THE FUTURE NOW
Pioneering cancer therapies promise treatments for multiple defects
By Dr. Roger Badillo
Forty percent of those alive today will be diagnosed with some form of cancer at some point in their lives."
This was the projection made by the United States Centers for Disease Control and Prevention in 2001, and some of it is now coming true. In 2000, the World Health Organization reported that 10 million people worldwide were diagnosed with some form of cancer. More than 60 percent of them have died. In the US alone, cancer is the second most common cause of death, accounting for almost a quarter of all deaths in the 1990s. There are over 1.2 million new cancer cases each year and half a million deaths.
The numbers keep growing. Aging populations, newer infections, lifestyle practices leading to obesity and inactivity, and increasing tobacco and alcohol consumption all essentially contribute to rising cancer cases.
This is in stark contrast to mortality rates for heart disease and stroke, traditional lifestyle-related diseases, which among recent studies have shown decreasing mortality rates in developed countries (Centers for Disease Control, 2001).
But while statistics tell a dark tale, there is hope for cancer therapy. An array of new ideas brings promising treatments to address cancer's multifactorial nature, not so much as lay claim to curing it, but with efforts aimed at controlling the disease and improving the quality of life of affected individuals.
DNA mutations
The cause of most cancers is historically unknown, but recent studies have led to significant advances towards a greater understanding of the molecular basis for the malignant proliferation of cells. Healthy cells regulate their division into daughter cells rather carefully to allow the development of multicellular organs that favor the survival of the body they inhabit. But as Darwinian evolution progresses, some degree of "genetic glitch" is bound to occur among the trillions of cells in the body, which serves to disable even its most careful regulatory processes. The resulting uncontrolled cell growth then gives rise to cancer.
Mutations in DNA sequences can lead to amplification and increased expression of "oncogenes" (responsible for cellular-growth factors), even deletion of tumor "suppressor genes" (responsible for suppressing growth), or both, which are heavily linked to the abnormal proliferation and malignancy of growth.
Such events may be due to environmental exposure, inherent genetic susceptibility, infectious agents, and other unknown causes. Cancers may also exhibit chromosomal abnormalities like deletions, inversions, translocations, or duplications. Determination of the specific anomaly may therefore aid in diagnosis and provide greater leverage in employing possible treatment options.
Target-specific "designer drugs"
For many decades, traditional cancer treatment was hinged primarily on surgery, chemotherapy, and radiation. The drugs that were developed during the 1970s were designed to attack and kill dividing cells, regardless of origin or function. Although they effectively contained and neutralized tumors, such were their action that they also preyed on normally dividing tissues, giving rise to a multitude of unwanted side effects--nausea and vomiting, fatigue, and weakened immune systems.
A new and definitely improved generation of anticancer drugs is now designed to address these problems by affecting only the deranged cells. By acting on specific molecular abnormalities, these drugs can zero in on some tumors via certain genes and proteins.
Imatinib (Gleevec) is one such development. Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the overproduction of white, myeloid blood cells. It is associated with a characteristic chromosomal abnormality, the Philadelphia chromosome, which is a reciprocal translocation between the long arms of chromosomes 9 and 22. When they break and join to form the hybrid 9-22 chromosome, two genes called BCR and ABL are brought together. The union of these genes results in the production of a specific enzyme called BCR-ABL, a tyrosine kinase that signals the myeloid cells to proliferate continuously. Imatinib blocks the activity of BCR-ABL by occupying the enzyme's active site, effectively switching off the signal to grow and further proliferate.
Gefitinib (Iressa) is another targeted molecule for lung cancers, designed to block the activity of a similar tyrosine kinase called EGFR (epidermal-growth-factor receptor), which signals growth pathways within the cell. Found in excessive amounts in over 80 percent of lung malignancies, investigators have theorized that blocking EGFR activity would logically arrest lung-cancer growth.
Results of trials, however, have not been impressive among Caucasians. For reasons yet to be explained, Asians--especially women and those who never smoked--suffering ffrom nonsmall lung cancer appeared to get mor ebenefits from Iressa treatment. The Iressa Survival Evaluation in Lung cancer study showed that Asian patients have a 97.7-percent chance of deriving benefit Iressa.
Combinations for multiple mutations
The Imatinib targeted treatment for CML may have been effective because of the proper identification of its lone chromosomal mutation. But while having a single molecular target could be an ideal situation in developing the appropriate therapies, the case for one mutation is unusual for most cancers. What is common is identifying multiple gene mutations that are responsible for a specific disease by the time a diagnosis is made. The logistical immensity of the problem means that no single magical drug would be effective for such. The need to combine several drugs to act on several loci becomes imperative.
Trastuzumab (Herceptin) is a lone-target drug designed for breast-cancer therapy in combination with one or more of the traditional nonspecific agents. As an antibody-based preparation, it blocks the activation of a cell-surface receptor protein called HER-2 (human-epidermal-growth-factor receptor), in the process making the tumor vulnerable by the time the traditional drugs are employed. Prognosis is significantly improved, although the associated toxicity of the nonspecific chemotherapeutic agents still need to be managed.
The combination of two newer agents, bevacizumab (Avastin) and erlotinib (Tarceva), presents a new trend toward future combinations by using both targeted agents for treatment without resulting in debilitating effects of the traditional nonspecific drugs. Tested against renal cancer, the former effectively blocks angiogenesis while the latter inhibits EGFR.
Other versatile chemotherapeutic systemic agents used either alone or in combination are:
-
Oxaliplatin (Eloxatin injection) is an antineoplastic agent with an organoplatinum complex in which the platinum atom is complexed with 1,2-diaminocyclohexane (DACH) and with an oxalate ligand as a leaving group. It undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, which covalently bind with macromolecules and where DNA crosslinks are formed. These crosslinks inhibit DNA replication and transcription. The cytotoxicity is cell-cycle nonspecific. In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with 5-fluorouracil (5-FU), oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models.
-
Letrozole (Femara) is hormonal therapy used in the treatment of breast cancer in postmenopausal women. As most breast cancers rely on supplies of the hormone estrogen to grow, the main source of estrogen among postmenopausal women is by changing androgens (sex hormones produced by the adrenal glands) into estrogen. This is carried out by an enzyme called aromatase. The conversion process is known as aromatisation, and occurs mainly in the fatty tissues. Letrozole is an aromatase inhibitor, blocking this process and reducing the amount of estrogen in the body.
In the United Kingdom, the standard hormonal therapy after surgical treatment for early breast cancer (without metastasis) is five years of tamoxifen, followed by adjuvant therapy letrozole.
-
Anastrozole (Arimidex) is first-line treatment for breast cancer in postmenopausal women. It slows the growth of advanced cancer within the breast and cancer that has spread to other parts of the body. It is also used to treat advanced breast cancer following treatment with tamoxifen. Arimidex combats the type of breast cancer that thrives on estrogen. It also suppresses aromatase, thereby reducing the level of estrogen circulating in the body.
-
Asparaginase (Elspar) contains the enzyme L-asparagine amidohydrolase, type EC-2, derived from Escherichia coli. In a significant number of patients with acute leukemia, particularly lymphocytic, the malignant cells are dependent on an exogenous source of asparagine for survival. Normal cells, however, are able to synthesize asparagine and thus are affected less by the rapid depletion produced by treatment with the enzyme asparaginase. This is a unique approach to therapy based on a metabolic defect in asparagine synthesis of some malignant cells.
-
Capecitabine (Xeloda) is a fluoropy-rimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR), which is converted to 5-fluorouracil. It has been approved in Europe as an innovative oral adjuvant chemotherapy for colon cancer.
-
Taxotere comes from of the taxane family, prepared by hemisynthesis from the renewable needles of yew trees of the species Taxus baccata. Taxanes, discovered at the beginning of the 1990s, exert their activity by disrupting the cell's microtubular network, which is essential for cell division.
-
Vinorelbine (Navelbine) is a vinca alkaloid that also interferes with microtubule assembly. The vinca alkaloids are structurally similar compounds comprised of two multiringed units, vindoline and catharanthine. Unlike other vinca alkaloids, the catharanthine unit is the site of structural modification for vinorelbine.
The antitumor activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, vinorelbine may also interfere with: amino acid, cyclic AP, and glutathione metabolism; calmodulin-dependent Ca++ -transport ATPase activity; cellular respiration; nucleic acid and lipid biosynthesis. Recent data suggest relative selectivity of vinorelbine for mitotic microtubules.
-
Rasburicase (Elitek) is a recombinant urate-oxidase enzyme produced by a genetically modified Saccharomyces cerevisiae strain. In humans, uric acid is the final step in the catabolic pathway of purines. Rasburicase catalyzes enzymatic oxidation of uric acid into an inactive and soluble metabolite (allantoin). Rasburicase is only active at the end of the purine catabolic pathway. Pharmacokinetics of rasburicase were evaluated studies that enrolled patients with lymphoid leukemia (B and T cell), non-Hodgkin's lymphoma (including Burkitt's lymphoma) or acute myelogenous leukemia.
-
Temozolomide (Temodar) an imidazotetrazine second-generation alkylating agent, is the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. In vitro, temozolomide has demonstrated schedule-dependent antitumor activity against highly resistant malignancies, including high-grade glioma. In clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100-percent per orem bioavailability, minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Temozo-lomide has recently been approved in the US for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy.
-
Zometa contains zoledronic acid, a bisphosphonic acid, an inhibitor of osteoclastic bone resorption. Bisphosphonates work against the abnormal cells that cause the wearing away of bone, and is used when cancer has spread (bone metastasis) by reducing or delaying the complications of metastases.
-
Tamoxifen citrate (Nolvadex) belongs to a group of medicines called antiestrogens, and is used mainly as anticancer treatment. Nolvadex is an antihormonal medicine and works primarily against the cancers that are stimulated by female sex hormones. It stops the action of estrogen, a natural chemical signal produced by the body, by preventing it from binding to receptors on cells, including cancer cells (estrogen is known to encourage the growth of many cancerous tumors of the breast). By stopping the actions of estrogen, Nolvadex is useful in slowing down the growth of the tumor and may even cause it to shrink.
Radioimmunotherapy
Another novel approach at therapy involved recruiting and harnessing the potential of the body's immune system to attack the tumor as though it were an invader, and maybe even prevent some forms of it from actually occurring. Called immunotherapy, this makes use of the immune system to fight or prevent infection and diseases by employing specialized antibodies. Mostly in its experimental stage, cancer treatment vaccines were intended to strengthen the body's natural defenses against a cancer that has already developed, while cancer preventive vaccines were given to healthy individuals designed to target infectious agents that can cause cancer.
Some investigators are going beyond immunotherapy alone by investigating its potential in combination with radiation. These try to locate cancer within the body, known as radioimmunoimaging (RII); and treat cancer itself, called radioimmunotherapy (RIT).
RII uses radioactive material attached to specially designed antibodies called monoclonal antibodies (MAbs). They are synthetically produced and can recognize substances on the surfaces of tumor cells. The MAbs are then "engineered" to bind radioactive metals such as indium-111, copper-64, or radioactive iodine (iodine-123, iodine-131, or iodine-124) which are visualized with special cameras. The images will show areas where the MAbs have localized in the body.
RIT, on the other hand, uses the same MAbs for therapy but switches the radioactive metal to yttrium-90, which delivers higher levels of local radiation to the tumor. The radiolabeled MAb is administered through a vein and circulates through the body to destroy tumor cells.
Different antibodies are used in current clinical trials. Some bind to carcinoem-bryonic antigen (CEA), a tumor antigen found in certain patients with breast, colon, lung, thyroid, and ovarian cancers. Others bind to CD20, an antigen found on the surface of certain lymphomas. A third antibody binds to her-2, which is overexpressed in approximately 25 percent of breast-cancer patients.
Better diagnostics
A giant leap in cancer chemotherapeutics is possible now because of a major revolution that was inconceivable when the earlier agents were developed--better diagnostics through molecular biology. The development of gene technology through DNA microarrays identifies mutations in specific gene sequences while monitoring the activity of other genes in a tumor, providing the clinician with a more personalized image of the patients' disease status and a greater leverage to tailoring a specific treatment regimen.
The future of cancer treatment does not promise the end of cancer as we know it--or at least not yet--but the vastly improved tools and agents promise the possibility of cancer prevention, higher cure and survival rates, and better quality of life for survivors.
|
