doxorubicin resistanceof the P388 MDR cells (Chen et al. 1993). Its low toxicity (Todorov 1988) andstructural similarity to other compounds that have a photoaffinity for P-glycoprotein(Beck and Qian 1992) make it a potential chemosensitizer with a promising prospect(Pajeva et al. 2004).
Mdr-like genes exist across the entire phylogenetic spectrum. The reversal of MDRphenotypes in mammalian cells by calcium channel antagonists has functionalanalogies with the effects of agents circumventing chloroquine resistance in parasiteprotozoa (Bitonti et al. 1988), in which the drug-resistant phenotype was conferredby a protein coded by a gene closely related to mammalian mdr1 (Wilson et al.
1989). The indole-containing antimalarial quinine and structurally related com-pounds such as its anti-arrhythmic stereoisomer sodium channel blocker quinidinehave been found to produce an MDR-reversing activity (Tsuruo et al. 1984; Lehnertet al. 1991; Sato et al. 1991). Many of those compounds are neurohumoral antag-onists that include reserpine (antihypertensive and antipsychotic) and yohimbine(α-adrenergic blocker chemically similar to reserpine) (Fan et al. 1994a). Althoughit is clear that the functionality of the human mdr1 gene product is distinct from themalarial counterpart (Ginsburg and Krugliak 1992), the reversal of drug resistancein both systems by similar compounds implies the possibility of similar responsesfor action (Vezmar and Georges 2000).
Cyclosporins and Analogs
Cyclosporin A, the complex hydrophobic fungal cyclic undecapeptide, is commonlyused as an immunosuppressant for organ transplantation. At concentrations achiev-able clinically, it is considered one of the most effective MDR-reversing agents.
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The original reports of Slater et al. (1986a, b) initiated extensive studies on MDR-reversal, mediated by cyclosporins and related compounds (Twentyman et al. 1987;Chao et al. 1990; Dorr and Liddil 1991; Spoelstra et al. 1991; Loor et al. 1992;Arceci et al. 1992). Although cyclosporins have high affinity for P-glycoprotein(Goldberg et al. 1988; Foxwell et al. 1989), the reversal effects of cyclosporinsdid not correlate consistently with either drug accumulation (Slater et al. 1986a,b; Chambers et al. 1989; Hait et al. 1989) or direct interaction with P-glycoprotein(Hait et al. 1989). Nevertheless, cyclosporins and related compounds continue toproduce reversal of experimental MDR phenotypes (Shen et al. 2008). Its derivativeSDZ PSC-833 (Boesch et al. 1991; Ludwig et al. 2006; Shen et al. 2008) and thesemi-synthetic cyclic peptolide derivative SDZ 280–446 (Loor et al. 1992; Lehneet al. 2000) showed MDR-reversing effects superior even to those of cyclosporin A,which was about one order of magnitude more active than other known chemosen-sitizers such as verapamil.
Hormones and Antihormones
The induction, in pregnant murine uterus, of high levels of mdr1 mRNA, mediatedby estrogen and progesterone (Arceci et al. 1988), and the cross-resistance of MDRbreast carcinoma cells to antiestrogens with concomitant loss of estrogen recep-tors (Vickers et al. 1988) and progesterone receptors (Kacinski et al. 1989) initiatedextensive studies on the role of steroid hormones in MDR-reversal (Berman et al.
1991; Hu et al. 1991; Fleming et al. 1992; Stuart et al. 1992; Mutoh et al. 2006).
Although the effects of antiestrogens tamoxifen, toremifene, and 4-hydroxy tamox-ifen may be influenced by serum protein binding (Wurz et al. 1993; Chatterjee andHarris 1990), the reversal effects by the most active hormone progesterone havebeen shown to interact directly with P-glycoprotein (Yang et al. 1989; Naito et al.
1989; Safa et al. 1990). Subsequently, it was demonstrated that progesterone dis-tinguishes two mdr gene products (Yang et al. 1990) and specifically regulates theactivity of the mdr1b promoter via the A form of the progesterone receptor (Piekarzet al. 1993). However, results from clinical trials with vinblastine and high-dosemegestrol acetate were unremarkable (Matin et al. 2002).
Woodcock et al. (1990) found that Cremophor EL, a relatively inert formula ofpolyethoxylated castor oil commonly used as pharmaceutical emulsifier (e.g., forpreparations of water-insoluble compounds such as cyclosporins and taxol), couldreverse experimental MDR at attainable clinical concentrations. This reversal effecthas been since confirmed by using various MDR cells and pharmaceutical surfac-tants such as Solutol HS15 (Coon et al. 1991), Triton X-100, and Thesit (Fricheet al. 1990; Spoelstra et al. 1991; Woodcock et al. 1992). There was also evidence 2 Metastasis and Drug Resistance that nontoxic amounts of Cremophor EL and Tween 80 could effectively competefor P-glycoprotein binding with photoaffinity azidopine (Friche et al. 1990). Thereformulation of conventional anticancer agents to include sufficient but nontoxicconcentrations of these surfactants may enhance their clinical efficacy and over-come MDR.
A major limitation to the use of anticancer drugs is their nonspecific clinicaltoxicities that impair the therapeutic efficacy of these agents. Liposomes arebiodegradable, nonimmunogenic, and relatively nontoxic, and they can be safelyused to modify pharmacokinetic properties such as distribution, circulatory transittime, and drug metabolism, to target drugs and biologicals to most of the majororgans in animals and humans (Lopez-Berestein et al. 1984; Fogler et al. 1985), toavert systemic clinical toxicities (Forssen and Tokes 1981), and to improve therapeu-tic efficacy of antimicrobials (Lopez-Berestein et al. 1985), anticancer drugs (Huanget al. 1992; Ahmad et al. 1993), immunomodulators (Fidler 1988), and growth fac-tors (Schackert et al. 1989; Fan et al. 1989). Other studies have shown that liposomescomposed of various phospholipids can enhance the cytotoxicities of MDR-linkeddrugs such as doxorubicin, vinblastine, vincristine, and annamycin (Fan et al. 1990;Seid et al. 1991; Rahman et al. 1992; Thierry et al. 1993). Although the mode ofaction for MDR-reversal by liposomes is not clearly understood, the experimentalreversal of drug resistance by liposomes containing specific phospholipids has beenattributed to perturbation of the plasma membranes (Fan et al. 1990), to increasingdrug incorporation and intracellular redistribution (Thierry et al. 1993), or to directinteraction with P-glycoprotein (Thierry et al. 1993). The practical utility of lipo-some encapsulation in cancer treatment is obvious, but its mechanism remains to bedefined (Zalipsky et al. 2007).
The studies using calcium channel blockers and calmodulin antagonists to over-come MDR phenotypes continued. Dexniguldipine (B-859-35), the (–) isomer ofantihypertensive niguldipine, was found better than verapamil in reversing MDR(Hofmann et al. 1991; Reymann et al. 1993; Dietel et al. 1996; He and Liu 2002).
Various less toxic derivatives of verapamil (e.g., Ro11-2933) (Abderrabi et al. 1996),dihydropyridine (e.g., S16324, S16317) (Saponara et al. 2007), benzothiazepines(MDL 201,307) (Newman et al. 1996), and isoquinolinesulfonamides (e.g., W-77,CKA-1083) (Maeda et al. 1993), have been found potential agents for overcomingMDR. In the past years, many innovative molecules have also been investigated fortheir ability to circumvent MDR. Those findings included the studies of employ-ing MRK16 anti-P-glycoprotein antibody to reverse bone marrow drug resistance D. Fan et al.
of MDR transgenic mice (Mickisch et al. 1992a, b). Another anti-P-glycoproteinantibody, UIC2, was also effective in reversing experimental MDR (Mechetner andRoninson 1992). Other important compounds capable of reversing MDR includethose of the adenyl cyclase inhibitor forskolin (Wadler and Wiernik 1988; Morriset al. 1991; Yin et al. 2000), potassium-sparing diuretic amilorides (Epand et al.
1991; Miraglia et al. 2005), α- or β-adrenoceptor antagonists amiodarone (Lehn-ert et al. 1996) and SKB 105854 (Fan et al. 1994b), antidepressant trazodone (Fanet al. 1994a), antipsychotic benzquinamide (Mazzanti et al. 1992), triazine S 9788(Dhainaut et al. 1992; Moins et al. 2000), and the hydrophobic platelet anticoagulantdipyridamole (Verstuyft et al. 2003) and its derivative BIBW22BS (Schr¨oder et al.
1996). The antihistaminic terfenadine (Seldane) restored the sensitivity of MDRcells to doxorubicin (Hait et al. 1993). FB642 is a systemic benzimidazole fungi-cide with antitumor activity against a broad spectrum of tumors and drug-resistantand MDR cell lines (Hammond et al. 2001). Furthermore, it was found that introduc-tion of an MDR1-targeted small interfering RNA duplex into drug-resistant cancercells markedly inhibited the expression of MDR1 mRNA and P-gp and restoredsensitivity to multidrug-resistant cancer cells (Wu et al. 2003).
Clinical Reversal of MDR
Extensive clinical trials have been conducted in the past decade. As the first ofsuch reversing agents entering clinical trials, calcium channel blocker verapamilwas met with mixed outcomes that were discouraging in some studies (no response)(Rougier et al. 1969; Benson et al. 1985; Saltz et al. 1994) but were exception-ally promising in others (>50–70% response rate) (Cairo et al. 1989; Holmeset al. 1989; Figueredo et al. 1990; Miller et al. 1991; Salmon et al. 1991). Lym-phoma was consistently more responsive to the chemosensitizing effects of vera-pamil (Holmes et al. 1989; Miller et al. 1991; Chabner et al. 1994). Although thenumber of patients was small, the combination trial of chloroquine with conven-tional chemotherapy and radiotherapy was clinically effective in improving mid-term survival for glioblastoma multiforme (Sotelo et al. 2006). Unfortunately, thenumber of clinical studies of phenothiazines such as the calmodulin-inhibitor triflu-operazine (Miller et al. 1988; Murren et al. 1996) and antiemetic prochlorperazine(Sridhar et al. 1993; Raschko et al. 2000) was small, and the outcome was marginal.
Likewise, trials of doxorubicin derivative 4-iodo-4-deoxydoxorubicin (Sessa et al.
1992), antiestrogen tamoxifen (Stuart et al. 1992; Trump et al. 1992; Millwardet al. 1992), and calcium channel blocker nifedipine (Philip et al. 1992) were nothighly remarkable. However, isolated trials of the benzothiazepine calcium chan-nel blocker diltiazem and antimalarial quinine showed enhancement of leukemiaresponses to cytarabine, mitoxantrone, and vincristine (Bessho et al. 1985; Solaryet al. 1992). Although cyclosporin A may not be effective in enhancing the efficacyof epidoxorubicin in colon cancer patients (Verweij et al. 1992), a Southwest Oncol-ogy Group study showed responses in poor-risk acute myeloid leukemia patients 2 Metastasis and Drug Resistance receiving sequential treatments with cytarabine and daunomycin with concurrentinfusion of cyclosporin A (List et al. 1992). Although clinical correlations are want-ing (Holzmayer et al. 1992; Hait and Yang 2005), the use of biochemical modu-lation of clinical MDR remains a viable approach to improve treatments of cancerwith conventional chemotherapy (Fojo and Bates 2003).
Overview of Experimental MDR-Reversal
Many compounds, whose primary mechanism of action is blocking calcium chan-nels, have been found to have MDR-reversing activities. It is not clear why chem-icals that affect the flux of calcium in cells can elevate the accumulation ofMDR-associated natural chemotherapeutic drugs. Many MDR-reversing agents arecationic amphiphiles (contains both hydrophobic and polar regions) that are highlylysosomotropic (Jaffr´ezou et al. 1991; Akiyama et al. 1984; Ramakrishnan et al.
1989) and could modulate intracellular turnover and trafficking of specific phos-pholipids that may affect the MDR phenotype (Jaffr´ezou et al. 1992; Jaffr´ezouand Laurent 1993). These implications may be unorthodox because of the seemingdeparture from the functionality of P-glycoprotein. It must be noted that proteinsare rigid in nature and their functionality (mechanisms of action) and efficiency(kinetics) are often conformationally regulated by phospholipid matrix. This wasshown by restoration of calcium accumulation across lipid bilayers by reconstitutivesarcoplasmic reticulum phospholipid-mediated, calcium- and magnesium-activatedATPase activity (Racker 1972) and by alterations in lipid fluidity that modulatesP-glycoprotein-mediated drug transport in rat liver canalicular membrane vesicles(Sinicrope et al. 1992). Amplification of mdr1 and overexpression of its messen-ger underline that typical MDR phenotypes are probably by way of induction viaplasma membrane with specific chemotherapeutic drugs.
Unlike proteins, phospholipid compositions are remarkably different in trans- formed and tumor cells (Bergelson et al. 1970; Hatten et al. 1977), and thelipolytic activity of neoplasms is accentuated (Elwood and Morris 1968; Fran-son Patriaria and Elsbach 1974). The negative headgroup of the commonly inter-nal phosphatidylserine (externalized in undifferentiated and neoplastic cells) hashigh affinity for calcium via coordination-chelation bonds (Paphadjopoulous 1968)that could initiate a localized drop in pH and a lateral phase separation of phos-phatidylserine in the plasma membrane (Ohnishi and Ito 1973; Tr¨auble and Eibl1974). Acidic pH can produce a reversible nonbilayer inverted micelle type in mem-branes containing phosphatidylserine (Hope and Cullis 1980). In addition to theregulatory effects of calcium and pH, phosphatidylserine was found deacylated bya unique membrane-associated phospholipase-A in SV40-transformed 3T3 fibrob-lasts and in human gastric carcinoma cells (Fan and Voelz 1977, 1980, 1984) to gen-erate short-lived but fusogenic lysophosphatidylserine (Stein Y and Stein O 1966;Ahkong et al. 1973). Therefore, the unique properties of plasma membrane lipidssuch as phosphatidylserine allow them to participate in biological phenomena by D. Fan et al.
means of a transient rearrangement of the membrane structure similar to that seenin MDR P388 leukemic cells (Garcia-Segura et al. 1992), and it regulates the effi-ciency (conformational changes and kinetic enhancements) of the efflux pump. Ithas been demonstrated that MDR phenotype of the human KB-V1 cell line (Ambud-kar et al. 1992) and expression of the human mdr1 in Sf9 insect cells can generatea high-capacity drug-stimulated membrane ATPase (Sarkadi et al. 1992), and alter-ations in lipid fluidity can modulate P-glycoprotein-mediated drug transport in ratliver canalicular membrane vesicles (Sinicrope et al. 1992) and partially in the puri-fied MDR CHRC5 Chinese hamster ovary cell plasma membrane P-glycoprotein(Doige et al. 1993). Therefore, the ATP-dependent calcium channel P-glycoproteinin cardiac and tumor cells could be retarded by blocking agents via a "nonspecific"perturbation (evidenced by the manifold variety of effectors) of the plasma mem-brane phospholipids to conformationally hinder ATPase activity (energy supply)and consequentially the functions of calcium channel and P-glycoprotein.
Metastasis and Drug Resistance
The various modes of MDR-reversal put into effect that cancer is biologicallyheterogeneous and metastatic cells are the champions of survival. The process oftumor metastasis is highly selective and consists of a series of sequential and unifiedsteps (Fidler 1990). Despite improvements in diagnosis, surgical techniques, patientcare, and adjuvant therapies, most deaths from cancer are due to metastases that areresistant to conventional therapies. The major obstacle to effective treatment is thebiologic heterogeneity of tumor cells. Moreover, metastases can be located in lymphnodes and different organs, and the specific organ microenvironment influences thebiologic behavior of metastatic cells, including their response to systemic therapy(Fidler 2002). One of the factors is the development of drug resistance phenotype inmetastatic cancer cells (Dutour et al. 2007; La Porta 2007). While cancer metastasesare of clonal origin (Talmadge et al. 1982), variant clones with diverse phenotypescan form and rapidly result in the generation of significant cellular diversity withinindividual metastases (Fidler and Hart 1982). The outcome of the metastatic processdepends on multiple and complex interactions of the metastatic cells with the hosthomeostatic mechanisms (Liotta et al. 1991; Fidler 1997).
We determined whether the expression level of metastasis-related genes is reg- ulated by specific organ microenvironments. Highly metastatic clones of humanprostate cancer were implanted into the prostate (orthotopic site) and subcutis(ectopic site). Tumors were harvested and processed for in situ hybridization (ISH)analysis. Spontaneous metastases in the lymph nodes were also evaluated. Tumorsgrowing in the prostate exhibited higher levels of epidermal growth factor-receptor(EGF-R), basic fibroblast growth factor (bFGF), interleukin (IL)-8, type IV collage-nase, and the multidrug resistance (mdr-1) gene than those growing in the subcutis(Greene et al. 1997).
2 Metastasis and Drug Resistance The orthotopic implantation of human cancer cells was mandatory for analysis of metastasis-related genes. Specifically, highly metastatic cells expressed highermRNA levels of type IV collagenase (which affects invasion), bFGF and IL-8(which affect angiogenesis), and mdr-1 compared with cells of low metastaticpotential. No difference in EGF-R expression (which affects growth) was foundbetween the cells, but the expression of E-cadherin (which affects cell cohesion)was decreased in the metastatic cells. Vascular endothelial growth factor/vascularpermeability factor (VEGF/VPF), which affects tumor angiogenesis, has also beenfound to be overexpressed in prostate cancer in comparison with normal epithe-lium or benign prostatic hyperplasia. We found that VEGF/VPF levels correlatedwith microvessel density and metastatic potential of human prostate cancer cellsgrowing in the prostate of nude mice (Balbay et al. 1999). Furthermore, there isan intratumoral heterogeneity of expression of tyrosine kinase growth receptorsfound in human colon cancer surgical specimens and in orthotopic tumors (Kuwaiet al. 2008). Collectively, these data suggest that the expression level of metastasis-regulating genes by metastatic cells can be induced by factors in the organ microen-vironment and can influence the drug resistant phenotype of metastases.
Since the expression of various cytokines, growth factors, and their receptors on metastatic tumor cells and their microenvironment (e.g., endothelial cells) caninteract to provide survival advantage and mediate MDR phenotype, combiningchemotherapy and targeting the receptors of specific tyrosine protein kinases maybe effective in treating metastatic diseases. Our group has been successful in suchcombination therapies against several metastatic cancers in orthotopic animal mod-els. These included inhibiting the EGFR signaling by PKI166 in human renal cellcarcinoma growing orthotopically in nude mice (Kedar et al. 2002); targeting theexpression of platelet-derived growth factor receptor (PDGF-R) by STI571 (Kimet al. 2006); targeting EGF-R by PKI166 and VEGF-R by AEE788 with irinotecanin orthotopic colon carcinoma (Kitadai et al. 2006; Sasaki et al. 2007); simultane-ously inhibiting EGF-R/VEGF-R by AEE788 and PDGF-R by STI571 with gem-citabine against human pancreatic carcinoma (Yokoi et al. 2005); targeting tumorcells and tumor-associated endothelial cells in human prostate cancer cells growingin the bone of nude mice by inhibiting EGF-R using PKI166 (Kim et al. 2003);inhibiting EGF-R by PKI166 and PDGF-R by STI571 with taxol (Kim et al. 2004);or STI571 with zoledronate and paclitaxel (Kim et al. 2005).
The survival and growth of cells is dependent on an adequate supply of oxygenand nutrients and on the removal of toxic molecules. Oxygen can diffuse fromcapillaries for only 150–200 μm. When distances of cells from a blood supplyexceed this, cell death follows (Gimbrone et al. 1974; Folkman and Klagsbrun 1987;Kerbel and Folkman 2002; Fidler and Ellis 2004). Thus, the expansion of tumormasses beyond 1 mm in diameter depends on neovascularization, i.e., angiogenesis D. Fan et al.
(Folkman 1986). The formation of new vasculature consists of multiple, interdepen-dent steps. It begins with local degradation of the basement membrane surround-ing capillaries, followed by invasion of the surrounding stroma and migration ofendothelial cells in the direction of the angiogenic stimulus (Fidler et al. 2005).
Proliferation of endothelial cells occurs at the leading edge of the migrating col-umn, and the endothelial cells begin to organize into three-dimensional structuresto form new capillary tubes (Auerbach and Auerbach 1994). Differences in cellu-lar composition, vascular permeability, blood vessel stability, and growth regulationdistinguish vessels in neoplasms from those in normal tissue (Fidler and Ellis 1994).
The onset of angiogenesis involves a change in the local equilibrium between proangiogenic and antiangiogenic molecules (Fidler 2001; Kerbel and Folkman2002). Some of the common proangiogenic factors include bFGF, which inducesproliferation in a variety of cells and has also been shown to stimulate endothelialcells to migrate, to increase production of proteases, and to undergo morphogene-sis (Folkman and Klagsbrun 1987). Likewise, VEGF/VPF has been shown to inducethe proliferation of endothelial cells, to increase vascular permeability, and to induceproduction of urokinase plasminogen activator by endothelial cells (Dvorak 1986;Dvorak et al. 1995). Additional proangiogenic factors include IL-8, a cytokine pro-duced by a variety of tissues and blood cells (Singh et al. 1994; Yoneda et al. 1998),platelet-derived endothelial cell growth factor, which has been shown to stimulateendothelial cell DNA synthesis and to induce production of FGF (Kim et al. 2005,2006), hepatocyte growth factor (HGF), or scatter factor, that increases endothelialcell migration, invasion, and the production of proteases (Bussolino et al. 1992), andplatelet-derived growth factor (PDGF) (Risau et al. 1992).
Moreover, the structure and architecture of tumor vasculature can dramatically differ from those found in normal organs (Ebhard et al. 2000; Nor and Pulverini1999; Nels et al. 1992). Indeed, blood vessels in tumors are different than thosefound in wound healing, and inflamed tissues. The blood flow through tumors can betortuous and is characterized by regions of necrosis, rapid cell division, and presenceof infiltrate cells. Receptors for VEGF (KDR in humans, Flt-1 in mice) are expressedspecifically by tumor endothelium as well as the angiopoietin tyrosine kinase recep-tor, Tie-2 (reviewed in Liu et al. 2000). In addition, receptors for PDGF and EGFare found on tumor endothelial cells (Uehara et al. 2003; Suhardja and Hoffman2003). The endothelium is fragile, and upregulation of survival factors (such asBcl-2 and survivin) by molecules found in abundance within the tumor microen-vironment such as VEGF and bFGF helps to prevent apoptosis of new endothelium(Wang et al. 2002; Karsan et al. 1997; Gerber et al. 1998). There is increased leak-iness to macromolecules (perhaps due to the presence of VEGF) (Jain 1987; Dvo-rak 1990), and vessels often lose distinct features of arteriole, capillary, and venuleformation. Modern techniques, such as phage-display targeting, have defined "vas-cular addresses" that may be distinct for different organs as well as tumors in thoseorgans and perhaps offer attractive targets for antivasculature therapy (Pasqualiniet al. 2002).
Angiogenic heterogeneity exists within a single tumor (zonal or intralesional) between different metastases even in a single organ, and different neoplasms of the 2 Metastasis and Drug Resistance same histologic type are also documented (Kumar et al. 1998; Yu et al. 2001). Forexample, the expression of proangiogenic molecules (and, therefore, blood vesseldensity) in murine or human tumors growing at orthotopic sites in athymic miceis zonal, i.e., demonstrates intralesional heterogeneity. Small tumors (3–4 mm indiameters) expressed more bFGF and IL-8 than large tumors (>10 mm in diame-ters), whereas more VEGF is expressed in large tumors. Immunostaining showed aheterogeneous distribution of these angiogenic factors within the tumor; expressionof bFGF and Il-8 was highest on the periphery of a large tumor, where cell divi-sion was maximal. VEGF expression was higher in the center of the tumor (Kumaret al. 1998). Similarly, heterogeneous dependence on angiogenesis was reported forcell subpopulations isolated from human melanoma xenografts having differentialexpression of hypoxia-inducing factor-1 (Yu et al. 2001).
Heterogeneity of blood vessel distribution in surgical specimens of human cancers is well documented (Weidner et al. 1992). Benign neoplasms are spar-ely vascularized and tend to grow slowly in contrast to highly vascularized andrapidly growing malignant tumors (Weidner et al. 1992). The distribution of ves-sels in a tumor, however, is not uniform, and Weidner et al. cautioned that topredict the aggressive nature of human cancers, one must determine the mean ves-sel density (MVD) in the "areas of most intense neovascularization", i.e., tumorsexhibit intralesional and zonal heterogeneity for MVD (Weidner et al. 1992; Jain1987, 2008). Similarly, the expression of proangiogenic molecules in surgical speci-mens of human colon carcinoma was determined by in situ hybridization technique.
Matrix metalloproteinase-9 and bFGF were overexpressed at the periphery of thetumor where cells were rapidly dividing, whereas VEGF expression was higher inthe center of the lesions (Kitadai et al. 1995).
The extent of angiogenic heterogeneity in malignant neoplasms is also regu- lated by the organ microenvironment. For example, human renal carcinoma cellsimplanted into the kidney of athymic mice produced a high incidence of lungmetastasis, whereas those implanted subcutaneously did not (Singh et al. 1994).
Histopathologic examination of the tissues revealed that the tumors grown in thesubcutis of nude mice had few blood vessels, as compared to tumors in the kidney.
The subcutaneous tumors also had a significantly lower level of mRNA transcriptsfor bFGF than tumor in the kidney, and the expression of the naturally occurringangiogenic inhibitor, IFN-β (which downregulates bFGF) was high in epithelialcells and fibroblasts surrounding the subcutaneous tumors. This was not detected inor around tumors grown in the kidney (Singh et al. 1995). The production of IL-8 bymelanoma cells is regulated by complex interactions with skin keratinocytes (Her-lyn 1990). IL-8 expression can be increased by co-culture of melanoma cells withskin keratinocytes, and this expression is inhibited by coincubation of melanomacells with hepatocytes from the liver (Gutman et al. 1995). The organ microenviron-ment also influences the expression of VEGF. Human gastric cancer cells implantedinto the stomach were highly vascularized and expressed high levels of VEGF, ascompared to implantation into an ectopic (subcutaneous) site, such as the skin. Inaddition, metastasis only occurred from the tumor implanted in the stomach (Taka-hashi et al. 1996).
D. Fan et al.
The molecular cross-talk that occurs with tumor cells and endothelium within the tumor microenvironment results in sufficient recruitment of a vascular sup-ply that has physiological properties that allow migration and eventual escape ofsubpopulations of tumor cells able to complete a cascade of events necessary formetastasis.
Antivascular Therapy of MDR Prostate Carcinoma
Cancer of the prostate is the most common cancer affecting men in North Americaand is the second leading cause of cancer-related deaths. Mortality from prostatecancer usually results from the metastasis of hormone-refractory cancer cells.
Reports examining the pattern of metastasis in advanced prostate cancer indicatethat dissemination to bone and lymph nodes occurs in over 80% of the cases (Gar-nick and Fair 1996). The pathophysiology of prostate cancer bone metastases iscomplex and involves the interaction of tumor cells with osteoclasts, osteoblasts,endothelial cells and an assortment of regulatory proteins (e.g., steroid hormones,cytokines, and growth factors).
To study the factors that are critical for growth of prostate cancer cells in the bone, we established a murine model of hormone-refractory prostate cancer bonemetastasis. To generate prostate cancer growth in the bone, we performed a per-cutaneous intraosseal injection on nude mice by inserting a 27-gauge needle intothe tibia immediately proximal to the tuberositas tibia (Uehara et al. 2003). Afterpenetrating the cortical bone, we deposited 20 μl of tumor cell suspension (2 ×105 androgen-independent PC3-MM2 cells) in the bone cortex with the use of acalibrated, push button-controlled dispensing device. Five weeks later, we resectedthe tumor-bearing leg and performed an extensive immunohistochemical survey ofthe bone lesions in an effort to identify potential factors that may be involved inthe regulation of prostate tumor cell growth. A preliminary immunohistochemicalevaluation revealed robust tumor cell expression of bFGF, VEGF, IL-8, PDGF BB,and its receptor PDGFR-Rβ. Expression of these proteins was most pronounced intumors that were growing adjacent to the bone. In contrast, in those tumors thathad lyzed the bone and extended their growth to include the surrounding muscle,we detected only minimal levels of the angiogenic proteins, suggesting that factorswithin the bone environment were influencing the phenotype of the tumor cells.
A more comprehensive examination of distribution pattern of PDGFRβ revealed that PDGFR-β was present on both prostate tumor cells and on tumor-associatedendothelium and that, moreover, this receptor tyrosine kinase was activated. Phos-phorylated PDGFR-β was not found in either the contralateral nontumor leg or intumor cells growing away from the bone, i.e., in the muscle. These findings indicatethat the PDGF BB produced by tumor cells was acting in an autocrine manner tostimulate tumor cells and in a paracrine fashion to convey information to tumor-associated endothelial cells. The expression pattern of activated PDGFR-β in thebone metastases suggested that it might be a target for therapy in that inhibition of 2 Metastasis and Drug Resistance this signaling cascade could potentially affect both the malignant cell population andthe tumor blood supply. To test this hypothesis, we treated mice with experimentalbone metastasis using the tyrosine kinase inhibitor of PDGFR-β, STI571 (imatinibmesylate, Gleevec). In mice treated with STI571 or the combination of STI571 pluspaclitaxel, we found induction of significant apoptosis of endothelial cells and tumorcells that resulted in inhibition of tumor growth, a significant decrease of lymphaticmetastases, and a significant decrease of bone lysis (Uehara et al. 2003). Theseexperiments demonstrated that tumor-associated endothelial cells express phospho-rylated PDGFR when adjacent tumor cells express PDGF, and that inhibition of thisactivation with a PDGFR tyrosine kinase inhibitor, particularly in combination withchemotherapy, can produce significant therapy.
To determine the molecular mechanism for the antiangiogenic effects observed on the tumor-associated endothelial cells in vivo, we established cultures of murinebone microvascular endothelial cells and examined their response to stimulationwith PDGF BB ligand and to blockade of PDGFR signaling with STI571 (Lang-ley et al. 2004). Cultured bone endothelial cells expressed PDGFR-β, and PDGFBB-induced phosphorylation on these cells could be inhibited by STI571 in a dose-dependent manner. Stimulation of the bone endothelial cells with PDGF BB resultedin activation of Akt and ERK1/2, and this signaling cascade could be completelyabrogated by STI571. In addition, we found that bone endothelial cells respondto PDGF BB by increasing their cell division and upregulating the anti-apoptoticprotein Bcl-2. We then examined the response of bone endothelial cells to treat-ment with STI571 and taxol. Treatment of bone endothelial cells with only a singleagent produced little effect. However, the combined treatment of STI571 and taxolresulted in a significant increase in the number of cells expressing activated caspase-3 and a concomitant decline in Bcl-2. Consistent with these results, we found thatwhen bone endothelial cells were confronted with both STI571 and low levels oftaxol, there was a threefold increase in their cytotoxicity.
Collectively, these data suggest that a primary target for the STI571 and pacli- taxel therapy may be the tumor-associated blood vessels. To test this hypothesis,we established a multidrug resistant prostate cell line by chronically exposing PC3-MM2 cells to increasing concentrations of taxol (Kim et al. 2006). The resultingcell line, PC3-MM2-MDR, is 70 times more resistant to paclitaxel in vitro, and thegrowth of the cells is not affected by treatment with paclitaxel or the combinationof paclitaxel and STI571. When the PC3-MM2-MDR cells were implanted into thebone microenvironment, they displayed the same angiogenic profile as the parentalcell line. Endothelial cells in normal tissues rarely divide, whereas 2–3% of theendothelial cells in prostate cancer divide daily (Augustin et al. 2002; Eberhard et al.
2000). These dividing endothelial cells should be sensitive to anticycling drugs suchas paclitaxel. Nevertheless, in the present experiment, paclitaxel did not decreasethe MVD appreciably, likely because of the fact that stimulation of endothelial cellswith PDGF leads to resistance to paclitaxel, and that blockade of PDGF-R phospho-rylation with imatinib reverses the resistance to paclitaxel (Langley et al. 2003). Asstated above, the first wave of apoptosis in bone tumors from mice treated with ima-tinib and paclitaxel for only 2 weeks occurred in tumor-associated endothelial cells, D. Fan et al.
followed by apoptosis of tumor cells and ultimately tumor necrosis. By the fourthweek of treatment with imatinib and paclitaxel or imatinib alone, concurrent apop-tosis of tumor cells and tumor-associated endothelial cells was observed. Withoutpaclitaxel, imatinib may produce therapeutic effects by the blockade of PDGF-R,which serves as a survival factor (Langley et al. 2003).
Thus, the imatinib-induced blockade of PDGF-R combined with paclitaxel appears to target the tumor-associated endothelial cells. Whether this approach canbe useful for other types of tumors is unknown. The heterogeneity of angiogenesisin human tumors and the findings that endothelial cells of different organs are phe-notypically distinct (Langley and Fidler 2007) indicate that further investigations tounderstand the interaction of different types of tumor cells and endothelial cells indifferent organs are necessary for the development of optimal regimens of targetedantivascular therapies. For this reason, we performed another series of experimentsusing the multidrug resistant PC-3MM2-MDR cells growing in the prostate of nudemice and treated the mice with paclitaxel and the tyrosine kinase inhibitor, AEE788,that targets phosphorylation of EGF-R/VEGF-R (Busby et al. 2006). The significantinhibition of local tumor growth and lymph node metastases again demonstratedthat tumor-associated endothelial cells, rather than the tumor cells, were the pri-mary target of the chemotherapy. Those studies provide a better understanding ofthe molecular mechanisms that regulate the process of metastasis and of the com-plex interactions between the metastatic cells and the organ microenvironment (Kimet al. in press).
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Antibiotic Therapy vs Appendectomy for Treatmentof Uncomplicated Acute AppendicitisThe APPAC Randomized Clinical Trial Paulina Salminen, MD, PhD; Hannu Paajanen, MD, PhD; Tero Rautio, MD, PhD; Pia Nordström, MD, PhD; Markku Aarnio, MD, PhD;Tuomo Rantanen, MD, PhD; Risto Tuominen, MPH, PhD; Saija Hurme, MSc; Johanna Virtanen, MD; Jukka-Pekka Mecklin, MD, PhD;Juhani Sand, MD, PhD; Airi Jartti, MD; Irina Rinta-Kiikka, MD, PhD; Juha M. Grönroos, MD, PhD

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