General Problems In Development Of Cancer Treatment

Cancer remains the major cause of death in most advanced
countries in the world, and the incidence of cancer increases as
populations age. The best treatment of malignancies such as gastric,
colonic, and cervical cancers is surgical removal of early-stage tumors
that are small and confined to a limited area, without metastasis.
Chemotherapy, and to a limited extent radiotherapy, have been the
last resort to control cancer. However, conventional chemotherapy,
which utilizes small molecular drugs, is far from successful, similar to
the situation that we have experienced with antibiotics given for
microbial infections. This problem derives mostly from the lack of
tumor selectivity, or so-called selective toxicity, of these agents, so
that severe adverse effects limit usage. Thus, an urgent need exists to
develop drugs with high selectivity to target tumors, which may
greatly reduce drug toxicity and enhance the therapeutic efficacy of
Another so far unsuccessful direction of recent cancer treatment is
so-called molecular target therapy, which usually focuses on specific
kinases or receptors that are overexpressed in cancer cells or tissues.
Recent clinical results for those molecular target drugs have been
disappointing [1'3]. The benefit for patients undergoing these
treatments is a 1'2 month extension of the usual 3- to 5-year overall

survival [1,3]. In another study, a combination of two different types
of molecular target drugs resulted in shorter overall survival [2].
Adverse side effects were not easily overcome, and the frequency of
medical emergencies was not reduced. Among these drugs, one
exception was imatinib (Gleevec), which is used for chronic
myelogenous leukemia. However, most cases demonstrated drug
resistance after several months of its use. The problems associated
with molecular target drugs probably relate to the intrinsic genetic
diversity of human solid tumors, which these drugs do not account for
[4,5]. Usually, multiple genes or their product proteins, which make
up sophisticated networks, support or promote the growth, cell
regulation, invasion and metastasis of tumor cells. These genes are
now known to undergo extensive mutations. Findings for 11 patients
with breast cancer and 11 patients with colorectal cancer showed that
individual tumors demonstrated an average of approximately 90
mutated genes, and 189 genes mutated at a significantly high
frequency [5]. These data mean that the patients had only a small
(few percent) chance of the likelihood of a positive response to the
molecular target drugs. In addition to the high frequency of occurrence
of mutant genes, redundant genetic and molecular or metabolic
pathways, which constitute the backup system of vital molecular
pathways,may invalidate the single gene or receptor concept and single
pathway assumption. Thus, such a highly specific molecular approach,
targeted to even a single epitopic antigen, receptor, or kinase, seems to
be an imperfect if not an unwise approach.
Another problem may reside in the in vitro screening method for
cancer chemotherapeutics. This method utilizes the individual cancer
cell type panel model, and a drug is thus screened on the basis of
tumor cell type. However, even after more than 30 years of screening
at least 50 cell types, such as glioblastoma, malignant melanoma,
hepatoma, pancreatic cancer and cervical cancer, no revolutionary
discovery of new useful drugs has been reported. One problem with
this screening system is probably related to a lack of considering
pharmacokinetics and the vascular phenomenon named the enhanced
permeability and retention (EPR) effect, so that only cytotoxic
compounds were identified.

1.2. The EPR effect: the cutting edge
The greatest breakthrough leading to more general targeted
antitumor therapy was the discovery of the EPR effect, as commented
by Torchilin [6], (in this issue of ADDR).
The EPR effect was first reported by Matsumura and Maeda in 1986
[7] and was described in greater detail and validated by Maeda et al.
[8'14]. Their investigations showed that most solid tumors have
blood vessels with defective architecture and usually produce
extensive amounts of various vascular permeability factors. Most
solid tumors therefore exhibit enhanced vascular permeability, which
will ensure a sufficient supply of nutrients and oxygen to tumor
tissues for rapid growth. The EPR effect considers this unique
anatomical'pathophysiological nature of tumor blood vessels that
facilitates transport of macromolecules into tumor tissues. Macromolecules
larger than 40 kDa selectively leak out from tumor vessels
and accumulate in tumor tissues. In contrast, this EPR effect-driven
drug delivery does not occur in normal tissues [7'14]. This unique
phenomenon in solid tumors'the EPR effect'is thus considered to be
a landmark principle in tumor-targeting chemotherapy and is
becoming an increasingly promising paradigm for anticancer drug
development. For example, Doxil, which is a PEGylated (polyethylene
glycol-coated) liposome-encapsulated formulation of doxorubicin,
was approved for treatment of Kaposi sarcoma and other cancers.
Many other polymeric or micellar drugs are in clinical stage
development (phases I and II) [15,16], of which only a few are
reviewed in this special issue. Compared with conventional anticancer
drugs, most of which are small molecular drugs, these macromolecular
drugs have superior in vivo pharmacokinetics (e.g., a prolonged
plasma half-life) and, more important, greater tumor selectivity, so
that they produce improved antitumor effects with no or less adverse
reactions [15'17].
The EPR effect has thus now become the 'gold standard' in
anticancer drug design and anticancer strategies using macromolecular
agents, including gene delivery, molecular imaging, antibody
therapy, micelles, liposomes, and protein'polymer conjugates (see
Torchilin [6] in this issue of ADDR). As evidence of this status, the
numbers of citations related to the EPR effect have been progressively
increasing in recent years (Fig. 1).
1.3. Problems related to the EPR effect and their solutions
Regardless of the popularity of EPR effect-based drug delivery,
many problems with that strategy still exist. We know that large
tumors show great pathophysiological heterogeneity.

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