THALIDOMIDE AND ITS ANALOGUES IN ANTICANCER THERAPY

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ABOUT AUTHORS:
Shikha Attri, Arti Choudhary, Devendra Gupta
M.Pharm in Pharmaceutical Chemistry, Lachoo
Memorial College of Science and Technology,
Jodhpur University, Rajasthan University Of Health Sciences, Jaipur
*shikhu921@gmail.com

ABSTRACT
Thalidomide, removed from clinical use because of severe teratogenicity, is back. In a comeback that has proceeded with remarkable speed, the drug that adversely affected more than 10,000 infants just over four decades ago now seems to be a lifesaver for patients with advanced plasma cell malignancies. Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body’s immune system, some of which are thought to mediate the anticancer and anti- inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. Immunomodulatory activities along with anti-angiogenic, anti-proliferative,and pro-apoptotic properties are thought to mediate the IMiDs’antitumor responses observed in relapsed and refractory multiple myeloma and some solid tumor cancers. This has led to their use in various oncology clinical trials.
A review is presented of the history of thalidomide and its analogues properties with an emphasis on applications in malignant disease.


REFERENCE ID: PHARMATUTOR-ART-1830

1.INTRODUCTION
Thalidomide caused severe malformations in babies born to mothers taking the drug for morning sickness in the late 1950s and early 1960s. It is now known that these teratogenic effects are due to potent anti-angiogenic and immunomodulatory actions. These properties have lead to the testing of thalidomide in a number of infective, inflammatory and malignant conditions. Promising activity has been reported in myeloma, AIDS-related Kaposi's sarcoma, renal cell carcinoma and glioblastoma multiforme.

Thalidomide(Thal) is a derivative of glutamic acid and is pharmacologically classified as an immunomodulatory agent . Structurally, thalidomide contains 2 amide rings and a single chiral center, and its full chemical name is alpha-N{phthalimido}glutarimide [C13H10N2O4] with a gram molecular weight of  258.2. The currently available formulation is a non-polar racemic mixture present as the optically active S and R isomers at physiologic pH, which can effectively cross cell membranes.[1]The S isomer has been linked to thalidomide’s teratogenic effects, whereas the R isomer appears to be primarily responsible for its sedative properties. The isomers rapidly interconvert at physiologic pH in vivo, and thus efforts at formulating only the R isomer have failed to obviate the teratogenic potential of thalidomide.[2]


2. HISTORY
Thalidomide was first synthesized in Germany in 1954 from the glutamic acid derivative α-phthaloylisoglutamine and soon thereafter animal studies showed it to be extremely nontoxic. It was erroneously concluded that the purported structural resemblance to the then widely used barbiturates could indicate its potential as a “safe” sedative. A single questionable study in mice was performed to show its sedative-hypnotic effects. Based on this study, human trials were initiated in Germany under the lax pharmaceutical regulatory environment without comprehensive animal toxicology studies. These studies should have included reproductive toxicology in a non-rodent species such as rabbits or monkeys. Thalidomide was found to be an effective sedative and sleep-inducing agent in humans with less potential for overdose compared with the barbiturates. It was approved in Germany in 1957 and subsequently in other countries including the United Kingdom, Canada, and Australia under brand names such as Contergan, Distaval, Talimol, and Kevadon. Thalidomide was also found to be an effective anti-emetic in pregnancy and its use in this group of patients subsequently increased. The error in this presumption of good efficacy with limited toxicity became apparent when reports of deformed babies started appearing from late 1956. By the time it was withdrawn in 1961, ~5000 to 12000 deformed babies (and an unknown number of aborted fetuses) from 46 countries were already born. Thalidomide was never approved in the United States because of the diligence of the Food and Drug Administration (FDA) reviewer Frances Kelsey who requested more information from the petitioning company on the reported peripheral neuritis. The company was not forthcoming and the application was withdrawn. This would have been the end of the drug were it not for subsequent reports of its effectiveness in treating various inflammatory and dermatological conditions such as ENL. [3]

In August 1998, thalidomide (Figure 1) was approved for sale in the United States for the chronic treatment of erythema nodosum leprosum (ENL), a painful inflammatory dermatologic reaction of lepromatous leprosy. This marked the approval of the world’s most controversial drug after it was withdrawn from Europe more than 40 years ago. [3]

3.CANCER TREATMENT
Thalidomide was first studied as an anticancer agent by astute investigators intrigued by its potent teratogenic potential. In 1962, only 4 months after the initial reports of teratogenicity, Woodyatt6 treated a woman with malignant mixed mesodermal tumor of the uterus. The interest in studying thalidomide as an anticancer agent led to at least three clinical trials in the early 1960s, including a study by the Eastern Cooperative Oncology Group. These trials did not show any significant activity, and interest in thalidomide as an anticancer agent diminished greatly.[4]

In 1994 Harvard Professor Robert D'Amato at Boston Children's Hospital discovered that thalidomide was a potent inhibitor of new blood vessel growth (angiogenesis), which is required for tumor growth.[5] He then showed in a rabbit cancer model that thalidomide suppressed tumor growth in animals.[6]He also found that a subset of anti-inflammatory drugs, such as sulindac and dexamethasone, had moderate anti-angiogenic activity. When these anti-inflammatory anti-angiogenic drugs were combined with thalidomide they increased both thalidomide's anti-angiogenic and anti-tumor activity. Based on these discoveries, numerous cancer clinical trials for thalidomide were initiated with and without dexamethasone.[7]

Thalidomide was initially tested in humans as a single agent for the treatment of multiple myeloma due to its anti-angiogenic activity.[8] The early foundation for this work was laid out in a 1993 keynote lecture at the American Society of Hematology by Dr. Folkman when he hypothesized that all blood borne malignancies are angiogenesis dependent based upon his discovery that the levels of the angiogenic growth factor FGF were elevated in the urine of patients with leukemia.[9]  Further studies in his lab showed efficacy with the angiogenesis inhibitor TNP-470 in mouse models of leukemia. Additionally, in 1994 Vacca had shown a five fold increase in angiogenesis in the bone marrow of multiple myeloma patients.[10] When the family of a patient with late stage multiple myeloma requested any possible help from Dr. Folkman in 1997, he attempted to obtain TNP-470 as a therapy. However TNP-470 could not be obtained outside of the ongoing clinical trial and thus Dr. D'Amato suggested that thalidomide be used instead for this patient. A small study was then initiated with thalidomide for this patient and several others by Dr. Bart Barlogie with dramatic effects.[11]

Since then, many studies have shown that thalidomide, in combination with dexamethasone, has increased the survival of multiple myeloma patients.

In 2006 the U.S. Food and Drug Administration granted accelerated approval for thalidomide in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients.[12]

Thalidomide appears to inhibit disease progression in multiple myeloma by several mechanisms:

  • Inhibition of angiogenesis in the bone marrow, which is needed for myeloma cell proliferation.
  • Inhibition of the production of interleukin-6 (IL?6), which is a growth factor for the proliferation of myeloma cells.[13]
  • Activation of apoptotic pathways through caspase 8-mediated cell death[13]
  • At the mitochondrial level, thalidomide results in induction of c-jun terminal kinase (JNK).[13]
  • Activation of T cells to produce IL?2, thereby altering the amount and function of natural killer cells (NK cells), thus augmenting the activity of NK?dependent cytotoxicity.[13]

All physicians prescribing and patients receiving thalidomide must go through the STEPS process to ensure that no more children are born with birth defects traceable to the medication. Celgene has sponsored numerous clinical trials with analogues to thalidomide, such as lenalidomide, that are substantially more powerful and have fewer side effects — except for greater myelosuppression.[14]

The activity of thalidomide in solid tumors is less prominent. Studies in Kaposi’s sarcoma, malignant melanoma, renal cell carcinoma and prostate cancer appear more promising especially when thalidomide is combined with biological agents or with chemotherapy. Limited activity was demonstrated in patients with glioma, while thalidomide appears to be inactive in patients with head and neck cancer, breast or ovarian cancer. In a small trial, Australian researchers found thalidomide caused a doubling of the number of T cells in patients, allowing the patients' own immune system to attack cancer cells.[15]

4. THALIDOMIDE ANALOGUES
The use of angiogenesis inhibitors for the treatment of cancer was first conceptualized over 30 years ago, when Dr. Folkman introduced the idea that angiogenesis is required for continued solid tumor growth [16]. Since then, a number of antiangiogenic agents have emerged for use in cancer therapy. Thalidomide (α -N-phthalimido-glutarimide) has emerged as a potent treatment for several disease entities. The exploration of the antiangiogenic and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide analogues. In 2005 Celgene received FDA approval for lenalidomide (Revlimid) as the first commercially useful derivative. Revlimid is available only in a restricted distribution setting to avoid its use during pregnancy. Further studies are being conducted to find safer compounds with useful qualities. Another more potent analog, pomalidomide, is now FDA approved.[17] These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.[18]


Figure 1. Structures of thalidomide and its potent analogues (immunomodulatory drugs, ImiDs).

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