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.

Alkylating agents

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 cancers.

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.

Antiangiogenesis therapy

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 cells.

Antiangiogenesis drugs now in clinical trials for colorectal cancer are thalidomide, heparin, and BAY 12-9566.

Antibody therapy

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 include:

• A33, attached either to iodine I-131 or to cisplatin-epinephrine (intradose MPI-5010)
• 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

Anti-cytokine therapy

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).

Antimetabolite therapy

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 to fail.
• 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 impaired.

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.

Chemoprotectants

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.

Chemosensitization/potentiation

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, and O6-benzylguanine.

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 environments.

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 is administered.

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 Advanced Cancer
• 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 Adenocarcinoma
• Phase II Study of MOAB 17-1A/GM-CSF for 5-FU-Resistant Metastatic Colorectal Cancer

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 growth.

Flavopiridol is being tested for this purpose.

Cytokine therapy

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 include:

• Interferon-alfa
• Interleukin-2
• 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

Differentiation therapy

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 cells.

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.

Drug modulation

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 cancer are:

• 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.

Gene therapy

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 certain drugs.

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 artery.
• 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 blood cells.
• 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.

Idiotype vaccines

See Tumor-cell derivative vaccines.

Leukocyte therapy

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 reinserted.

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.

Liposomal encapsulation

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 lipids.

A drug being used in this way is doxorubicin.

See also Colloidal drug delivery.

Monoclonal antibodies

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 chemotherapy:

• 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

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.

Radioimmunotherapy

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.

Radiosensitization

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 radiotherapy

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 systems.

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 soon.

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 division.
• 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

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 B7-1.
• 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.

Chronomodulated therapy

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.

Cryosurgery

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 Hepatic Metastases
• 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

Embolization

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 embolization.

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 http://cnetdb.nci.nih.gov/trialsrch.shtml.

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 underway.

Two trials are underway to gauge the success of this approach for colorectal cancer:

• Phase II Study of Nonmyeloblative Allogeneic Peripheral Blood Stem Cell and Donor Lymphocyte Infusions in Patients with Refractory Metastatic Solid Tumors
• 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.

Intraoperative radiotherapy

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.

Intraperitoneal chemotherapy

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

Isolated perfusion

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 leucovorin
• 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 vein:

• 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.

Radiofrequency ablation

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 ultrasonography.