Cancer treatment

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Cancer Treatment

Chemotherapy

Cancer Drug Development: New Targets for Cancer Treatment - 1996

Cancer Drug Development: New Targets for Cancer Treatment.

Curt GA

There is often a considerable lapse of time between the definition of what causes a disease in the laboratory and the development of successful therapy. However, the history of medicine teaches us that the need to understand the scientific basis of disease before the discovery of new treatments is both essential and inevitable. During the middle of the 19th century, the work of the great German pathologist, Rudolf Virchow, defined disease as having an anatomic or histologic basis. In the clinic, this scientific perspective would lead to increasingly effective and, often, increasingly aggressive surgical approaches to disease. Later in the 19th century, Koch's discovery of the tubercle bacillus (a discovery Virchow disbelieved and publication of which he thwarted, since he hypothesized that cancer, not microbes, caused consumption!), would define a microbiological basis for disease. With bacteria defined as a major cause of human suffering, the stage was set for the development of the discovery of effective antibiotics. In the early 20th century, the pioneering work of Banting, Best and others would show that disease can also have an endocrine or metabolic basis. This new body of scientific knowledge would lead not only to the specific discovery of insulin as an effective treatment for diabetes but also to a more general understanding of the role of hormones, vitamins and co-factors in human health and disease. Basic medical research and its successful translation into effective treatments has fundamentally altered the cause of human death. In the developed world, where access to the benefit of this work is available, infectious disease is not the problem it was in the days of Pasteur, Metchnikoff and Ehrlich. As we approach the millennium, science is now teaching us that diseases, particularly cancer, can have a molecular or genetic basis. Can successful application of this new knowledge be far behind? We are already seeing the application of this new knowledge in cancer drug screening and cancer drug development.

Anticancer Drug Development: The Way Forward - 1996

Anticancer Drug Development: The Way Forward

[2]

Connors T.

Cancer chemotherapy celebrated its fiftieth anniversary last year. It was in 1945 that wartime research on the nitrogen mustards, which uncovered their potential use in the treatment of leukaemias and other cancers, was first made public. Fifty years later, more than sixty drugs have been registered in the USA for the treatment of cancer, but there are still lessons to be learnt. One problem, paradoxically, is that many anticancer agents produce a response in several different classes of the disease. This means that once a new agent has been shown to be effective in one cancer, much effort is devoted to further investigations of the same drug in various combinations for different disorders. While this approach has led to advances in the treatment of many childhood cancers and some rare diseases, a plethora of studies on metastatic colon cancer, for example, has yielded little benefit. 5-fluorouracil continues to be used in trials, yet there is no evidence for an increase in survival. The lesson to be learnt is that many common cancers are not adequately treated by present-day chemotherapy, and most trials of this sort are a waste of time. Significant increases in survival will only occur if the selectivity of present-day anticancer agents can be increased or new classes of more selective agents can be discovered.

Colorectal Cancer

FDA approved drugs

Fluorouracil

Fluorouracil (5-FU) is a drug that is used in the treatment of cancer. It belongs to the family of drugs called antimetabolites. It is a pyrimidine analog.

The chemotherapy agent 5-FU (fluorouracil), which has been in use against cancer for about 40 years, acts in several ways, but principally as a thymidylate synthase inhibitor, interrupting the action of an enzyme which is a critical factor in the synthesis of pyrimidine-which is important in DNA replication.

Some of its principal use is in colorectal cancer and pancreatic cancer, in which it has been the established form of chemotherapy for decades (platinum-containing drugs are a recent addition).

As a pyrimidine analogue, it is transformed inside the cell into different cytotoxic metabolites which are then incorporated into DNA and RNA, finally inducing cell cycle arrest and apoptosis by inhibiting the cell's ability to synthesize DNA. It is an S-phase specific drug and only active during certain cell cycles.

Capecitabine is a prodrug that is converted into 5-FU in the tissues. It can be administered orally.

From: Fluorouracil

Uracil can be used for drug delivery and as a pharmaceutical. When elemental fluorine is reacted with uracil, 5-fluorouracil is produced. 5-Fluorouracil is an anticancer drug (antimetabolite) used to masquerade as uracil during the nucleic acid replication process. The drug molecule also fools the enzymes that help in this process to incorporate this compound in the replication and not uracil, this causes the biological polymer (cancer) not to continue synthesizing.

From: Uracil

The backbone of treatment for colorectal cancer is fluorouracil, a fluorinated pyrimidine, which is thought to act primarily by inhibiting thymidylate synthase, the rate-limiting enzyme in pyrimidine nucleotide synthesis. Fluorouracil is usually administered with leucovorin, a reduced folate, which stabilizes the binding of fluorouracil to thymidylate synthase, thereby enhancing the inhibition of DNA synthesis. In patients with advanced colorectal cancer, treatment with fluorouracil and leucovorin reduces tumor size by 50 percent or more in approximately 20 percent of patients (the "objective-response rate") and prolongs median survival from approximately 6 months (without treatment) to about 11 months.

From: Systemic Therapy for Colorectal Cancer

Thymidylate synthase (TS) catalyzes the transfer of a methyl group from methylenetetrahydrofolate (CH2H4PteGlu) to dUMP forming TMP. Inhibition of TS results in apoptotic cell death due to intracellular thymidine depletion. Since cancer cells undergo rapid multiplication, they are much more sensitive to thymidine depletion and TS is the target of several anticancer agents used in colon, neck, and breast chemotherapy.

From: Thymidylate synthase

Antimetabolite drugs work by inhibiting essential biosynthetic processes, or by being incorporated into macromolecules, such as DNA and RNA, and inhibiting their normal function. The fluoropyrimidine 5-fluorouracil (5-FU) does both. Fluoropyrimidines were developed in the 1950s following the observation that rat hepatomas used the pyrimidine uracil — one of the four bases found in RNA — more rapidly than normal tissues, indicating that uracil metabolism was a potential target for antimetabolite chemotherapy1. The mechanism of cytotoxicity of 5-FU has been ascribed to the misincorporation of fluoronucleotides into RNA and DNA and to the inhibition of the nucleotide synthetic enzyme thymidylate synthase (TS).

5-FU is widely used in the treatment of a range of cancers, including colorectal and breast cancers, and cancers of the aerodigestive tract. Although 5-FU in combination with other chemotherapeutic agents improves response rates and survival in breast and head and neck cancers, it is in colorectal cancer that 5-FU has had the greatest impact. 5-FU-based chemotherapy improves overall and disease-free survival of patients with resected stage III colorectal cancer. Nonetheless, response rates for 5-FU-based chemotherapy as a first-line treatment for advanced colorectal cancer are only 10–15% (REF. 3). The combination of 5-FU with newer chemotherapies such as Irinotecan and Oxaliplatin has improved the response rates for advanced colorectal cancer to 40–50%. However, despite these improvements, new therapeutic strategies are urgently needed.

Understanding the mechanisms by which 5-FU causes cell death and by which tumours become resistant to 5-FU is an essential step towards predicting or overcoming that resistance. So, what do we know about the mechanism of action of 5-FU and what strategies have been used to enhance its activity?

...5-FU is an analogue of uracil with a fluorine atom at the C-5 position in place of hydrogen. It rapidly enters the cell using the same facilitated transport mechanism as uracil6. 5-FU is converted intracellularly to several active metabolites: fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP) (FIG. 1) — these active metabolites disrupt RNA synthesis and the action of TS. The rate-limiting enzyme in 5-FU catabolism is dihydropyrimidine dehydrogenase (DPD), which converts 5-FU to dihydrofluorouracil (DHFU).More than 80% of administered 5-FU is normally catabolized primarily in the liver, where DPD is abundantly expressed.

From: 5-Fluorouracil: Mechanisms of Action and Clinical Strategies

Clinical pharmacology of 5-fluorouracil - April 1989

Clinical pharmacology of 5-fluorouracil

[3]

Diasio RB, Harris BE.

5-Fluorouracil, first introduced as a rationally synthesized anticancer agent 30 years ago, continues to be widely used in the management of several common malignancies including cancer of the colon, breast and skin. This drug, an analogue of the naturally occurring pyrimidine uracil, is metabolised via the same metabolic pathways as uracil. Although several potential sites of antitumour activity have been identified, the precise mechanism of action and the extent to which each of these sites contributes to tumour or host cell toxicity remains unclear. Several assay methods are available to quantify 5-fluorouracil in serum, plasma and other biological fluids. Unfortunately, there is no evidence that plasma drug concentrations can predict antitumour effect or host cell toxicity. The recent development of clinically useful pharmacodynamic assays provides an attractive alternative to plasma drug concentrations, since these assays allow the detection of active metabolites of 5-fluorouracil in biopsied tumour or normal tissue. 5-Fluorouracil is poorly absorbed after oral administration, with erratic bioavailability. The parenteral preparation is the major dosage form, used intravenously (bolus or continuous infusion). Recently, studies have demonstrated the pharmacokinetic rationale and clinical feasibility of hepatic arterial infusion and intraperitoneal administration of 5-fluorouracil. In addition, 5-fluorouracil continues to be used in topical preparations for the treatment of malignant skin cancers. Following parenteral administration of 5-fluorouracil, there is rapid distribution of the drug and rapid elimination with an apparent terminal half-life of approximately 8 to 20 minutes. The rapid elimination is primarily due to swift catabolism of the liver. As with all drugs, caution should be used in administering 5-fluorouracil in various pathophysiological states. In general, however, there are no set recommendations for dose adjustment in the presence of renal or hepatic dysfunction. Drug interactions continue to be described with other antineoplastic drugs, as well as with other classes of agents.

Dendrimer grafts for delivery of 5-fluorouracil - April 2002

Dendrimer grafts for delivery of 5-fluorouracil

[4]

Tripathi PK, Khopade AJ, Nagaich S, Shrivastava S, Jain S, Jain NK

Polyamidoamine (PAMAM) dendrimers were prepared by linking methyl methacrylate and ethylenediamine successively on an amine core. Surface modification of PAMAM dendrimer was done by fatty acid grafting converting them to a unimolecular micellar system (Dendrimer grafts). IR, 1H NMR, 13C NMR studies confirmed the structure. The drug 5-fluorouracil (5-FU) was entrapped in dendrimer grafts. The effects of various solvents (ethanol, dichloromethane, tetrahydrofuran), pH and ionic strength on solubilization of 5-FU were determined. Phospholipid was further coated on the dendrimer grafts. The product was lyophilized and obtained as yellowish-white powder. Average particle size was ca. 375 nm as determined by Malvern's Mastersizer 4. Drug loading was ca. 53% by weight. Stability studies were conducted for 1 month at room temperature and 40 degrees C, where the systems were relatively stable. Release rate was sustained across cellulose tubing in PBS. In vivo studies were performed in albino rats and pharmacokinetic parameters and bioavailability were determined from the plasma profile of 5-FU. The phospholipid coated dendrimer graft formulation was found to be more effective orally than free drug. The lymphatic uptake was also increased indicating absorption of the developed formulation through the lymphatic route.

A New Class of Nanoscopic Containers and Delivery Devices - April 2003

Dendrimers: a new class of nanoscopic containers and delivery devices

[5]

F. Aulenta, W. Hayes, S. Rannard

Zhuo et al. synthesised 5-fluorouracil (5FU)–PAMAM conjugates with cyclic cores, and investigated the drug release in vitro. 5FU has potent anti-tumour activity although the high cytotoxicity prevents possible application in cancer treatments. The dendritic system thus developed was synthesised using the time-sequenced propagation technique and conjugation of the drug was performed on the fourth and fifth generation dendrimers. Although slow release of the drug was observed, the toxicity and the properties of the dendritic systems have not yet been evaluated.

5-Fluorouracil: Mechanisms of Action and Clinical Strategies - May 2003

5-Fluorouracil: Mechanisms of Action and Clinical Strategies

[6]

Daniel B. Longley, D. Paul Harkin, Patrick G. Johnston

5-Fluorouracil (5-FU) is widely used in the treatment of cancer. Over the past 20 years, increased understanding of the mechanism of action of 5-FU has led to the development of strategies that increase its anticancer activity. Despite these advances, drug resistance remains a significant limitation to the clinical use of 5-FU. Emerging technologies, such as DNA microarray profiling, have the potential to identify novel genes that are involved in mediating resistance to 5-FU. Such target genes might prove to be therapeutically valuable as new targets for chemotherapy, or as predictive biomarkers of response to 5-FU-based chemotherapy.

Capecitabine (Xeloda)

Capecitabine (INN) (IPA: [keɪpˈsaɪtəbin]) is an orally-administered chemotherapeutic agent used in the treatment of metastatic breast and colorectal cancers. Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil in the tumor by the tumor-specific enzyme PynPase, where it inhibits DNA synthesis and slows growth of tumor tissue. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), to form 5-fluorouracil. Capecitabine is marketed under the trade name Xeloda (Roche).

Capecitabine is FDA-approved for:

Adjuvant Stage III Dukes'C Colon Cancer - used as first-line monotherapy.
Metastatic Colorectal Cancer - used as first-line monotherapy, if appropriate.
Metastatic Breast Cancer - used in combination with docetaxel, after failure of anthracycline-based treatment. Also as monotherapy, if the patient has failed paclitaxel-based treatment, and if anthracycline-based treatment has either failed or cannot be continued for other reasons (i.e., the patient has already received the maximum lifetime dose of an anthracycline).

From: Capecitabine

Irinotecan (Camptosar)

Irinotecan is a chemotherapy agent that is a topoisomerase 1 inhibitor.

Its main use is in colon cancer, particularly in combination with other chemotherapy agents. This includes the regimen FOLFIRI which consists of infusional 5-fluorouracil, leucovorin, and irinotecan.

Irinotecan is marketed by Pfizer as Camptosar®. It is also known as CPT-11.

Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1). Eventually, this process inhibits DNA replication and transcription.

From: Irinotecan

Oxaliplatin (Eloxatin)

Oxaliplatin is a platinum-based chemotherapy drug in the same family as cisplatin and carboplatin. It is typically administered in combination with fluorouracil and leucovorin in a combination known as FOLFOX for the treatment of colorectal cancer. Compared to cisplatin the two amine groups are replaced by cyclohexyldiamine for improved antitumour activity. The chlorine ligands are replaced by the oxalato bidentate derived from oxalic acid in order to improve water solubility.

Oxaliplatin is marketed by Sanofi-Aventis under the trademark Eloxatin®.

In vivo studies showed oxaliplatin has anti-tumor activity against colon carcinoma through its (non-targeted) cytotoxic effects. Median patient survival is approximately 5 months greater compared to the previous standard treatment.

From: Oxaliplatin

Cetuximab (Erbitux)

Cetuximab (Erbitux®) is a chimeric monoclonal antibody given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer.

Cetuximab is distributed inside the United States by ImClone Systems and Bristol-Myers Squibb, while it is distributed outside North America by Merck KGaA. It faces stiff competition from bevacizumab (Avastin), made by Genentech, and potential competition from panitumumab, currently under development by Amgen and Abgenix.

Cetuximab is believed to operate by binding to the extracellular domain of the epidermal growth factor receptor (EGFR) of cancer cells, preventing ligand binding and activation of the receptor. This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation.

Cetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar®), a form of chemotherapy that blocks the effect of DNA topoisomerase I, resulting in fatal damage to the DNA of affected cells. While there is a medical laboratory test to detect if a cancer tumor overexpresses epidermal growth factor receptor(EGFR) on its cells surface, this overexpression has recently been shown to not have any bearing on whether a patient will respond to Cetuximab or not. Whether this is because the current tests are just not sensitive enough to detect EGFR overexpression or because EGFR overexpression is not linked to the drugs effectiveness has not been established. Cetuximab was approved by the FDA in March 2006 after the publication of research performed by Dr J. Bonner [1] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapy.

The probability of successfully responding to Cetuximab therapy is linked to the incidence of acne like rash, one of the drugs side effects. The worse the rash that develops for the patient the higher the response rate.

From: Cetuximab

Bevacizumab (Avastin)

Bevacizumab (trade name Avastin®) drug used in treatment of cancer that targets the angiogenesis pathway.

It is used in combination with standard chemotherapy drugs in patients with metastatic colorectal cancer. The U.S. Food and Drug Administration approved bevacizumab for use in colon cancer 2004. The medicine was developed by Genentech and is marketed, in the United States by Genentech and elsewhere by Roche (Genentech's parent company), under the brand name Avastin.

Bevacizumab is a humanized monoclonal antibody, and was the first commercially available angiogenesis inhibitor. It stops tumor growth by preventing the formation of new blood vessels by targeting and inhibiting the function of a natural protein called vascular endothelial growth factor (VEGF) that stimulates new blood vessel formation.

The drug was first developed as a genetically engineered version of a mouse antibody that contains both human and mouse components. Genentech is able to produce the antibody in production-scale quantities.

Bevacizumab was approved by the Food and Drug Administration (FDA) in February 2004 for use in colorectal cancer when used with standard chemotherapy treatment. It was approved by the EMEA in January 2005 for use in colorectal cancer. Israel has also approved the use of bevacizumab.

Bevacizumab is usually given intravenously through the arm every 14 days. In colon cancer, it is given in combination with the chemotherapy drug 5-FU (5-fluorouracil), leucovorin, and oxaliplatin or irinotecan.

Bevacizumab has also demonstrated activity in renal cell cancer and ovarian cancer when used as a single agent, and in lung cancer and breast cancer when combined with chemotherapy.

From: Bevacizumab

Systemic Therapy for Colorectal Cancer - February 2005

Systemic Therapy for Colorectal Cancer

[7]

Jeffrey A. Meyerhardt, M.D., M.P.H., and Robert J. Mayer, M.D.

"...we will consider newer cytotoxic chemotherapies and biologic agents effective against colorectal cancer and will assess their uses for the treatment of metastatic disease and as components of adjuvant therapy."

Protease

High levels of proteolytic enzymes are associated with many tumors. This may be a result of adaptation to rapid cell cycling; removal of unnecessary regulatory proteins; and for secretion to sustain invasion, metastasis formation, and angiogenesis. Proteolytic enzymes represent an attractive target of antitumor imaging strategies and potentially antitumor prodrug activation therapy.

Protease activated Near-Infrared Fluorescent Probes- February 1999

In vivo imaging of tumors with protease activated near-infrared fluorescent probes

[8]

Ralph Weissleder, Ching-Hsuan Tung, Umar Mahmood, and Alexei Bogdanov Jr.

Intratumoral NIRF signal was generated by lysosomal proteases in tumor cells that cleave the macromolecule, thereby releasing previously quenched fluorochrome. In vivo imaging showed a 12-fold increase in NIRF signal, allowing the detection of tumors with submillimeter-sized diameters. This strategy can be used to detect such early stage tumors in vivo and to probe for specific enzyme activity.