• Vol 7 • August 2005
Although surgical resection alone is potentially curative in
colorectal cancer, local or distant recurrences develop in many
patients. A number of cooperative group trials and analyses
have shown that 5-fluorouracil-based systemic adjuvant chemo-
therapy improves survival in high risk patients [1,2]. Combina-
tion regimens of 5-FU and leukovorin or levamizole have now
become standard care in patients with stage II (T3/N0/M0 or
T4/N0/M0) and stage III CRC. Fluorouracil-based chemotherapy
is also used in stage IV CRC.
CRCs develop as a consequence of genomic instability.
Microsatellite instability is involved in the genesis of about
15% of sporadic CRCs and in most hereditary non-polyposis
CRCs [3–5]. The multiple errors in repetitive DNA sequences
(microsatellites) are due to a failure of the DNA mismatch re-
pair system to edit errors that occur during DNA replication
. The DNA MMR system is inactivated either by hypermeth-
ylation of the promoter, which silences gene transcription of
hMLH1 (epigenetic phenomenon; sporadic CRC), or because of
germ-line mutations in MMR genes MLH1, MSH2, MSH6 and
others (HNPCC) [7,8]. Tumors with high frequency MSI tend
to be diploid, to possess a mucinous histology, and to have a
surrounding lymphoid reaction. They are more prevalent in the
proximal colon and have a fast (2–3 years) pass from polyp to
cancer. Nevertheless, they are associated with longer survival
than stage-matched low frequency MSI tumors or tumors with
microsatellite stability [9–15]. It is still not clear whether this
favorable prognosis is attributable to the inherently lower ag-
gressiveness of MSI-H tumors or to their greater sensitivity to
chemotherapy. Confounding factors, such as age and anatomic
site of the tumor, may also be important and should be tak-
en into consideration. Sporadic MSI-H tumors may occur in
the elderly because of CpG island hypermethylation and gene
silencing , and right-sided tumors were found to respond
favorably to chemotherapy irrespective of MSI status . Still,
it is unlikely that tumors with these distinct pathways would re-
spond similarly to chemotherapeutic agents that damage DNA.
This article attempts to clarify this issue by reviewing the cur-
rent literature on the biologic behavior and treatment of CRC
In vitro studies
Cell models may provide clues to the mechanism of colorectal
tumor resistance or sensitivity to 5-FU. At 5-FU concentrations
similar to in vivo tissue concentrations, ≥10% of 5-FU is incorpo-
rated into the DNA of CRC cells, indicating the potential of the
Colorectal cancers develop as a consequence of genomic instability.
Microsatellite instability is involved in the genesis of about 15% of
sporadic colorectal cancers and in most hereditary non-polyposis
cancers. High frequency MSI has been associated with a favorable
prognosis, however it is not clear whether this is because MSI-H
tumors are inherently less aggressive or because they are more
sensitive to chemotherapy. Chemotherapy with a combination of
5-fluorouracil and leukovorin or levamizole has been the standard
of care for high risk stage II and stage III CRC; it is also used in
stage IV CRC. Several in vitro studies have shown that colon can-
cer cell lines displaying MSI-H are less responsive to fluorouracil
than microsatellite-stable cell lines. Human studies, all of them
retrospective, yielded conflicting results. The selection of patients
with CRC for 5-FU treatment has been based so far on the stage
of the tumor rather than the biology of the tumor. Although surgi-
cal staging is highly predictive of survival, there are indications
that the form of genomic instability within a patient’s colorectal
tumor has clinical implications, with and without 5-FU treatment.
This review suggests that patients with MSI-H colorectal tumors
may not benefit from 5-FU-based chemotherapy and can avoid
its potential side effects (nausea, diarrhea, stomatitis, dermatitis,
alopecia, and neurologic symptoms) that occur in half the treated
patients. If confirmed by future prospective randomized controlled
studies, these findings would indicate that microsatellite-instability
testing should be conducted routinely and the results used to direct
rational adjuvant chemotherapy in colon cancer.
Biologic Behavior of Microsatellite-Unstable Colorectal Cancer and
Treatment with 5-Fluorouracil
Yaron Niv MD
Department of Gastroenterology, Rabin Medical Center (Beilinson Campus), Petah Tiqva, Israel
Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
Key words: chemotherapy, cancer, colorectal cancer treatment, microsatellite instability
MSI = microsatellite instability
MSI-H - high frequency MSI
CRC = colorectal cancer
5-FU = 5-fluorouracil
MMR = mismatch repair
HNPCC = hereditary non-polyposis CRC
• Vol 7 • August 2005
Microsatellite-Unstable Colorectal Cancer
DNA MMR system to tolerate the altered nucleo-
tide . How the DNA MMR proteins recognize
5-FU is still unknown. Certainly the lack of MMR
might allow incorporated 5-FU to adversely affect
DNA synthesis and replication, but not necessar-
ily to inhibit cell growth. A competent MMR sys-
tem may trigger a cell death program, which is
either additive to or independent of the effect of
5-FU on RNA metabolism and thymidylate syn-
thetase activity, and might be operative in MSS
Merkelbach-Bruse and colleagues  inves-
tigated the association between MSI status and
mRNA expression, as well as polymorphisms of
the cellular target of 5-FU therapy, thymidylate
synthase. Polymorphisms in the 3’ and the 5’-
UTR of the thymidylate synthase gene were de-
termined by a polymerase chain reaction assay in
53 CRC tissue samples. No significant correlation
was observed either between the polymorphisms
in the TS gene and the MSI phenotype or be-
tween the mRNA expression and the MSI status.
Other in vitro studies have shown that colon cancer cell lines
displaying MSI-H are less responsive to 5-FU than MSS cell
lines [17,19–25]. One study using three different methods (cell
enrichment assay, cell growth, and colony formation) found that
5-FU treatment killed MSS cells that were proficient in MMR
but spared MSI-H colon cancer cells . In another study, re-
expression of hMLH1 in a MSI-H cell line with hypermethylated
hMLH1 overcame resistance to treatment with 5-FU .
The ability to treat CRC stage II and III has significant implica-
tions for survival and cost. Before initiating treatment it is of
utmost importance to determine if MSI-H tumors are sensitive
or resistant to chemotherapy. The main problems with the hu-
man studies conducted so far were their retrospective design,
small number of MSI-H patients, and scarcity of direct com-
parisons of outcome of 5-FU treatment between patients with
MSI-H and those with MSI-L tumors [12,14,16,17,26–31]. The
studies listed in Table 1 show a direct comparison of prognosis
between treated stage II-III MSI-H and MSS or MSI-L tumors.
Furthermore, the studies that controlled for the effects of adju-
vant therapy used small or non-randomized study populations
harboring potential selection biases [14,16,17,26] and there was
no clear distinction between sporadic CRC and HNPCC cases.
Carethers et al.  evaluated 204 patients with stage II
and III CRC for whom pathologic material was available and
the chemotherapeutic regimen known. Formalin-fixed, paraf-
fin-embedded pathology blocks from each patient’s tumor were
cut into 5 µm slices and placed onto slides for DNA extraction.
Using the panel of five microsatellite markers (BAT25, BAT26,
D5S346, D2S123, and D17S250) recommended by the National
Cancer Institute, the authors classified the tumor as MSI-H (two
or more markers showing novel alleles compared with non-
tumor tissue), MSI-L (one marker with a novel allele), and MSS
(no marker with a novel allele). Owing to the similar features of
the MSI-L and MSS tumors and their common absence of as-
sociation with DNA MMR inactivation, they were grouped into
a single category and compared with MSI-H tumors, which are
associated with DNA MMR inactivation . Polymerase chain
reaction assay performed on the micro-dissected template DNA
showed a significant overall survival benefit in the patients with
CRC who were treated with 5-FU-based chemotherapy compared
to those who were not. However, within the MSI-H group there
was no difference in survival by 5-FU treatment, whereas in the
non-MSI-H group the authors noted a significant difference in
survival between patients treated with 5-FU and untreated pa-
tients. These findings indicate that the type of genomic insta-
bility within a colorectal tumor might dictate patient response
to 5-FU-based chemotherapy.
In a study of 298 patients with sporadic stage III CRC treat-
ed with 5-FU-based regimens, Watanabe and team  found
62 MSI-H tumors (21%), of which 38 (61%) had a mutation of
TS = thymidylate synthase
MSS = microsatellite stability
MSI-L = low frequency MSI
Table 1. 5-FU-based chemotherapy by microsatellite status
No. of MSS/L
Carethers et al.
de Vos et al.
Ribic et al.
Brueckl et al.
Liang et al.
Hemminki et al.
Elsaleh et al.
70%/70% 5 yrs in 28
treated vs. 64 not treated
33 months/19 months
24 months/13 months
∗∗ Only BAT26 examined, MSI-H more common in women.
Estimated from survival curves.
High frequency microsatellite instability in
colorectal cancer tissue is associated
with a favorable prognosis
• Vol 7 • August 2005
the gene controlling the type II receptor for transforming growth
factor-beta 1. The 5 year survival rate was 74% in those with
a mutated gene and 46% in those without this mutation (P =
0.03). Thus, in cancers with high levels of MSI, the presence
of a mutation of the gene for the type II receptor for TGF-β1
is indicative of a favorable outcome for adjuvant chemotherapy.
This finding was supported by Goel et al.  who described a
significant association of RUNX3 (a gene related to the RUNT
transcription factor, an important target of the TGF-β super-
family proteins) promoter hypermethylation and MSI-H colon
cancers. They suggested that RUNX3 is a novel target of meth-
ylation, along with the hMLH1 gene, in the evolution of MSI-H
By contrast, other large selected case series of patients
with stage III colon cancer demonstrated a significant associa-
tion between MSI-H and increased survival in patients receiving
adjuvant chemotherapy [16,35]. MSI status was determined by
screening for deletions in the BAT26 mononucleotide repeat
only. Systemic adjuvant 5-FU-based chemotherapy was delivered
to 266 patients. MSI-H status was predictive of excellent surviv-
al benefit from chemotherapy but was not associated with bet-
ter prognosis for patients who did not receive treatment. How-
ever, the patients who did not receive chemotherapy were older
than those who did, which may have introduced a bias into the
study. Older age has been associated with poor outcome in
CRC after adjustment for MSI status . A significantly older
mean age also implies that the presence of coexisting disease
was an important reason for not offering adjuvant treatment to
patients in this non-randomized sample .
Hemminki and co-workers  followed 95 patients with
stage III cancer who had received adjuvant chemotherapy for
7–63 months (median 31 months). The 3 year recurrence-free
survival rate was 90% in the MSI-H group (n=11) compared to
43% in the MSS group (n=84) (P = 0.020). In another retrospec-
tive study, de Vos and associates  noted a 70% 5 year sur-
vival rate in 92 patients with stage III CRC from HNPCC families
regardless of treatment with adjuvant 5-FU.
Ribic and co-investigators  used specimens from patients
with resected stage II or stage III colon cancer who were pre-
viously enrolled in prospective randomized trials of 5-FU-based
chemotherapy. These included phase 3 studies with groups that
received no treatment, thus permitting analysis of the true sur-
vival advantage for patients with MSI-H tumors untreated by
adjuvant protocols. In addition, this design made it possible to
analyze whether the phenotype of MSI-H was an independent
predictor of benefit from 5-FU-based adjuvant chemotherapy.
Of the 570 tumor samples tested, 16.7% were categorized as
MSI-H, 10.5% as MSI-L, and 72.8% as MSS. Among the patients
who had not received adjuvant chemotherapy, those with MSI-
H tumors had longer overall survival and higher rates of 5 year
disease-free survival than patients with MSI-L or MSS tumors.
On multivariate analysis, controlling for disease stage and tu-
mor grade, the MSI-H status in patients who did not receive
5-FU-based adjuvant chemotherapy was significantly and inde-
pendently associated with a better survival. However, analysis
of the patients who did receive adjuvant therapy did not yield
significant differences in overall or disease-free survival accord-
ing to MSI status. Patients with MSI-L or MSS tumors who re-
ceived adjuvant chemotherapy had a significantly greater overall
survival than patients who did not. Among the group with MSI-
H tumors, treatment was associated with a worse outcome for
both stage II and stage III cancer. Barratt et al.  found no
improvement in survival among patients with MSI-H adjusted
for tumor site.
One study in patients with stage IV CRC reported that pa-
tients with MSI-H tumors treated with 5-FU had a better surviv-
al than patients with non-MSI-H tumors . This finding was
confirmed in a study of 43 patients with stage IV CRC, of whom
7 had MSI-H tumors .
Fluorouracil is a fluoropyrimidine that is incorporated into
RNA (messenger, ribosomal, and transfer RNA), and acts as
an inhibitor of thymidylate synthetase, which catalyzes the
conversion of deoxyuridine monophosphate (dUMP) to de-
oxythymidine monophosphate (dTMP) . It is generally
accepted that it is the incorporation of 5-FU into RNA (in
which uracil is one of the four bases and replaces thymine)
that is the important mechanism of 5-FU toxicity . Un-
der normal conditions, deoxyuridine triphosphatase prevents
the incorporation of deoxyuridine triphosphate (dUTP) and
5-fluoro-deoxyuracil triphosphate (FdUTP) into DNA by de-
phosphorylating the nucleotides to dUMP and 5-fluoro-deoxy-
uracil monophosphate (FdUMP), respectively . Fluoroura-
cil, however, inhibits thymidylate synthetase, which prevents
the synthesis of dTMP and deoxythymidine triphosphate. As
a result, dUMP and FdUMP accumulate, thereby exhaust-
ing the ability of deoxyuridine triphosphatase to metabolize
dUTP and FdUTP. As levels of dUTP and FdUTP increase and
levels of thymidine triphosphate (TTP) decrease, dUTP and
FdUTP replace TTP as substrates for DNA polymerases and
are incorporated into DNA. This facilitates the incorporation
of 5-FU into DNA. Although uracyl-N-glycosylase, an enzyme
that removes uracil bases from DNA after the spontaneous
deamination of deoxycytidine, will typically also remove the
incorporated uracil bases, TTP is not available, and the DNA
strand is repaired with dUTP or FdUTP as a substrate. Fluoro-
uracil has been detected in cellular DNA in previous studies,
but no correlation between 5-FU incorporation into DNA and
cytotoxicity has been reported .
TGF-β1 = transforming growth factor-beta 1
These tumors may not be sensitive to
• Vol 7 • August 2005
Microsatellite-Unstable Colorectal Cancer
It is not known whether the MMR system can recognize
and respond to 5-FU incorporated into DNA. Unlike bulky in-
tercalating adducts such as cisplatin, or incorporated purines,
5-FU may not physically distort the DNA double helix. Because
it has a pyrimidine base (smaller than purine), 5-FU does not
directly interfere with interstrand hydrogen bonding of DNA. It
may be recognized by the position of attachment of chemical
groups on the altered nucleotide or by the physical nature of
the compound itself; the highly charged fluoropyrimidine may
deform the DNA double strand enough to be recognized by
MMR proteins. Another possibility is that the MMR system rec-
ognizes the strand distortion produced when uracil-N-glycosyl-
ase removes incorporated FdUTP or dUTP. These pyrimidines are
eventually reincorporated in place of TTP (a pyrimidine) because
thymidylate synthetase is inactivated.
Carethers and team  found neither cell cycle alterations
in MMR-proficient cells after 5-FU treatment nor a G2/M cell
cycle arrest within the first 24 hours after treatment, and this
state was sustained for more than 5 days. Lack of cell cycle
perturbations after 5-FU treatment suggests that 5-FU cytotox-
icity induces an alternative pathway of response by the MMR
system that does not trigger G2/M cycle arrest. The authors
also reported a seven- to ninefold lesser DNA than RNA incor-
poration. The effect of the incorporation of 5-FU into DNA on
subsequent cell divisions remains unclear. Moreover, it is not
apparent that 5-FU would induce point mutations.
The finding that fluorouracil-based adjuvant chemotherapy does
not always increase, and may potentially decrease, overall and
disease-free survival among patients with tumors exhibiting
high frequency microsatellite instability raises several challeng-
ing questions regarding postoperative management of stage II
and stage III colon cancer. In future studies, identification of
the form of genomic instability will be paramount for interpre-
tation of the results. Microsatellite testing of colorectal tumors
will need to be more commonplace to implement any findings,
since a favorable outcome in MSI-H cases does not result from
higher sensitivity to chemotherapy. Prospective randomized con-
trolled studies are necessary to reach a final conclusion as to
whether MSI-H CRC is sensitive or stabile to 5-FU-based che-
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Correspondence: Dr. Y. Niv, Chief, Dept. of Gastroenterology, Rabin
Medical Center (Beilinson Campus), Petah Tiqva 49100, Israel.
Phone: (972-3) 937-7237
Fax: (972-3) 921-0313
email: firstname.lastname@example.org; email@example.com
Fungal malaria control
There is a pressing need for alternatives to chemical insecticides
for targeting adult mosquitoes, the vectors of malaria, owing
to the development of resistance and worries about human
toxicity. Blanford and co-researchers (Science 2005;308:1638)
found that treating surfaces with a fungal pathogen of insects
reduced the number of mosquitoes able to transmit malaria
after an infectious blood meal by more than 100-fold. Fungal
infection via contact with netting or solid surfaces was sufficient
to cause more than 90% mortality. Scholte et al. (p. 1641)
performed field-based research in rural African village houses,
using a fungus in real-life conditions, to target wild mosquito
vector populations. Large numbers of mosquitoes could be
infected with the fungus, which could inhibit malaria parasite
development. Even at moderate coverage rates, a dramatic fall
in malaria transmission intensity should be achievable.
Toxoplasma infection and TLR
Mammalian Toll-like receptors (TLRs) are critical modulators of
the immune response to pathogens. TLR recognition of bacteria
and some viruses are well known, but there have been few
examples of recognition of parasite ligands. Yarovinsky et al.
describe the detection of a profilin-like protein derived from the
protozoan parasite Toxoplasma gondii by a recently characterized
mouse TLR, TLR11. The ligand induced the production of the
pro-inflammatory cytokine interleukin-12 (IL-12) by engaging the
TLR signaling pathway. In the absence of TLR11, loss of IL-12
production rendered mice susceptible to T. gondii infection. Similar
detection of parasite proteins by TLRs may influence the course
of immunity against a range of protozoan parasitic diseases.
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