Liposomal-Encapsulated Chemotherapy: Preliminary Results of a Phase I Study of a Novel Liposomal Paclitaxel

May 1, 2001

Liposome encapsulation of antineoplastic drugs entered clinical testing in the late 1980s. As carriers for a variety of agents, liposomes can allow successful delivery of agents that may be subject to rapid degradation in

ABSTRACT: Liposome encapsulation of antineoplastic drugs entered clinicaltesting in the late 1980s. As carriers for a variety of agents, liposomes canallow successful delivery of agents that may be subject to rapid degradation inthe serum and can modify the toxicity profile. In general, liposomes havedemonstrated an ability to attenuate toxicities by their differentpharmacokinetic profile and pattern of distribution. Differences in theconstitution of the liposome can greatly affect the pharmacokinetic profileresulting in different patterns of toxicity. Characteristics such as size,charge, composition, and integrity can affect performance of the liposome.Liposome encapsulation of doxorubicin has been shown to reduce cardiac toxicity.Preliminary data suggest that encapsulation of paclitaxel can greatly modifyneurotoxicity without the need for cremephor. [ONCOLOGY 15(Suppl 7):44-48, 2001]


The majority of anticancer drugsare nonspecific, cytotoxic agentsthat damage tumor cells as well as normal healthy tissue. Given their narrowtherapeutic index, antineoplastic drugs have the potential for serious sideeffects. A variety of drug-delivery systems are currently being used in aneffort to make anticancer agents more efficient and less toxic. Liposomalencapsulation of chemotherapeutic agents represents one method of achieving thisgoal.

Ideal Candidates forDrug-Delivery Systems

First described by Bangham more than 30 years ago,[1] liposomeshave undergone significant refinements over the decades to evolve into importantmodern-day drug carriers. Liposomes are spherical vesicles comprised of an outerphospholipid membrane with an internal aqueous compartment. Water-soluble drugscan be contained in the aqueous compartment while hydrophobic drugs incorporatewithin the lipid bilayer.

Liposomes are ideal candidates for drug-delivery systems. As aresult of their similarity to biological membranes, they are safe,biocompatible, and biodegradable. Liposomes are extremely versatilemacromolecules. By manipulating certain physical parameters such as phospholipidcomposition, size, or membrane characteristics, liposomes can be engineered toefficiently encapsulate and effectively transport a variety of drugs. Smallchanges in these parameters can also have profound effects on thepharmacokinetic and pharmacodynamic profiles of a drug.[2-9]

The advancement of the liposomal drug-delivery system in theoncology field was predicated on preclinical and clinical data demonstrating thebenefits of liposomal encapsulation of chemotherapeutic agents. Some of theliposomal preparations significantly increase the half-life of the incorporatedagent vs that of the free drug.[10-13]

Shielding the free drug within a liposome protects it fromplasma protein interaction and metabolic degradation. As a result,pharmacokinetic parameters of the free drug are altered by liposomalencapsulation. Indeed, chemotherapeutic agents incorporated into liposomesexhibit longer circulation lifetimes with a greater area under the curve, lowerrate of clearance, and smaller volume of distribution as compared with that ofthe free drugs.[13-19] The narrow therapeutic index of many small-moleculechemotherapeutic drugs is, in part, a consequence of their large volume ofdistribution. Incorporation into liposomes significantly reduces the volume ofdistribution, thereby decreasing the toxicity to normal tissue and increasingthe amount of drug that can be effectively delivered to the tumor.[20,21]

Advantages of Liposomal Encapsulation of Doxorubicin

The anthracycline doxorubicin is one of the most importantcytotoxic agents used in anticancer therapy. It has significant clinicalactivity in hematologic malignancies, such as lymphomas and leukemias, as wellas in numerous solid tumors. However, our ability to achieve maximum clinicalefficacy with doxorubicin is limited by the development of irreversiblecardiotoxicity and multidrug resistance (MDR).

Myelosuppression is the dose-limiting toxicity, butcardiotoxicity remains the therapy-limiting toxicity. In order to avoid thiscomplication, therapy is generally discontinued when the cumulative dose reaches450-500 mg/m2, at which point the risk of cardiotoxicity is significant.[22-24]Liposomes have been successfully employed to circumvent some of the limitationsof free doxorubicin. Liposomal encapsulation of doxorubicin significantly altersits pharmacokinetic profile, attenuates its toxicity patterns in clinicalsettings, and demonstrates in preclinical trials an ability to reverse multidrugresistance.[25-28]

Alters Pharmacokinetic Profile

Numerous phase I studies have clearly demonstrated significantlyhigher areas under the curve for liposomal-encapsulated doxorubicin (LED) thanfor similar intravenous bolus doses of free doxorubicin.[29-32] Free doxorubicinreaches a peak concentration within minutes after administration and has aterminal elimination half-life of 30 hours. Depending on the specific liposomalformulation, doxorubicin-containing liposomes can increase the area under thecurve by 20 to 600 times.[31,32] Therefore, the pharmacokinetic pattern ofliposomal-encapsulated doxorubicin more closely mimics the prolonged infusionregimen of doxorubicin, which has demonstrated less systemic toxicity, mostnotably diminished cardiotoxicity and gastrointestinal toxicity.[33]

Attenuates Toxicity Patterns

Additionally, liposomal-encapsulated doxorubicin exhibits a muchsmaller volume of distribution as compared with free doxorubicin. The estimatedvolume of distribution for free doxorubicin is approximately 25 L/kg, or 1,875liters for a 70-kg person, reflecting significant tissue uptake.[34,35] Incontrast, liposomal preparations can reduce the volume of distribution by 10- to60-fold.[10-12,31,32] The relatively large size of liposomes probably accountsfor the marked reduction in the volume of distribution.

These large macromolecules are usually unable to traverse thesmall endothelial gaps of normal tissue, especially cardiac endothelialcells.[21,36] Indeed, a large body of clinical data supports findings thatcancer patients treated with liposomal-encapsulated doxorubicin have asignificant reduction in cardiac toxicity.[37-41] Diminished hematologictoxicity (myelosuppression), gastrointestinal toxicity (nausea/vomiting),mucositis, and venous sclerosis have also been noted with liposomal-encapsulateddoxorubicin.[37]

Shown in Preclinical Trials to Reverse Multidrug Resistance

Multidrug resistance is an important impediment that isdifficult to circumvent in the treatment of cancer. Overexpression ofP-glycoprotein (Pgp170) in neoplastic cells can lead to marked resistance todoxorubicin. Preclinical studies have demonstrated liposomal modulation ofMDR.[25-28] In one study, liposomal-encapsulated doxorubicin was shown toprevent effective multidrug resistance by binding to the P-glycoprotein plasmamembrane pump expressed by the multidrug resistant genes.[27] This may helpexplain why liposomal-encapsulated doxorubicin has been effective in thetreatment of various chemotherapy-refractory cancers.[42-44]

Extensively Studied in Treatmentof Advanced Breast Cancer

Liposomal doxorubicin is steadily proving to be an importantantitumor agent. It has been extensively studied in the treatment of advancedbreast cancer, ovarian cancer, and Kaposi’s sarcoma.

The first phase II study of liposomal-encapsulated doxorubicinin advanced breast cancer included 20 patients who had not receivedanthracycline treatment within the past year.[42] Sixteen of the 20 patientsreceived doxorubicin doses of 75 mg/m2 every 3 weeks, while the four remaining patients, all of whom hadundergone extensive radiotherapy, received either 45 or 60 mg/m2.

Overall, five patients demonstrated a complete response in theirindex lesion, while four others demonstrated objective disease regression. Themean duration of response was 7 months.

Most patients had some degree of myelosuppression, but the meannadir leukocyte count for all the cycleswas only 3,740/mL, and no patient developed sepsis or infection. Other toxiceffects included two episodes of grade 4 nausea/vomiting, two episodes of mildstomatitis, and complete alopecia in all patients.

Cardiotoxicity was also assessed. Two patients had leftventricular ejection fraction decreases (13% and 17%), and endomyocardialbiopsies performed on five patients who received cumulative doses of more than500 mg/m2 revealed four grade 0 and one episode of grade 1 structural changes.These data demonstrate the clinical activity of liposomal-encapsulateddoxorubicin against breast cancer, and suggest that liposomal-encapsulateddoxorubicin causes less cardiotoxicity, myelosuppression, and gastrointestinaltoxicity than equivalent doses of free doxorubicin.

Subsequent trials in advanced breast cancer have demonstratedgood response rates and a favorable toxicity profile, especially reducedcardiotoxicity.[39,45] A recent phase III trial was reported comparingcyclophosphamide (Cytoxan, Neosar) and either TLC D-99 or standard doxorubicinas first-line treatment of metastatic breast cancer.[46] Response rates were 43%in both arms with a median survival of 21.2 months for the TLC D-99 patients and16.4 months for those receiving standard doxorubicin. As expected, those treatedwith TLC D-99 had significantly less cardiotoxicity and grade 4myelosuppression.

Clinical Response Against Refractory Ovarian Cancer

Favorable results have also been demonstrated in patients withrefractory ovarian cancer. A phase II trial of liposomal doxorubicin wasconducted in 35 women with ovarian cancer refractory to platinum- and paclitaxel(Taxol)-based regimens.[47] Patients received 50 mg/m2 IV every 3 weeks. Nineclinical responses were observed (one complete response and eight partialresponses) in 35 patients (25.7% response rate). The median progression-freesurvival was 5.7 months with an overall survival of 1.5 to 24 + months (median:11 months).

Four patients developed fever and grade 3 neutropenia, while tendeveloped grade 3 hand-foot syndrome. No cases of alopecia, cardiotoxicity,phlebitis, or hepatic dysfunction were observed. This result suggests thatliposomal doxorubicin might be useful as second-line therapy for this disease,and the lack of moderate-to-severe myelosuppression indicates that it canpotentially be integrated into combined drug modalities for ovarian cancerwithout requiring dose attenuation.

Favorable Response Among Kaposi’s Sarcoma Patients

Patients with Kaposi’s sarcoma also respond favorably to thisformulation. A number of phase II and III trials have shown liposomaldoxorubicin to be an effective agent in the treatment of AIDS-associated Kaposi’ssarcoma. Single-agent therapy produced a significantly better overall responserate with much less toxicity and greater patient compliance vs a multidrugregimen.[44,48-50] Future trials, testing the formulation in combination withother active agents, are planned.

Liposomal Formulation Attenuates Toxicity of Paclitaxel

Paclitaxel is an active antineoplastic agent that was derivedfrom the bark extract of the Pacific yew (Taxus brevifolia). It promotesassembly and enhances stability of microtubules, the components of theintracellular skeleton, which modulate mitosis as well as other biologicalfunctions such as protein secretion, intracellular transport, and cellmotility.[51,52] By altering the dynamic nature of microtubule assembly anddisassembly, which is critical for entry into and execution of the mitotic cellcycle, paclitaxel leads to functional mitotic arrest of affected cells in the G2and M phases.[53,54] Numerous clinical studies have demonstrated the activity ofpaclitaxel in a variety of malignancies, including breast, ovarian, lung, andhead and neck tumors.[55-59]

Despite its broad and promising antitumor profile, paclitaxel isassociated with many clinically relevant toxic side effects. Peripheralneuropathy is a significant clinical toxicity. Hypersensitivity reactionscharacterized by dyspnea, hypotension, angioedema, and generalized urticaria aswell as cardiac arrhythmias may occur. Other problematic side effects includemyalgia and arthralgia, alopecia, nausea, vomiting, diarrhea, mucositis, andphlebitis.[60-62]

Given the potent and extensive antitumor effects of paclitaxel,attenuation of its systemic toxicity would be a significant accomplishment inthe field of oncology. Because liposomes have successfully reduced the toxicityprofile of various other chemotherapeutic agents while maintaining and sometimesimproving efficacy, the application of the liposomal vector to paclitaxel isintriguing.

Modulates Multidrug Resistance

A liposome-encapsulated paclitaxel preparation has beendeveloped that overcomes the stability and solubility problems associated withconventional paclitaxel. Preclinical evaluations demonstrated thatliposome-encapsulated paclitaxel modulates multidrug resistance in humanpromyelocytic leukemia HL-60/VCR cells by ninefold, and in human ovarian SKVLBcancer cells by eightfold compared with conventional paclitaxel.

Intracellular paclitaxel accumulation in these cell lines wasenhanced by threefold to fourfold when presented in liposomes.Liposome-encapsulated paclitaxel also showed a significant reduction in theefflux rate of paclitaxel from the cells as compared with that of conventionalpaclitaxel.[63]

Significantly Less Toxic

Another preclinical study was designed to evaluate thepharmacokinetics, tissue distribution, toxicity, and therapeutic efficacy ofliposome-encapsulated paclitaxel in comparison to conventional paclitaxel. Innormal mice, liposome-encapsulated paclitaxel was much less toxic than standardpaclitaxel with comparable antitumor activity. The area under the curve wastwofold higher and the elimination half-life was two times longer withliposome-encapsulated paclitaxel than with conventional paclitaxel.

As expected, conventional paclitaxel displayed nonlinearpharmacokinetics with a disproportionate increase in area under the curvecompared to the dose administered. Interestingly, at the dose levels studied,liposome-encapsulated paclitaxel demonstrated linear kinetics. Tissuedistribution of paclitaxel after administration of liposome-encapsulatedpaclitaxel showed levels 10-fold higher in the spleen and 3.5-fold higher in theliver as compared to levels achieved with conventional paclitaxel. However, inkidneys, lungs, the brain, and lymph nodes, the paclitaxel concentrations weretwo to three times lower with liposome-encapsulated paclitaxel compared to thosewith conventional paclitaxel.[64] The significant decrease in toxicity andincrease in plasma area under the curve and half-life with liposome-encapsulatedpaclitaxel indicate that this liposomal formulation may be a viable alternativeto the conventional preparation of paclitaxel for therapeutic use.

Paclitaxel Is First Liposomal Taxane to Enter Clinical Trials

Based on successful results obtained in preclinical studies ofliposome-encapsulated paclitaxel, a phase I clinical trial was conducted inpatients with advanced malignancies. Liposome-encapsulated paclitaxel is thefirst liposomal taxane to enter clinical trials.

Liposome-encapsulated paclitaxel was administered over 45minutes every 3 weeks without antiemetics. To date, 26 patients have beentreated at escalating dose levels: 3 patients at 90 mg/m2, 3 at 135mg/m2, 11 at175 mg/m2, 6 at 250 mg/m2, and 3 at 300 mg/m2.

A distinct toxicity profile was observed. Indeed, no clinicallysignificant neuropathies or myalgias have been observed at the MTD level (175mg/mg2). Alopecia was also absent at the MTD or less. Dose-limiting toxicitiesincluded mucositis at 300 mg/m2 (two patients); neutropenic sepsis, anaphylaxisat 250 mg/m2 (two patients); and anaphylaxis at 175 mg/m2 (one patient). Grade 4neutropenia and leukopenia and grade 3 thrombocytopenia and anemia were firstobserved at the 175 mg/m2 dose. Grade 3-4 mucositis and neutropenia wereobserved at liposome-encapsulated paclitaxel doses of 250 mg/m2 or higher.

Liposome infusion reactions included transient back pain andflushing in five patients and rigors in one patient, but since routinepremedication with diphenhydramine and hydrocortisone has been instituted, theseeffects have been mostly ameliorated. Two partial responses and three minorresponses have been observed.[65]

Conclusion and Implications

Liposomes are safe and effective drug carriers. Liposomalencapsulation of cytotoxic drugs diminishes toxicity to normal tissue whilemaintaining therapeutic efficacy. The pharmacokinetic and pharmacodynamicprofiles of the free drug are favorably attenuated by liposomes. Throughimprovements and modifications of liposomal formulations, liposomes willcontinue to be important drug-delivery systems in oncology.


1. Bangham AD, Standish MM, Watkins JC: Diffusion of univalentions across the lamellae of swollen phospholipids. J Mol Biol 13:238-252, 1965.

2. Gregoriadis G: Targeting of drugs. Nature 265:407-411, 1977.

3. Gabizon A, Price DC, Huberty J, et al: Effect of liposomecomposition and other factors on the targeting of liposomes to experimentaltumors: Biodistribution and imaging studies. Cancer Res 50:6371-6378, 1990.

4. Allen TM, Hansen C: Pharmacokinetics of stealth versusconventional liposomes: Effect of dose. Biochim Biophys Acta 1068:133-141, 1991.

5. Allen TM, Hansen C, Martin F, et al: Liposomes containingsynthetic lipid derivatives of poly(ethylen glycol) show prolonged circulationhalf-lives in vivo. Biochim Biophys Acta 1066:29-36, 1991.

6. Gabizon A, Papahadjopoulos D: The role of surface charge andhydrophilic groups on liposome clearance in vivo. Biochim Biophys Acta1103:94-100, 1992.

7. Woodle MC, Matthay KK, Newman MS, et al: Versatility in lipidcompositions showing prolonged circulation with sterically stabilized liposomes.Biochim Biophys Acta 1105:193-200, 1992.

8. Ahl PL, Bhatia SK, Meers P, et al: Enhancement of the in vivocirculation lifetime of L-a-distearoylphsphatidylcholine liposomes: Importanceof liposomal aggregation versus complement opsonization. Biochim Biophys Acta1329:370-382, 1997.

9. Needham D, Zhelev DV, McIntosh TJ: Surface chemistry of thesterically stabilized PEG liposome, in Janoff AS (ed): Liposomes: RationalDesign, pp 13-62. New York, Marcel Dekker Inc, 1999.

10. Hwang KJ: Liposome Pharmacokinetics, in Ostro MJ (ed):Liposomes: From Biophysics to Therapeutics. New York, Marcel Dekker Inc, 1987.

11. Papahadjopoulos D, Allen TM, Gabizon A: Stericallystabilized liposomes: Improvements in pharmacokinetics and antitumor therapeuticefficacy. Proc Natl Acad Sci USA 88:11460-11464, 1991.

12. Allen TM, Hansen CB, Lopes de Menezes DE: Pharmacokineticsof long-circulating liposomes. Adv Drug Del Rev 16:267-284, 1995.

13. Allen TM, Stuart DD: Liposome pharmacokinetics. Classical,sterically-stabilized, cationic liposomes and immunoliposomes, in Janoff AS(ed): Liposomes: Rational Design, pp 63-87. New York, Marcel Dekker Inc, 1999.

14. Rahman A, Treat J, Roh HK, et al: A Phase I clinical trialand pharmacokinetic evaluation of liposome-encapsulated doxorubicin. J ClinOncol 8:1093-1100, 1990.

15. Gabizon A, Amselem S, Goren D, et al: Preclinical andclinical experience with doxorubicin-liposome preparation. J Liposome Res1:491-502, 1990.

16. Perez-Soler R, Lopez-Berestein G, Lautersztain J, et al:Phase I clinical and pharmacological study of liposome-entrappedcis-bis-neodecanoato-trans-R, R-1,2-diaminocyclohexane platinum (II). Cancer Res50:4254-4259, 1990.

17. Pestalozzi B, Schwendener R, Sauter C, et al: Phase I/IIstudy of liposome-complexed mitoxantrone in patients with advanced breastcancer. Ann Oncol 3(6):445-449, 1992.

18. Gill PS, Espina BM, Muggia F, et al: Phase I/II clinicalpharmacokinetic evaluation of liposomal daunorubicin. J Clin Oncol 13(4):996-1003, 1995.

19. Newman MS, Colbern GT, Working PK, et al: Comparativepharmacokinetics, tissue distribution, and therapeutic effectiveness ofcisplatin encapsulated in long-circulating, pegylated liposomes (SPI-077) intumor-bearing mice. Cancer Chemother Pharmacol 43:1-7, 1999.

20. Papahadjopoulos D, Gabizon AA: Sterically stabilized(Stealth) liposomes. Pharmacological properties and drug carrying potential incancer, in Philippot JR and Schuber F (eds): Liposomes as Tools in BasicResearch and Industry, pp 177-188. Boca Raton, FL, CRC Press, 1995.

21. Gabizon A, Martin F: Polyethylene glycol-coated (pegylated)liposomal doxorubicin. Drugs 54(suppl 4):15-21, 1997.

22. Rinehart JJ, Louis RP, Baleerzak SP: Adriamycincardiotoxicity in man. Ann Intern Med 81:475-478, 1974.

23. Von Hoff DD, Layard MW, Basa P, et al: Risk factors fordoxorubicin-induced congestive heart failure. Ann Intern Med 91:710-717, 1979.

24. Doroshaw JH: Anthracyclines and antracenediones, in ChabnerBA and Longo DL (eds): Cancer Chemotherapy and Biotherapy: Principles andPractice, pp 409-433. Philadelphia, PA, Lippincott-Raven Publishers, 1996.

25. Richardson VJ, Ryman BE: Effect of liposomally trappedantitumour drugs on a drug-resistant mouse lymphoma in vivo. Br J Cancer45:552-558, 1982.

26. Thierry AR, Jorgensen TJ, Forst D, et al: Multidrugresistance in Chinese hamster cells: Effect of liposome encapsulateddoxorubicin. Cancer Commun 1:311-316, 1989.

27. Rahman A, Hussain SR, Siddiqui J, et al: Liposome-mediatedmodulation of multidrug resistance in human HL-60 leukemia cells. J Natl CancerInst 84:1909-1915, 1992.

28. Rahman A, Treat J, Thierry A, et al: Clinical evaluation ofliposome encapsulated doxorubicin and the modulation of multidrug resistance incancer cells. J Liposome Res 4:167-192, 1994.

29. Gabizon A, Peretz T, Sulkes A, et al: Systemicadministration of doxorubicin-containing liposomes in cancer patients: A phase Istudy. Eur J Clin Oncol 25(12):1795-1800, 1989.

30. Rahman A, Treat J, Roh JK: A phase I clinical trial andpharmacokinetic evaluation of liposome-encapsulated doxorubicin. J Clin Oncol8:1093-1100, 1990.

31. Cowens JW, Creaven PJ, Greco WR: Initial clinical (phase I)trial of TLC D-99 (doxorubicin encapsulated in liposomes). Cancer Res53:2796-2802, 1993.

32. Conley BA, Egorin MJ, Whitacre MY: Phase I andpharmacokinetic trial of liposome-encapsulated doxorubicin. Cancer ChemotherPharmacol 33:107-112, 1993.

33. Bielack SS, Erttmann R, Winkler K, et al: Doxorubicin:Effect of different schedules on toxicity and anti-tumor efficacy. Eur J CancerClin Oncol 25:873-882, 1989.

34. Greene RF, Collins JM, Jenkins JF, et al: Plasmapharmacokinetics of Adriamycin and adriamycinol: Implications for the design ofin vitro experiments and treatment protocols. Cancer Res 43:3417-3421, 1982.

35. Speth PA, Van Hoesel QG, Haanen C, et al: Clinicalpharmacokinetics of doxorubicin. Clin Pharmacokinet 15:15-31, 1988.

36. Working PK, Newman MS, Huang SK: Pharmacokinetics,biodistribution, and therapeutic efficacy of doxorubicin encapsulated in Stealthliposomes (Doxil). J Liposome Res 4:667-687, 1994.

37. Treat J, Rahman A: Liposome encapsulated doxorubicin:Preliminary results of phase I and phase II trials, in Lopez-Berenstein G andFidler I (eds): Liposomes in the Therapy of Infectious Diseases and Cancer, vol89, pp 353-365. New York, Alan R. Liss Inc, 1989.

38. Casper ES, Schwartz GK, Sugarman A, et al: Phase I trial ofdose-intense liposome-encapsulated doxorubicin in patients with advancedsarcoma. J Clin Oncol 15:2111-2117, 1997.

39. Ranson MR, Carmichael J, O’Byrne K, et al: Treatment ofadvanced breast cancer with sterically stabilized liposomal doxorubicin: Resultsof a multicenter phase II trial. J Clin Oncol 15:3185-3191, 1997.

40. Batist G, Winer E, Navari R, et al: Decreased cardiactoxicity by TLC D-99 (liposome-encapsulated doxorubicin) vs doxorubicin in arandomized trial of metastatic breast carcinoma (MBC) (abstract 443). Proc AmSoc Clin Oncol 17:115a, 1998.

41. Berry G, Billingham M, Alderman E, et al: The use of cardiacbiopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi’s sarcoma patientstreated with pegylated liposomal doxorubicin. Ann Oncol 9:711-716, 1998.

42. Treat J, Greenspan A, Forst D: Antitumor activity ofliposome-encapsulated doxorubicin in advanced breast cancer. Phase II study. JNatl Cancer Inst 82:1706-1710, 1990.

43. Muggia FM, Hainsworth JD, Jeffers S, et al: Phase II studyof liposomal doxorubicin in refractory ovarian cancer: Antitumor activity andtoxicity modification by liposomal encapsulation. J Clin Oncol 15:987-993, 1997.

44. Northfelt DW, Dezube BJ, Thommes JA, et al: Efficacy ofpegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi’ssarcoma after failure of standard chemotherapy. J Clin Oncol 15:653-659, 1997.

45. Harris L, Winer E, Batist G, et al: Phase III study of TLCD-99 (liposome-encapsulated doxorubicin) vs free doxorubicin in patients withmetastatic breast carcinoma (MBC) (abstract 474). Proc Am Soc Clin Oncol17:124a, 1998.

46. Batist G, Rao SC, Ramakrishnan G, et al: Phase III study ofliposome-encapsulated doxorubicin (TLC D-99) vs doxorubicin (DOX) in combinationwith cyclophosphamide (CPA) in patients with metastatic breast cancer (abstract486). Proc Am Soc Clin Oncol 18:127a, 1999.

47. Muggia FM, Hainsworth JD, Jeffers S: Phase II study ofliposomal doxorubicin in refractory ovarian cancer: Antitumor activity andtoxicity modification by liposomal encapsulation. J Clin Oncol 15(3):987-993,1997.

48. Harrison M, Tomilinson D, and Stewart S: Liposomal-entrappeddoxorubicin: An active agent in AIDS-related Kaposi’s sarcoma. J Clin Oncol13:914-920, 1995.

49. Northfelt DW, Dezube BJ, Thommes JA, et al:Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristinein the treatment of AIDS-related Kaposi’s sarcoma: Results of a randomizedphase III clinical trial. J Clin Oncol 16:2445-2451, 1998.

50. Stewart S, Jablonowski H, Goebel FD: Randomized comparativetrial of pegylated liposomal doxorubicin versus bleomycin and vincristine in thetreatment of AIDS-related Kaposi’s sarcoma. J Clin Oncol 16:683-691,1998.

51. Schiff PB, Fant J, Horowitz SB: Promotion of microtubuleassembly in vitro by Taxol. Nature 277:655-667, 1979.

52. Schiff PB, Horowitz SB: Taxol stabilizes microtubules inmouse fibroblast cells. Proc Natl Acad Sci USA 77(93):1561-1565, 1980.

53. Manfredi JJ, Horowitz SB: Taxol: An antimitotic agent with anew mechanism of action. Pharmacol Ther 25:83-124, 1984.

54. Rowinsky EK, Cazenave LA, Donehower RC: Taxol: A novelinvestigational antimicrotubule agent. J Natl Cancer Inst 83:1779-1781, 1991.

55. Holmes FA, Walters RS, Theriault RL, et al: Phase II trialof Taxol: An active agent in the treatment of metastatic breast cancer. J NatlCancer Inst 83:1797-1805, 1991.

56. Perez EA: Paclitaxel in breast cancer. Oncologist 3:373-389,1998.

57. McGuire WP, Rowinsky EK, Rosenshein NS, et al: Taxol: Aunique antineoplastic agent with significant activity in advanced ovarianepithelial neoplasms. Ann Intern Med 111:273-279, 1989.

58. Forastiere AA, Neuberg D, Taylor SG IV, et al: Phase IIevaluation of Taxol in advanced head and neck cancer: An Eastern CooperativeOncology Group Trial. Proc Am Soc Clin Oncol 12:277, 1993.

59. Crown J, O’Leary M: The taxanes: An update. Lancet355:1176-1178, 2000.

60. Donehower RC, Rowinsky EK, Grochow LB, et al: Phase I trialof Taxol in patients with advanced cancer. Cancer Treat Rep 71(12):1171-1177,1987.

61. Huizing MT, Misser VH, Pieters RC, et al: Taxanes: A newclass of antitumor agents. Cancer Invest 13:381-404, 1995.

62. Rowinsky EK, Donehower RC: Paclitaxel (Taxol). N Engl J Med332:1004-1014, 1995.

63. Rafaeloff R, Hussain SR, Rahman A: Liposomal encapsulatedTaxol is an effective modality to circumvent multidrug resistance phenotype(abstract 2883). Proc Am Assoc Cancer Res, 1992.

64. Cabanes A, Briggs KE, Gokhale PC, et al: Comparative in vivostudies with paclitaxel and liposome encapsulated paclitaxel. Int J Oncol12:1035-1040, 1998.

65. Treat JA, Zrada S, Kesslehelm A, et al: Phase I trial inadvanced malignancies with liposome-encapsulated paclitaxel (LEP) (abstract888). Proc Am Soc Clin Oncol 18:881a, 1999.