The practice of treating patients with relatively nonspecific cytotoxic compounds, such as chemotherapy, is now being complemented by a new era of targeted lymphoma drug development. Researchers are now able to identify a wide array of molecular targets and agents. The new agents include several broad classes of drugs that:
- modulate or change the expression of important genes in the cancer cell.
- intercept the messages generated by detrimental gene expression.
- represent repackaged or reformulated derivatives of tried-and-true favorites.
Several newly available drugs have a unique effect on DNA. In normal cells, DNA exists in two states: condensed and open.
A simple way to envision a molecule of DNA is to think of a long piece of thread upon which an important message is encrypted. If that piece of thread were rolled up into a tight ball, it would be in a condensed state and we would be unable to read the encrypted message. If that piece of thread were uncurled, it would exist in an open state, at which point it would be possible to read the encoded message. canadian antibiotics
In the cell, the balance between these two DNA states is tightly maintained by two sets of opposing enzymes: the his-tone acetyl-transferases (HATs) and the histone deacetylases (HDACs). Some theories suggest that cancer cells behave abnormally because the cells cannot read certain important messages that instruct them how to behave, although this is admittedly an overly simplistic interpretation.
HDAC Inhibitors. Recently, a class of drugs known as HDAC inhibitors has been developed. Examples include:
- the anticonvulsant agent valproic acid (e.g., Depakene, Abbott).
- phenylbutyrate (triButyrate, Triple Crown America/Euro-health), originally developed for urea cycle disorders.
- depsipeptide (Romidespin, Gloucester Pharmaceuticals).
- suberoylanilide hydroxamic acid (SAHA, Aton Pharma; Zolinza, Merck).
- LAQ-824 (Novartis Oncology).
These drugs are being studied in various phase 1 and 2 clinical trials, and they have shown intriguing activity in the treatment of many kinds of lymphoma.
For example, in patients with T-cell lymphomas of the skin that are refractory to standard chemotherapy, depsipeptide has brought about significant regression of disease. Vorinostat has produced significant tumor shrinkage in patients who have experienced a relapse of disease even after stem-cell transplantation. One patient with a difficult-to-treat transformed lymphoma, in fact, achieved a complete remission.
Several studies have suggested that these agents might work by turning on genes that instruct lymphoma cells to stop dividing and even to die. Although the precise mechanism of action is probably more complicated than this, HDAC inhibitors will undoubtedly emerge as valuable adjuncts to future lymphoma therapies.
Oblimersen. If HDAC inhibitors can play a role in determining gene expression, drugs like oblimersen (G3139, Gena-sense, Genta Corp.) help to prevent information in the DNA that has already been “turned on” (transcribed) from becoming a frank messenger (protein). Oblimersen belongs to a new class of agents known as antisense oligonucleotide molecules; they are against the “sense” (the normal message); the prefix oligo- represents “a short piece of;” and nucleotide represents “nucleic acid.” These antisense molecules are short pieces of nucleic acid that bind to and destroy specific messages (messenger RNA) produced by cancer cells.
Oblimersen binds to a specific message in the cell known as Bcl-2. Bcl-2 is overexpressed in many kinds of lymphoma, including DLBCL and follicular lymphoma, and it helps to prevent cells from undergoing apoptosis. Bcl-2 is often referred to as being anti-apoptotic, because it promotes tumor cell survival and it can compromise the effects of chemotherapy.
Many laboratory studies have validated the potent activity of oblimersen, and many clinical studies are now under way to determine its importance in the treatment of several cancers. Oblimersen probably works best when it is integrated into existing chemotherapy programs; in theory, it should sensitize lymphoma cells to the toxic effects of chemotherapy.
Epratuzumab. Epratuzumab (AMG 412, LymphoCide, Amgen/Immunomedics), a monoclonal antibody, targets the CD22 antigen, a protein found on the surface of B lymphocytes, particularly on B-cell cancers. The combination of rituximab and epratuzumab appears to be well tolerated and potentially effective in the treatment of patients with relapsed or refractory B-cell NHL. Even though only six patients of the 23 in this study had aggressive NHL (the rest had low-grade disease), detectable cancer completely disappeared in 50% of these patients after the combination treatment. The most common side effects of treatment were fever, shivering, and fatigue. tadalis sx
Bevacizumab. Bevacizumab (Avastin, Genentech) interferes with the cancer cell’s blood supply, which is needed for cell survival and growth. The FDA has approved this drug for patients with advanced colon cancer in combination with chemotherapy. Bevacizumab has demonstrated modest anti-cancer activity as a single agent in the treatment of aggressive, relapsed NHL. Future studies are planned to evaluate beva-cizumab in combination with chemotherapy for patients with advanced NHL.
Gemcitabine. In combination with rituximab, gemcitabine (Gemzar, Eli Lilly) may offer the advantage of fewer adverse events than other therapies for relapsed NHL. In seven patients with aggressive NHL that had relapsed after CHOP, treatment with gemcitabine and rituximab resulted in two complete remissions and three partial remissions.
DICE. A phase 2 study of dexamethasone, ifosfamide, cis-platin (Platinol, Bristol-Myers Squibb), and etoposide (VePesid, Cipla) (DICE) as salvage chemotherapy for patients with relapsed and refractory lymphoma resulted in responses in the treatment of patients with relapsed NHL who had not responded to an autologous transplant. Overall, 40% of patients lived three years or more after treatment.
Epothilone B. A phase 2 study of the epothilone B analogue BMS-247550 (NSC 710428, Bristol-Myers Squibb) in patients with relapsed aggressive NHL is currently in progress. The epothilones are a new class of cytotoxic molecules, including epothilone A, B, and D, and are identified as potential chemotherapy drugs. Their mechanism of action is similar to that of the taxanes, but their chemical structure is simpler and they are more soluble in water. tadacip 20 mg
Early studies in cancer cell lines and in human cancer patients indicate superior efficacy to the taxanes. Epothilones were originally identified as metabolites produced by the myxobacterium Sorangium cellulosum.