APLIDIN
Apladin, a registered trademark of aplidine (dehydrodidemnin
B, 10) is a second-generation didemnin.
Apladin (10), first reported in 1990 in a patent application,
was isolated from the Mediterranean tunicate, Aplidium albicans,
[100]. The antitumor property of aplidin was first reported
in 1996 by PharmaMar [101, 102]. Total synthesis of
this compound was achieved recently [103]. Aplidin was
found to be active against solid tumors, and non-Hodgkins
lymphoma. Mechanistic study of aplidin revealed that it interferes
with the synthesis of DNA, proteins and induces
G1–G2 cell cycle arrest [104]. Aplidin exhibit cytotoxicity
since it inhibits the ornithine decarboxylase, an enzyme that
is critical in the process of tumor formation and growth and
angiogenesis. Recently, Taraboletti et al. [105] showed that
aplidin also inhibits the expression of the vascular endothelial
growth factor gene, having antiangiogenic effects.
Aplidin was found to be more active than didemnins in the
preclinical studies, and exhibited substantial activity against
a variety of solid tumor models, including tumors noted to be
resistant to didemnins [106]. On the basis of promising preclinical
data aplidin entered into phase I clinical trials in
Spain, Canada, UK, and France for the treatment of solid
tumors, and non-Hodgkins lymphoma utilizing different
schedules of administration [107-110]. It was observed that
treatment with aplidin has generally been well tolerated, and
most common side effects were asthenia, nausea, vomiting,
transient transaminitis and hypersensitivity reactions. Interestingly
aplidine does not induce hematological toxicity,
mucositis or alopecia. The main dose limiting factor was the
occurrence of neuromuscular toxicity with the elevation of
creatine kinase levels [109, 110]. Biopsies of affected muscles
showed muscular atrophy and loss of thick myosin filaments.
Interestingly, the use of L-carnitine appears to prevent
and ameliorate muscular toxicity [110]. Apladin was
found to selectively target and preferentially kill human leukemic
cells in blood samples taken from children and adults.
In these studies, it was observed that apladin was more selective
towards leukemia and lymphoma cells than towards
normal cells. In addition, the activity of Apladin was found
independent of other anticancer drugs commonly used in
leukemia and lymphoma. Recently this compound entered
into Phase II clinical trials. Phase II trials are going on in
Europe and Canada covering renal, head and neck, and medullary
thyroid. The mode of action of this novel molecule is
not yet known, but it appears to block VEGF secretion and
blocks the corresponding VEGF-VEGF-Receptor-1
autocrine loop in leukemic cells [105].
Item Type: Article or Paper
Subjects: Q Science > QD Chemistry
ID Code: 50
Deposited By: Dr. Diwan S. Rawat
Deposited On: 11 May 2006
Anti-Cancer Agents - Med. Chem., 2006, 6, 000-000 1
/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.
Marine Peptides and Related Compounds in Clinical Trial+
Diwan S. Rawat*, Mukesh C. Joshi, Penny Joshi and Himanshu Atheaya
Department of Chemistry, University of Delhi, Delhi-110007 India
******************************************************
Item Type: Article or Paper
Subjects: Q Science > QD Chemistry
ID Code: 50
Deposited By: Dr. Diwan S. Rawat
Deposited On: 11 May 2006
Anti-Cancer Agents - Med. Chem., 2006, 6, 000-000 1
/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.
Marine Peptides and Related Compounds in Clinical Trial+
Diwan S. Rawat*, Mukesh C. Joshi, Penny Joshi and Himanshu Atheaya
Department of Chemistry, University of Delhi, Delhi-110007 India
KAHALALIDE F
Number of depsipeptides have been isolated from the
sacoglossan mollusk Elysia rufescens Pease 1871 [39-41].
Later it was discovered that an alga, a Bryopsis sp. (Bryopsidaceae)
on which the mollusk feeds has also been a source of
kahalalide F (1) but concentration of the peptide in mollusk
was found to be much higher. Other peptides such as kahalalide
A-E, O [41] and liner peptide H, and J [40] were isolated
from E. rufescens, while kahalalide G was found in the
diet of the animal [40]. Kahalalide F and G possess unusual
2-dihydroaminobutyric acid moiety and these peptides also
contains 13 amino acids and 5-methylhexanoic acid at the Nterminus.
Kahalalide F (1) was isolated in poor yield from
the animal, and the alga collected at the same site, and was
found to be most active peptide in the series [43-45]. The
structure of kahalalide F (1) was determined by Hamann et
al. [39] but later questions were raised about the stereochemistries
given in the original structure [46].
Reinvestigation of stereochemical assignment revealed
that Valine 3 should be D-Valine and Valine 4 should be LValine,
rather than the reverse as reported earlier [47]. In
addition to potent activity against human colon and lung
cancers, kahalalide F exhibits activity against some pathogenic
microorganisms that causes opportunistic infections of
HIV/AIDS. Actual mode of action of this compound had not
yet been fully determined, but it is known that kahalalide F
target lysosomes [48] and has selectivity for tumor cells such
as prostate tumor. The compound was synthesized by solid
phase peptide techniques [49]. Kahalalide F (1) exhibits potent
in vitro cytotoxic activity against various cell lines such
as prostate, breast, colon carcinomas, neuroblastoma, chondrosarcoma,
and osteosarcoma [50, 51] with IC50 ranging
from 0.07 mM (PC3) to 0.28 mM (DU145, LNCaP, SKBR-
3, BT474, MCF7). Importantly, nontumor human cells such
as MCF10A, HUVEC, HMEC-1, and IMR90 were found to
be 5-40 times less sensitive to the drug (IC50 = 1.6-3.1 mM).
Kahalalide F exhibits cytotoxicity against human tumor
specimens such as breast, colon, non-small cell lung, and
ovarian carcinomas and has also shown in vivo activity
against human prostate cancer xenografts [52]. It has been
confirmed by flow cytometry analysis that kahalalide F induced
neither cell-cycle arrest nor apoptotic hypodiploid
peak. Confocal laser and electron microscopic study revealed
that kahalalide F treated cells underwent a series of profound
alterations including severe cytoplasmic swelling and vacuolization,
dilation and vesiculation of the endoplasmic reticulum,
mitochondrial damage, and plasma membrane rupture.
This compound was licensed to PharmaMar by University
of Hawaii in the 1990s, and preclinical studies were
conducted. On successful completion of preclinical studies,
in December 2000 this compound entered in phase I clinical
trials in Europe for the treatment of androgen independent
prostate cancer [53]. In the preclinical developments, the
compound was administered iv to male and female rats in
multiple doses (daily for 5 days) and dose dependent toxicities
were determined. Physiological changes such as clinical
signs and body weight of the rats during this procedure
were kept under observation. After the completion of the
experiment animals were necropsied, clinical signs and organ
weights were recorded, and tissues were examined microscopically.
It was observed that kahalalide F produced
lethality at 375 and 450 mg/kg in males and females, respectively,
and the maximum tolerated dose (MTD) was determined
to be 300 mg/kg (1800 mg/m2). The nervous system
was found to be a potential site of action for the lethality of
this compound. In the organ toxicity, kidney was found to be
the main target at dose level of 150 and 300 mg/kg. High
dose of kahalalide F (300 mg/kg) caused necrotizing inflammation
of bone marrow and peritrabecular osteocyte
hyperplasia of bone on day four, which recovers thereafter.
Due to local cytotoxicity, injury to blood vessels and surrounding
tissue at the injection site was observed. When kahalalide
F was administered once daily for five days at a
dose of 80 mg/kg per day (400 mg/kg total dose), gain of
slightly decreased body weight was the main drug related
effect. Therefore, this drug is considered to be safe at or near
80 mg/kg per day. These results demonstrate that daily administration
of kahalalide F for 5 days reduces drug-induced
toxicity, so this compound was taken up for further clinical
evaluation for the treatment of cancer. Currently this compound
is in the phase II clinical trials for the treatment of
prostate cancer [54]. Recently, conducted studies demonstrated
that kahalalide F induces cell death via “oncosis”
possibly triggered by lysosomal membrane depolarization in
both prostate and breast cancer cell lines [55].