The following excerpt is taken from Chapter
23 of Colon & Rectal Cancer: A Comprehensive Guide for
Patients & Families by Lorraine Johnston, copyright 2000 by
O'Reilly & Associates, Inc. For book orders/information, call
(800) 998-9938. Permission is granted to print and distribute this
excerpt for noncommercial use as long as the above source is
included. The information in this article is meant to educate and
should not be used as an alternative for professional medical care.
Novel substances being used in trials for colorectal cancer are listed
below, grouped alphabetically by modes of action. You'll note that some
substances, such as phenylbutyrate, fit more than one category.
DNA strands are held together by a variety of forces, one being electrical
bonds. Alkylating agents form new electrochemical bonds within the DNA strand.
This disrupts many normal functions of DNA, including its ability to divide.
Alkylating agents are able to affect a cancer cell's DNA even when the DNA is
not uncoiled and separated--in other words, they are not cell-cycle
specific--which may explain their relatively high activity against many
New alkylating agents being tested for colorectal cancer are carmustine,
cisplatin, carboplatin, Melphalan (L-PAM), and 6-hydroxymethylacylfulvene (HMAF
or MGI-114), an extract of a mushroom toxin.
Most tumors trigger growth of many new blood vessels to support the
increased metabolic needs of the tumor. This growth of new blood vessels is
called angiogenesis. Antiangiogenic agents interrupt the ability of the body to
grow new blood vessels, causing tumors to shrink.
Some of the substances being studied now to reduce the blood supply to
starve tumors, an approach called antiangiogenesis, cause concern because they
also are likely to reduce the blood supply to normal tissues. The normal
tissues of concern are found near the healing wound and, for example, in the
uterus of a menstruating woman. Refined methods of curtailing a tumor's blood
supply are being examined, such as triggering clots only in tumor blood vessels
by preferentially binding clotting substances to proteins found only on tumor
Antiangiogenesis drugs now in clinical trials for colorectal cancer are
thalidomide, heparin, and BAY 12-9566.
Antibodies are substances, proteins, secreted by white blood cells called
B-cells. They attach to foreign material and pathogens so that the invaders can
be destroyed by other white blood cells called T-cells and macrophages.
Antibodies engineered in the lab to attach to only one cell surface
receptor--monoclonal antibodies--have long been used in research and cancer
diagnosis to tag cancer cells for visibility and quantification. Now they're
beginning to be used to treat cancers.
Monoclonal antibodies (moabs) being tested for colorectal cancer
- A33, attached either to iodine I-131 or to cisplatin-epinephrine (intradose
- LMB-9 for tumors that express the Lewis Y Antigen (B3 antigen)
- Moab 17-1A
- The bispecific antibody 520C9xH22 (MDX-H210) for HER2/neu-positive (p185)
tumors, in combination with interferon gamma
- The monoclonal antibody F19 (BIBH-1), an antibody expressed on fibroblasts,
in those with fibroblast activation protein-positive tumors
This is a broad category of anticancer drugs that contains some agents also
in other categories.
By definition, cytokines are proteins our bodies manufacture to trigger
activity in other cells, "cyto" meaning cell, and "kine"
meaning activity. Using this definition, almost any protein or enzyme is a
cytokine, but for cancer and inflammatory processes, special cytokines are in
play. All of the interleukins and interferons are cytokines, as is tumor
necrosis factor and the colony stimulating factors.
Some cytokines appear to cause cancer growth under certain circumstances,
such as interleukin-6 (IL-6) in myeloma studies. Some cytokines work in
opposition to each other, such as interleukin-10 and interleukin-12.
The substances being tested as anti-cytokines for colorectal cancer are
interleukin-12 and low molecular weight heparin (Dalteparin).
As the word antimetabolite implies, these substances in some way impede the
cell's metabolism, its building up and breaking down of cell parts. Each of the
antimetabolites used for colorectal cancer works a bit differently from the
others, and some may fit into other categories described in this chapter, such
as the antifolates.
- Gemcitabine (difluorodeoxycytidine) is an antimetabolite that substitutes
for an enzyme in the process that constructs DNA from RNA, causing the process
- Hydroxyurea, a cell cycle-phase specific antimetabolite, blocks the enzyme
ribonucleotide reductase. This enzyme is responsible for converting
ribonucleotides to deoxyribonucleotides. DNA, but not RNA, synthesis is
Antisense molecules (antisense oligonucleotides)
DNA wants to exist in paired strands, except when a cell is dividing.
Because cancer cells are known to have one or more faulty genes somewhere along
the length of their DNA, some researchers are experimenting with delivering to
the tumor short pieces of DNA or RNA that will match the faulty genes and
couple with single strands of the cancer cell's DNA. In theory, these short
pieces of DNA or RNA might interfere with a cancer cell's division and
replication in a variety of ways.
Antisense substances being tested against colorectal cancer are ISIS 3521
and ISIS 5132.
These agents are used to offset dangerous effects of chemotherapy by
shielding healthy cells from damage, or by promoting their regrowth.
A substance being tested for this purpose among those being treated for
colorectal cancer is Amifostine (Ethyol), which protects bone marrow, the
central nervous system, and kidneys.
Research has shown that some drugs, while having no direct ability to kill
cancer cells, appear to heighten the cancer cell's vulnerability to other
drugs. Other studies have shown that some drugs can both kill cancer cells and
improve the ability of other drugs to do so.
Substances being tested for these purposes are ethynyluracil, hydroxyurea,
See also Drug modulation and Radiosensitization.
Colloidal drug delivery
Certain drugs are not absorbed well by the body because they are not readily
soluble in blood, or cannot survive the acid of the gastrointestinal tract.
Attempts to overcome these drawbacks include creation of these drugs in
soluble forms, or attached to vehicles that traverse inhospitable biological
A form of 9-aminocamptothecin (9-AC) has been created in a colloidal
dispersion that is injected directly into the abdominal cavity in an effort to
improve its concentrations within cancerous tissue.
Colony-stimulating factor therapy
Some treatments, particularly those that target the immune system, may work
better if red or white blood cells or platelets are abundant when the substance
Trials for colorectal cancer exploiting this theory include:
- Phase I Study of Mutant MGMT Gene Transfer into Human Hematopoietic
Progenitors to Protect Hematopoiesis During O6-Benzyguanine and Carmustine
Therapy of Advanced Solid Tumors and Non-Hodgkin's Lymphoma
- Phase II Study of Vaccine Therapy with Tumor Specific Mutated Ras Peptides
in Combination with Interleukin-2 or Granulocyte-Macrophage Colony-Stimulating
Factor for Adults with Metastatic Solid Tumors
- Phase II Randomized Study of Autologous Tumor Cell Vaccine in Patients with
- Phase I/II Study of ALVAC-CEA-B7.1 Vaccine Alone or in Combination with
Sargramostim (GM-CSF) in Patients with Recurrent or Refractory CEA-Expressing
- Phase II Study of MOAB 17-1A/GM-CSF for 5-FU-Resistant Metastatic
Cyclin-dependent kinase inhibitor therapy
Cyclins are proteins that govern the progression of the cell from one stage
of cell division to the next. The cyclin-dependent kinases are enzymes that
join with cyclins, forming several unique cyclin/cdk complexes, to mediate this
progression. Substances that can inhibit these enzymes inhibit tumor
Flavopiridol is being tested for this purpose.
Cytokines, as discussed earlier under Anti-cytokine therapy, are proteins
our bodies manufacture to trigger activity in other cells, such as the release
of prostaglandins at the site of injury or the growth of new white blood cells.
All of the interleukins and interferons are cytokines, as is tumor necrosis
factor and the colony stimulating factors. Cytokines such as G-CSF are used in
clinical trials in conjunction with other substances to boost an immune
response or to support patient recovery.
Manmade cytokines being tested for use against colorectal cancer
- Intraperitoneally administered interleukin-12 (IL-12)
Dendritic cell vaccines
Dendritic cells are accessory cells of the immune system. They can be
educated to stimulate other white blood cells to kill tumors.
Current clinical trials for dendritic cell vaccines include:
- Phase I/II Study of Active Immunotherapy with Carcinoembryonic Antigen RNA
Pulsed Dendritic Cells in Patients with Resected Hepatic Metastases from
Adenocarcinoma of the Colon
- Phase I Study of a CEA Peptide-Pulsed Dendritic Cell Vaccine for Metastatic
Breast or Gastrointestinal Cancer
- Phase I Pilot Study of Active Immunotherapy with Carcinoembryonic Antigen
(CEA) Peptide-Pulsed Autologous Dendritic Cells in Metastatic Adenocarcinomas
that Express CEA
Cell differentation into distinct functional types is part of the normal
cell's maturation process. When cancer cells are continually dividing, however,
they might not mature and differentiate into the adult, functioning form of the
tissue in which they arose. The result is a large group of cells that not only
fail to carry out the function the organ was designed to do, but that also
crowd out other cells, and commandeer a disproportionate share of the body's
resources. Some cancer cells are so poorly differentiated that it's not
possible to tell what organ gave rise to the tumor, and the diagnosis is by
default carcinoma of unknown primary origin (CUP).
Some substances can force cancer cells to mature as normal cells do,
stopping the cycle of uncontrollable cell division that characterizes cancer
Bryostatin 1 and phenylbutyrate are possible differentiators being tested
for colorectal cancer.
DNA adduct formation
Drugs that form DNA adducts interfere with the cancer cell's ability to copy
its DNA for cell division. Adducts confuse and derail the enzymes responsible
for cell division and replication.
Oxaliplatin, a platinum-based substance, is a DNA adduct forming drug being
tested against colorectal cancer.
Certain anticancer drugs seem to make other drugs more effective in killing
cancer cells for reasons that vary. Fluorouracil (5-FU), for example, works
more effectively in the presence of methotrexate, trimetrexate,
interferon-alpha, leucovorin, or N-(phosphonacetyl)-L-asparte acid (PALA).
Being tested with 5-fluorouracil and leucovorin for use against colorectal
- Trimetrexate glucuronate
- N-(phosphonacetyl)-L-asparte acid (PALA)
See also Chemosensitization.
Farnesyl transferase (FTPase) inhibitors
In several cancers, including colorectal cancers, a gene called ras, which,
along with other genes, is responsible for orderly cell division, is mutated.
Certain substances can inhibit the growth of cancerous cells that contain a
mutated copy of ras, while leaving normal cells unaffected.
L-778,123 is a substance being tested for this purpose.
Folate antagonist therapy
Folate is needed to make the building blocks of DNA, purines and
thymidylates. Without these, new copies of DNA cannot be made. Because cancer
cells divide more rapidly than most normal cells, and because they commandeer
major supplies of the body's nutrients, treatments such as folate antagonists
are expected to affect cancer cells more strongly than most healthy cells.
Phenylbutyrate and Tomudex (also called raltitrexed, ICI D1694, or ZD1694)
are classified as antifolates. See also Thymidylate synthase inhibitors.
In its broadest sense, gene therapy is a name applied to several kinds of
cancer treatment that involve modifying genes, such as triggering the body's
white cells to attack tumors. Conforming to the strictest definition of gene
therapy are experiments to reinsert genes into cancer cells lacking properly
functioning copies of these genes, or inserting a manmade suicide gene into the
tumor cell that will make the cell more susceptible to the toxic effects of
Modification of white blood cells to attack a tumor can occur, for example,
if a weakened virus, modified genetically to contain a piece of the tumor's
DNA, is inserted into the white blood cell. When this weakened virus is
unleashed in the body, our white blood cells recognize it as an enemy, and
destroy it. Because the virus also is expressing part of the tumor's DNA, white
blood cells become sensitized to this tumor protein as well, and attack it
wherever they find it, that is, either on the virus coat or on the tumor.
Currently, these gene therapy trials are underway:
- Inserting a working copy of the p53 tumor suppressor and apoptosis (cell
death) gene into liver tumors, using one of the common cold viruses as a
carrier. This therapy is infused directly into the liver by way of the hepatic
- Inserting a copy of the cytosine deaminase gene into colon cancer tumors
using one of the common cold viruses. The cytosine deaminase gene will cause
the otherwise impervious cell to react to the harmless prodrug Flucytosine
(5-fluorocytosine) and convert it to 5-fluorouracil, a drug that can kill
colorectal cancer cells. Cytosine deanimase in cells makes nearby cells more
likely to be killed by 5-FU.
- Transfer of a mutant copy of the alkyltransferase gene, MGMT, into young
blood cells to protect them from chemotherapies such as O6-benzylguanine and
carmustine (BCNU). These chemotherapies target the enzyme alkyltransferase,
which results in cell death, a desirable outcome for colon cancer cells but not
- Gene therapy using SCH-58500, a recombinant adenovirus with a modified p53
cell death gene, via hepatic artery infusion in those with liver tumors.
Growth factor antagonist therapy
This approach is similar to antiangiogenesis therapy, which aims to stop
growth of blood vessels supplying tumors with nutrients. Growth factor
inhibition aims at depriving the tumor of other substances and structures
needed for growth.
A substance being tested for this purpose is suramin.
See Tumor-cell derivative vaccines.
This approach uses white blood cells to challenge a tumor. The patient's
blood cells are extracted from a vein, resensitized to the tumor, and
The following trials using leukocyte therapy are underway:
- Dendritic cells, which are accessory immune system cells that can be
pretreated to recognize carcinoembryonic antigen (CEA). They are reinserted
into the body to attack tumor cells that express CEA.
- Injection of a tumor-specific vaccine containing either the cell-death p53
gene, or ras, a growth signaling gene, with or without cellular immunotherapy
with peptide-activated lymphocytes plus interleukin-2.
Some drugs appear to work better, to be less toxic to liver or kidney, and
to be effective when taken orally if they are first encased in a layer of
A drug being used in this way is doxorubicin.
See also Colloidal drug delivery.
See Antibody therapy.
Non-specific immune-modulator therapy
Nonspecific immune modulators are substances that aid in redirecting,
suppressing, or boosting the immune system in ways that are either somewhat
general or perhaps poorly understood.
Vaccine adjuvants may contain aluminum or small pieces of protein, for
instance, that are not related to the vaccine material, but are known to elicit
a stronger immune response.
The vaccine adjuvant QS-21, like vaccine adjuvants in general, has been
shown to heighten the immune response, and thus the effectiveness of a vaccine
created from tumor cells. (See Tumor-cell derivative vaccines.)
The following substances are being tested as nonspecific immune stimulants
against colorectal cancer, in combination with vaccines or traditional
- Corynebacterium granulosum P40
- Alum precipitate
- QS-21 adjuvant
- Flt3 ligand, which appears to boost the antitumor activity of NK (natural
killer) white blood cells
Prodrugs are substances that have no activity against cancer until some
biological event converts them to another drug that is tumoricidal.
Uracil-tegafur (UFT, Orzel), currently being tested against colorectal
cancer, is a prodrug of 5-fluorouracil (5-FU), and is slowly metabolized to
5-FU in the cancer cell and by the liver.
Peripheral blood lymphocyte therapy
See Leukocyte therapy.
These substances are compounds usually consisting of manmade monoclonal
antibodies (see Antibody therapy) and a radioactive isotope. The antibody
attaches preferentially to tumor cells; the isotope decays within, upon, or
very near the tumor, damaging or killing the cell, and in some cases, other
nearby tumor cells, with radiation.
Monoclonal antibodies conjugated to radioisotopes for colorectal cancer
include yttrium-90 joined to Biotin.
Certain drugs can make tumors more sensitive to damage by radiotherapy.
5-FU prior to or during radiotherapy appears to make colorectal cancer cells
more sensitive to radiotherapy.
Recombinant viral vaccines
Viruses engineered to target only cancer cells are being considered as one
way to damage tumors and spare healthy tissue. The virus itself could attack
and kill the tumor, or it could insert its DNA or RNA into the tumor--DNA that
has been modified in the lab to contain a killer sequence or to weaken the
tumor's defenses or ability to replicate.
A vaccine made of combined carcinoembryonic antigen (CEA) and Vaccinia
virus, with postvaccination CEA protein injections as a booster, is currently
being tested against colorectal cancer.
Stereotactic surgery is surgery guided by a three-dimensional image of the
tumor and by multiple targeting criteria that allow precisely aimed
microsurgeries. Stereotactic radiosurgery is the aiming of one or more small,
precise beams of radiation at cancerous tissue using these stereotactic guiding
A clinical trial of fractionated stereotactic radiotherapy following
surgical removal of brain metastases is being conducted to determine the
efficacy of this method as follow-up treatment for brain metastases.
Thymidylate synthase inhibitors
Certain anticancer drugs such as 5-FU inhibit the enzyme thymidylate
synthase, which in turn affects DNA synthesis. Certain newer drugs in this
class are capable of avoiding degradation inside the tumor cell, thus
increasing its presence in the cell.
Two drugs that behave as thymidylate synthase inhibitors and are being
tested for colorectal cancer are:
- Tomudex (also called raltitrexed, ICI D1694, or ZD 1694)
- Uracil-tegafur (UFT, Orzel)
Topoisomerase inhibitor therapy
Topoisomerases are enzymes that our cells use to untwist DNA before copying,
and to repair breaks in DNA after copying. Topoisomerase inhibitors interfere
with DNA repair, causing the cancer cell to die because damaged DNA cannot be
translated into proteins, such as transport and digestive proteins, that each
cell needs to breathe or eat.
Topoisomerase inhibitors being tested against colorectal cancer include
aminocamptothecin, doxorubicin, and oxaliplatin. Oxaliplatin appears to be the
most promising of the three at this time and might be approved by the FDA
Tubulin inhibitor therapy
When a cell has made a copy of all of its chromosomes and is ready to
divide, spindles made of tubulin form to pull the two copies of each chromosome
apart into two identical clusters of 46 chromosomes apiece. Tubulin inhibitors
stop spindles from forming, thus stopping the tumor cell from dividing.
A novel tubulin inhibitor being tested is dolastatin 10, a substance found
in a marine animal.
Tumor-cell derivative vaccines
Vaccines made from tumor cells that have been removed from the body and
cultured in the lab can cause our bodies to become resensitized to tumors,
resulting in renewed attacks against the tumor by our immune systems.
The trials currently underway that exploit this technique are:
- Vaccine therapy with tumor-specific mutated ras peptides, aimed at causing
an attack against tumor cells expressing this mutated protein (peptide) in the
cell's membrane. Ras proteins, a product of the ras gene, frequently are
mutated in human cancers, where they are known to be involved in the
development of tumors by incorrectly signaling for ongoing growth and cell
- Intralymphatic immunotherapy with interferon-alfa-treated tumor cells.
Tumor cells are incubated with interferon-alfa, then the tumor cells are
reinjected directly into lymphatic ducts. Some patients show an antibody
response to tumor cells after this treatment.
- Tumor-specific vaccines made with either the cell-death gene p53, or the
ras oncogene; with or without cellular immunotherapy consisting of
peptide-activated white blood cells and the cytokine interleukin-2.
Vaccines against cancer also can be made without using tumor cells as a
basis, using instead synthetically engineered molecules thought to stimulate an
immune response in any one of a variety of ways.
The following vaccines are being tested against colorectal cancer:
- ALVAC-CEA-B7.1 vaccine, which targets two cell surface antigens, CEA and
- A vaccine made of Carcinoembryonic Antigen Peptide-1 (CAP), a protein
expressed by colorectal cancer cells.
Novel techniques and devices
Not only new substances are tested for efficacy against colorectal cancer,
but new techniques and devices as well. Listed below are novel methods and
devices currently being funded by NCI.
Bone marrow ablation with stem cell support
See High-dose therapy with stem cell support.
Several clinical trials have shown that some drugs are more effective
against cancer if administered at certain times of the day, week, or month. One
trial for colorectal cancer, using fluorouracil, leucovorin calcium, and
oxaliplatin, attempts to exploit this theory.
Continuous infusion therapy
Several trials are underway to exploit the observation that fluorouracil may
be more effective against colorectal tumors and appears to operate
biochemically in different ways if it is administered slowly over long periods,
instead of injected all at once during a brief office visit. As with other
cell-cycle-specific anticancer drugs, 5-FU will kill cancer cells only if it is
present as they divide. Continuous infusion allows 5-FU to be present
continuously as cancer cells enter the process of cell division across several
days or weeks.
Freezing of colorectal cancer cells that have lodged in the liver is being
examined as a possible alternative for those whose tumors are not removable
using standard surgeries:
- Phase II Study of Cryoablation for Treatment of Unresectable Colorectal
- Phase II Study of Multiple Metastasectomy Combined with Systemic 5-FU/CF
and Hepatic Artery Infusion of FUDR in Patients with Colorectal Carcinoma
Metastatic to the Liver
Some trials are designed to eliminate the blood supply to the tumor or to
halt the flow of chemotherapy out of an organ (during isolated perfusion) by
causing a blood clot in the tumor or in one or more blood vessels exiting an
organ. This technique is known as tumor embolization or simply
Hepatic arterial infusion (HAI)
Also see Isolated perfusion. Isolated perfusion in the purest sense targets
a single organ with chemotherapy. Hepatic arterial infusion targets the liver,
but some of the drug administered also travels to other organs. Nonetheless,
the National Cancer Institute currently classifies HAI as isolated perfusion,
for which see their web site at
High-dose therapy with stem cell support
Very high doses of chemotherapy and radiation therapy may kill all tumor
cells, but they also quickly kill bone marrow, which causes death when new
blood cells cannot be created. Marrow can be harvested and frozen, however, and
reinserted after chemotherapy has ended. This technique has been used with
success against the lymphomas and leukemias.
Trials using doses of drugs that do not kill all marrow, but are followed by
infusions of one's marrow, stem cells, or white blood cells also are
Two trials are underway to gauge the success of this approach for colorectal
- Phase II Study of Nonmyeloblative Allogeneic Peripheral Blood Stem Cell and
Donor Lymphocyte Infusions in Patients with Refractory Metastatic Solid
- Phase I Pilot Study of Sequential High-Dose Cisplatin, Cyclophosphamide,
Etoposide and Ifosfamide, Carboplatin, Paclitaxel with Autologous Stem Cell
Support for Advanced Carcinomas
Interstitial laser photocoagulation
This technique, typically used for liver metastases, causes tumor cells to
die by generating heat within the tumor, coagulating its blood supply. Optic
fibers that conduct laser light are inserted through the skin and into the
tumor while the tumor is being visualized with ultrasonography.
Irradiating the tumor bed during surgery after tumor removal is considered
by some researchers to be a good means of destroying any remaining cancerous
tissue, while sparing a large amount of nearby healthy tissue from unnecessary
radiation exposure. Moreover, the single large dose delivered in this setting
is thought to be more effective than the fractionated doses usually
administered over many days or weeks.
Chemotherapy administered directly to the abdominal cavity may be more
effective against tumors than is intravenous chemotherapy. Several trials are
testing this theory:
- Phase I Study of Intraperitoneal Interleukin-12 for Mullerian and
Gastrointestinal Carcinomas with Abdominal Carcinomatosis
- Phase I Study of Recombinant Human Interleukin-12 in Refractory Advanced
Stage Ovarian Cancer and Other Abdominal Carcinomatosis
- Phase I Study of Intraperitoneal Aminocamptothecin Colloidal Dispersion in
Patients with Cancer Predominantly Confined to the Peritoneal Cavity
- Phase III Adjuvant Study of Levamisole versus Alfa Interferon 2a Plus
Fluorouracil and Leucovorin Calcium for Intraperitoneal Colorectal Cancer
Targeting only a specific organ with chemotherapy is an attractive goal, as
it may allow much higher doses of cancer-killing drugs to be delivered to the
tumor while sparing healthy tissue. Isolated perfusion in the purest sense
targets a single organ with chemotherapy. The National Cancer Institute
currently classifies these trials as isolated perfusion therapy, however,
although some of the drug administered during
hepatic arterial infusion also travels to other organs. Trials include:
- Gene therapy with SCH-58500 (rAd/p53) via hepatic artery infusion
- Intravenous versus intrahepatic arterial infusion of 5-fluorouracil and
- Hepatic perfusion with escalating dose Melphalan followed by postoperative
hepatic arterial floxuridine (FUDR) and leucovorin calcium
- Hepatic artery floxuridine, leucovorin calcium, and dexamethasone versus
systemic 5-fluorouracil and leucovorin
Portal vein infusion
This technique is similar to hepatic arterial perfusion, but uses the portal
- Phase II Study of Hepatic Resection Followed by Adjuvant Portal Vein
Infusion of Floxuridine plus Systemic Fluorouracil/Leucovorin Calcium in
Metastatic Colorectal Carcinoma
See Isolated perfusion.
This technique, like interstitial laser coagulation, is typically used for
liver metastases, and causes tumor cells to die by generating heat within the
tumor, coagulating its blood supply. Insulated electrode needles are inserted
through the skin and into the tumor while the tumor is being visualized with