"Adriamycin - Straight Up or Liposome-Encapsulated"
GULF COAST VETERINARY ONCOLOGY'S TUMOR TIDBITS
Volume 2, Number 2: January 2001
This Month's Feature: Adriamycin - Straight Up or Liposome-Encapsulated
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Editor: Kevin A. Hahn, DVM, PhD, Diplomate American College of
Veterinary Internal Medicine (Specialty of Oncology) & Overall Nice Guy;
Gulf Coast Veterinary Oncologists, Houston, TX 77027,
drhahn@gulfcoastvetspec.com
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Adriamycin - Straight Up or Liposome-Encapsulated
Introduction
Doxorubicin hydrochloride is a cytotoxic anthracycline antibiotic
isolated from Streptomyces peucetius var. caesius It is indicated in
the treatment of a variety of canine and feline malignant conditions.
The dose-limiting effects are myelosuppression and gastrointestinal
toxicoses in both the dog and the cat, and cardiotoxicity in the dog.
DOXIL® (doxorubicin HCl liposome injection) is doxorubicin hydrochloride
(HCl) encapsulated in STEALTH® liposomes for intravenous administration.
Greater than 90% of the drug is encapsulated in the STEALTH® liposomes.
The active ingredient of DOXIL® is doxorubicin HCl.
The mechanism of action of doxorubicin HCl is thought to be related to
its ability to bind DNA and inhibit nucleic acid synthesis. Cell
structure studies have demonstrated rapid cell penetration and
perinuclear chromatin binding, rapid inhibition of mitotic activity and
nucleic acid synthesis, and induction of mutagenesis and chromosomal
aberrations.
Liposomes are microscopic vesicles composed of a phospholipid bilayer
that are capable of encapsulating active drugs. The STEALTH® liposomes
of DOXIL® are formulated with surface-bound methoxypolyethylene glycol
(MPEG), a process often referred to as pegylation, to protect liposomes
from detection by the mononuclear phagocyte system (MPS) and to increase
blood circulation time.
Free doxorubicin HCl has a half-life of approximately 30 minutes in dogs
and 1 hour in humans. STEALTH® liposomes have a half-life of
approximately 55 hours in humans. They are stable in blood, and direct
measurement of liposomal doxorubicin shows that at least 90% of the drug
(the assay used cannot quantify less than 5-10% free doxorubicin)
remains liposome-encapsulated during circulation.
It is hypothesized that because of their small size (ca. 100 nm) and
persistence in the circulation the pegylated DOXIL® liposomes are able
to penetrate the altered and often compromised vasculature of tumors.
They differ from conventional liposomes in their ability to avoid rapid
uptake by the reticuloendothelial system, and to extravasate into tumor
interstitium at a higher rate than into normal tissue.
Evidence of penetration of STEALTH® liposomes from blood vessels and
their entry and accumulation in tumors has been seen in mice with C-26
colon carcinoma tumors and in transgenic mice with Kaposi's sarcoma-like
lesions. Once the STEALTH® liposomes distribute to the tissue
compartment, the encapsulated doxorubicin HCl becomes available. The
exact mechanism of release is not understood. STEALTH liposome
encapsulation of doxorubicin has been shown to abrogate the
myelosuppression and cumulative cardiotoxicity seen with the native
compound in the canine and human systems. Dose-limiting toxicity in
dogs is an ulcerative cutaneous reaction resembling palmar-plantar
erythrodysesthesia (PPES), or hand-foot syndrome in humans.
PPES is characterized by swelling, pain, erythema and, for some
patients, desquamation of the skin on the hands and the feet. The
syndrome is generally seen after six or more weeks of treatment but may
occur earlier. The incidence of this reaction may be higher when DOXIL®
is administered at doses that are higher or at intervals that are
shorter than those recommended. In most patients, the reaction is mild
and resolves in one to two weeks so that prolonged delay of therapy need
not occur. The reaction can be severe and debilitating in some patients,
however, and may require discontinuation of treatment.
Experience in cats
In a 1996 study, 32 cats with various malignancies were given DOXIL® as
a slow IV bolus every 3 weeks. Dosages ranged from 0.75 to 1.5 mg/kg
free doxorubicin equivalent as part of a phase I dose escalation trial.
Doses as high as 1.5 mg/kg every 3 weeks, 50% higher than the maximum
tolerated dose reported in dogs, were reported with no toxicity. Side
effects observed included mild to moderate localized hyperpigmentation
and alopecia, especially of the chin, mild transient gastrointestinal
symptoms, and sudden explained death (2/32). The deaths occurred at
lower dosages. No alterations in hemogram or biochemical profiles were
noted. Responses were observed in 10 of 32 cats (31%) including 6 of 13
soft tissue sarcomas, 3 carcinomas, and one osteosarcoma.
DOXIL® appears safe to administer at doses exceeding that which can be
given to dogs, and exceeding the MTD for free doxorubicin in cats. Non
dose-limiting cutaneous and GI side effects were well tolerated,
sporadic and not dose-dependent. The causes for the two cases of acute
death could not be determined. Since a MTD has not been established for
cats, further studies are needed. The tumor response against feline
sarcomas is of great interest and warrants further investigation.
Experience in dogs
In a 1996 study of 51 dogs with histologically confirmed malignancies, a
total of 103 DOXIL® treatments were given IV every 3 weeks at dosages
ranging from 0.75 mg/kg to 1.1 mg/kg in a phase I dose-escalation trial.
The maximally tolerated dose of DOXIL® was 1.0 mg/kg IV every 3 weeks.
The dose-limiting toxicity was PPES. Non dose-limiting, mild
gastrointestinal toxicity was also seen, yet less frequently than with
free doxorubicin treatments. No significant myelosuppression was seen.
Cardiotoxicity was not noted in any dog. An overall tumor response rate
of 25% was observed with 5 complete remissions and 8 partial remissions.
In this study, DOXIL® appeared to be well-tolerated at dosages similar
to those tolerated for free doxorubicin in tumor-bearing dogs. PPES,
not myelosuppression or cardiotoxicity was the dose-limiting toxicity.
DOXIL® appeared to have a broad spectrum of activity.
In a follow-up study conducted in 1997, concomitant pyridoxine (vitamin
B6) therapy was evaluated as a possible approach to prevent the
development of PPES during DOXIL® therapy. Forty-one dogs with
non-Hodgkin's lymphoma were randomized in a double-blind fashion to
receive either oral pyridoxine or placebo daily during DOXIL®
chemotherapy (1.0 mg/kg, i.v., every 3 weeks for a total of five
treatments). Cutaneous toxicity was determined by clinical and
histological scoring. No difference was observed in remission rates
(71.4 versus 75%) achieved between groups. The likelihood of developing
serious PPES and having to decrease or discontinue DOXIL® therapy was
4.2 times (relative risk) greater in placebo group dogs than in
pyridoxine group dogs. Pyridoxine did not completely abrogate PPES;
however, it occurred later and less dramatically than in placebo-treated
dogs and resulted in fewer treatment delays or discontinuations,
allowing a higher cumulative dose of DOXIL® to be received. Compared to
the 5.0 mg/kg cumulative target dose, pyridoxine-treated dogs received a
median cumulative dose of 4.7 mg/kg (mean, 4.1 mg/kg), and the
placebo-treated dogs received a median of 2.75 mg/kg (mean, 2.9 mg/kg. A
trend toward prolongation of remission length was observed in dogs
receiving pyridoxine, which was likely attributable to their ability to
receive more DOXIL® without delay or discontinuation.
Summary
The indications for DOXIL® appear to be similar to those of 'free'
doxorubicin. Although the MTD of DOXIL® and doxorubicin are similar in
the dog, the dose-limiting toxicities differ between the two drugs. In
the cat, DOXIL® may be efficacious, however until an MTD can be
established, the true indications and dose-limiting effects of DOXIL® in
the cat remain largely unknown.
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For further information on "Adriamycin - Straight Up or
Liposome-Encapsulated" or about any other cancer issue, please call us
(713-693-1166) or email Dr. Hahn at drhahn@gulfcoastvetspec.com
.
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