The majority of anticancer drugs
are nonspecific, cytotoxic agents
that damage tumor cells as well as normal healthy tissue. Given their narrow
therapeutic index, antineoplastic drugs have the potential for serious side
effects. A variety of drug-delivery systems are currently being used in an
effort to make anticancer agents more efficient and less toxic. Liposomal
encapsulation of chemotherapeutic agents represents one method of achieving this
First described by Bangham more than 30 years ago, liposomes
have undergone significant refinements over the decades to evolve into important
modern-day drug carriers. Liposomes are spherical vesicles comprised of an outer
phospholipid membrane with an internal aqueous compartment. Water-soluble drugs
can be contained in the aqueous compartment while hydrophobic drugs incorporate
within the lipid bilayer.
Liposomes are ideal candidates for drug-delivery systems. As a
result of their similarity to biological membranes, they are safe,
biocompatible, and biodegradable. Liposomes are extremely versatile
macromolecules. By manipulating certain physical parameters such as phospholipid
composition, size, or membrane characteristics, liposomes can be engineered to
efficiently encapsulate and effectively transport a variety of drugs. Small
changes in these parameters can also have profound effects on the
pharmacokinetic and pharmacodynamic profiles of a drug.[2-9]
The advancement of the liposomal drug-delivery system in the
oncology field was predicated on preclinical and clinical data demonstrating the
benefits of liposomal encapsulation of chemotherapeutic agents. Some of the
liposomal preparations significantly increase the half-life of the incorporated
agent vs that of the free drug.[10-13]
Shielding the free drug within a liposome protects it from
plasma protein interaction and metabolic degradation. As a result,
pharmacokinetic parameters of the free drug are altered by liposomal
encapsulation. Indeed, chemotherapeutic agents incorporated into liposomes
exhibit longer circulation lifetimes with a greater area under the curve, lower
rate of clearance, and smaller volume of distribution as compared with that of
the free drugs.[13-19] The narrow therapeutic index of many small-molecule
chemotherapeutic drugs is, in part, a consequence of their large volume of
distribution. Incorporation into liposomes significantly reduces the volume of
distribution, thereby decreasing the toxicity to normal tissue and increasing
the amount of drug that can be effectively delivered to the tumor.[20,21]
The anthracycline doxorubicin is one of the most important
cytotoxic agents used in anticancer therapy. It has significant clinical
activity in hematologic malignancies, such as lymphomas and leukemias, as well
as in numerous solid tumors. However, our ability to achieve maximum clinical
efficacy with doxorubicin is limited by the development of irreversible
cardiotoxicity and multidrug resistance (MDR).
Myelosuppression is the dose-limiting toxicity, but
cardiotoxicity remains the therapy-limiting toxicity. In order to avoid this
complication, therapy is generally discontinued when the cumulative dose reaches
450-500 mg/m2, at which point the risk of cardiotoxicity is significant.[22-24]
Liposomes have been successfully employed to circumvent some of the limitations
of free doxorubicin. Liposomal encapsulation of doxorubicin significantly alters
its pharmacokinetic profile, attenuates its toxicity patterns in clinical
settings, and demonstrates in preclinical trials an ability to reverse multidrug
Alters Pharmacokinetic Profile
Numerous phase I studies have clearly demonstrated significantly
higher areas under the curve for liposomal-encapsulated doxorubicin (LED) than
for similar intravenous bolus doses of free doxorubicin.[29-32] Free doxorubicin
reaches a peak concentration within minutes after administration and has a
terminal elimination half-life of 30 hours. Depending on the specific liposomal
formulation, doxorubicin-containing liposomes can increase the area under the
curve by 20 to 600 times.[31,32] Therefore, the pharmacokinetic pattern of
liposomal-encapsulated doxorubicin more closely mimics the prolonged infusion
regimen of doxorubicin, which has demonstrated less systemic toxicity, most
notably diminished cardiotoxicity and gastrointestinal toxicity.
Attenuates Toxicity Patterns
Additionally, liposomal-encapsulated doxorubicin exhibits a much
smaller volume of distribution as compared with free doxorubicin. The estimated
volume of distribution for free doxorubicin is approximately 25 L/kg, or 1,875
liters for a 70-kg person, reflecting significant tissue uptake.[34,35] In
contrast, liposomal preparations can reduce the volume of distribution by 10- to
60-fold.[10-12,31,32] The relatively large size of liposomes probably accounts
for the marked reduction in the volume of distribution.
These large macromolecules are usually unable to traverse the
small endothelial gaps of normal tissue, especially cardiac endothelial
cells.[21,36] Indeed, a large body of clinical data supports findings that
cancer patients treated with liposomal-encapsulated doxorubicin have a
significant reduction in cardiac toxicity.[37-41] Diminished hematologic
toxicity (myelosuppression), gastrointestinal toxicity (nausea/vomiting),
mucositis, and venous sclerosis have also been noted with liposomal-encapsulated
Shown in Preclinical Trials to Reverse Multidrug Resistance
Multidrug resistance is an important impediment that is
difficult to circumvent in the treatment of cancer. Overexpression of
P-glycoprotein (Pgp170) in neoplastic cells can lead to marked resistance to
doxorubicin. Preclinical studies have demonstrated liposomal modulation of
MDR.[25-28] In one study, liposomal-encapsulated doxorubicin was shown to
prevent effective multidrug resistance by binding to the P-glycoprotein plasma
membrane pump expressed by the multidrug resistant genes. This may help
explain why liposomal-encapsulated doxorubicin has been effective in the
treatment of various chemotherapy-refractory cancers.[42-44]
Extensively Studied in Treatment
of Advanced Breast Cancer
Liposomal doxorubicin is steadily proving to be an important
antitumor agent. It has been extensively studied in the treatment of advanced
breast cancer, ovarian cancer, and Kaposi’s sarcoma.
The first phase II study of liposomal-encapsulated doxorubicin
in advanced breast cancer included 20 patients who had not received
anthracycline treatment within the past year. Sixteen of the 20 patients
received doxorubicin doses of 75 mg/m2 every 3 weeks, while the four remaining patients, all of whom had
undergone extensive radiotherapy, received either 45 or 60 mg/m2.
Overall, five patients demonstrated a complete response in their
index lesion, while four others demonstrated objective disease regression. The
mean duration of response was 7 months.
Most patients had some degree of myelosuppression, but the mean
nadir leukocyte count for all the cycles
was only 3,740/mL, and no patient developed sepsis or infection. Other toxic
effects included two episodes of grade 4 nausea/vomiting, two episodes of mild
stomatitis, and complete alopecia in all patients.
Cardiotoxicity was also assessed. Two patients had left
ventricular ejection fraction decreases (13% and 17%), and endomyocardial
biopsies performed on five patients who received cumulative doses of more than
500 mg/m2 revealed four grade 0 and one episode of grade 1 structural changes.
These data demonstrate the clinical activity of liposomal-encapsulated
doxorubicin against breast cancer, and suggest that liposomal-encapsulated
doxorubicin causes less cardiotoxicity, myelosuppression, and gastrointestinal
toxicity than equivalent doses of free doxorubicin.
Subsequent trials in advanced breast cancer have demonstrated
good response rates and a favorable toxicity profile, especially reduced
cardiotoxicity.[39,45] A recent phase III trial was reported comparing
cyclophosphamide (Cytoxan, Neosar) and either TLC D-99 or standard doxorubicin
as first-line treatment of metastatic breast cancer. Response rates were 43%
in both arms with a median survival of 21.2 months for the TLC D-99 patients and
16.4 months for those receiving standard doxorubicin. As expected, those treated
with TLC D-99 had significantly less cardiotoxicity and grade 4
Clinical Response Against Refractory Ovarian Cancer
Favorable results have also been demonstrated in patients with
refractory ovarian cancer. A phase II trial of liposomal doxorubicin was
conducted in 35 women with ovarian cancer refractory to platinum- and paclitaxel
(Taxol)-based regimens. Patients received 50 mg/m2 IV every 3 weeks. Nine
clinical responses were observed (one complete response and eight partial
responses) in 35 patients (25.7% response rate). The median progression-free
survival was 5.7 months with an overall survival of 1.5 to 24 + months (median:
Four patients developed fever and grade 3 neutropenia, while ten
developed grade 3 hand-foot syndrome. No cases of alopecia, cardiotoxicity,
phlebitis, or hepatic dysfunction were observed. This result suggests that
liposomal doxorubicin might be useful as second-line therapy for this disease,
and the lack of moderate-to-severe myelosuppression indicates that it can
potentially be integrated into combined drug modalities for ovarian cancer
without requiring dose attenuation.
Favorable Response Among Kaposi’s Sarcoma Patients
Patients with Kaposi’s sarcoma also respond favorably to this
formulation. A number of phase II and III trials have shown liposomal
doxorubicin to be an effective agent in the treatment of AIDS-associated Kaposi’s
sarcoma. Single-agent therapy produced a significantly better overall response
rate with much less toxicity and greater patient compliance vs a multidrug
regimen.[44,48-50] Future trials, testing the formulation in combination with
other active agents, are planned.
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