Thalidomide- Its Past, Its Present and Its Revival in Cancer - Essay Example

Thalidomide- Its Past, Its Present and Its Revival in Cancer Research Introduction Thalidomide was introduced as an apparently safe sedative in West Germany in 1956 by Chemie Gruenenthal GmbH under the name Contergan. Properties like its speedy onset and low acute toxicity made it an attractive alternative to barbiturates and popularised it so much so that it could be purchased without a prescription. It gained widespread mass appeal in the rest of Europe, Canada, Australia and South Africa and began to be widely used in treatment for morning sickness by pregnant women. The Food and Drug Administration delayed the release of the drug in the United States of America following concerns over the results of Neurotoxicologcal studies conducted in animals (Von Moose, 2003). However the drug had to be immediately withdrawn from the market following a rapid rise in a severe birth defect called phocomelia, previously a rare condition, being linked to the exposure of thalidomide in the uterus. The link between Thalidomide and the severe teratogenic effect was worked out by two independently working physicians McBride and Lenz in 1961 by which time there were reported cases of about 6000-10000 affected children (Lenz, 1988). Interest in the drug was re-kindled a few years later following an unexpected discovery of anti inflammatory activity of Thalidomide in reactive lepromatous leprosy. However it was not until 1991 that interest in the drug intensified after its anti-tumour necrosis factor- activity was discovered (Sampio, 1991). The newly stimulated interest resulted in a significant amount of information on the potential of this drug and its mode of action in a number of diseases with a particular interest in cancer. Chemical structure of Thalidomide Thalidomide is -N-phthalimidoglutarimide (C13H10N2)4 having a molecular weight of 258.2. It is a glutamic acid derivative and is related structurally to neuropharmaceuticals bemegride (-ethyl--methyl-glutaramide C18H13NO2) which is an analeptic drug and glutethimide (-ethyl--phenyl-glutarimide C15H23NO4) which is a sedative and antiepileptic drug. A broad range of immunomodulatory and anti tumour properties other than sedation differentiates thalidomide from these drugs. Halidomide has a phthalimide ring on the left side and a glutaramide ring on the right side with an asymmetric carbon atom at 3' position of the glutarimide ring (Mujagic et al., 2002). Pharmacokinetics Thalidomide exists as a racemic mixture of its S and R isomers which interconvert rapidly at physiological pH. The drug is eliminated following pH dependent, non-enzymatic, spontaneous hydrolysis into multiple metabolites which are chemically inactive through non-renal pathways which minimises drug interaction risks. It is believed to have a half life of approximately five hours (Gordon and Goggin, 2003). Mechanism of action of thalidomide is complex and is incompletely understood despite the growing interest in the drug. However the properties are related to antiangiogenesis, immune modulation and cytokine regulation. The anti-angiogenesis property of Thalidomide interrupting basic fibroblast growth factor (bFGF) and vascular endothelial growth factor(VEGF) mediated processes was first reported by D'Amato et al. (1994). Thalidomide also reportedly induces the degradation of TNF - mRNA to inhibit TNF- synthesis (Moreira et al., 1993). Studies have also shown the role of thalidomide in blocking nuclear factor (NF)-B activation though IB kinase activity inhibition (Keifer et al., 2001). Other mechanisms of action of the drug include downregulation of adhesion molecules as demonstrated in experimental models (Geitz, 1996), co-stimulation of human T cells, mainly CD8+ subset cell proliferation along with the stimulation of IL-2 and IFN- production, while inhibition of cytokines IL-6 and IL-12 production (Moller et al., 1997). Thalidomide is also involved in the reduction of free radicals that is believed to have a hand in oxidative DNA damage (Richardson et al, 2002). A study designed to understand the molecular mechanism of the anti tumour activity of thalidomide by Du et al. (2005) showed a COX-2 degradation mechanism. Thalidomide effect was evaluated on human tumour cells MCF-7 and HL-60 expressing COX-2 and tumour cell lines HeLa and K562 not expressing COX-2 in vitro. Also studied in the cell lines were the effect of the drug on COX-1, bcl-2 expression, GSH, VEGF and cytochrome c. Inhibition of tumour growth in MCF-7 and HL-60 was observed in a concentration dependent manner while no such effect was seen in HeLa and K562. A decrease in COX-2 expression accompanied by a decrease in levels of bcl-2 protein, VEGF, GSH, TNF- and a cytochrome c increase but no effect on COX-1 in HL-60 and MCF-7. In vivo studies in mouse xenograft models showed results that were consistent with the in vitro studies indicating that a COX-2 degradation pathway might be present in tumour inhibition independent of antiangiogenesis (Du et al., 2005). The wave of enthusiasm brought forth by the potential of Thalidomide in cancer treatment strategies is marred by the accompanying side-effects of the drug. The common side effects of the drug are summarised in the following table. Organ system Symptoms Central Nervous system Somnolence, fatigue, depression, tremor, blood pressure fluctuation, headache Peripheral Nervous system Numbness, burning sensation, paresthesia Gastrointestinal Constipation, increased appetite, nausea, xerostomia Cardiovascular Hypo and hypertension, bradycardia, deep vein thrombosis Dermatologic Pruritus, skin rash, toxic epidermal necrolysis, brittle fingernails Haematological Neutropaenia, granulocytopaenia Endocrine Hypothyroidism, oedema Genital system Teratogeicity, menstrual irregularities, phocomelia (Source: Von Moose et al., 2003) Thalidomide in haematological malignancies Angiogenesis being an important factor in the progression of haematological malignancies such as myeloma, lymphoma, leukaemia and myelodysplasia, thalidomide has been looked upon with considerable interest as a potential treatment agent with antiangiogenic and immunomodulatory properties. Multiple myeloma has shown the most promising result with the first positive report by Singhal et al. in 1999 in which about 30% patients with refractory myeloma treated with Thalidomide showed partial or complete response. These findings have been confirmed by several studies showing published response rates of 25%-35% demonstrating decreased levels of bFGF, VEGF and TNF- in plasma and bone marrow (Dmosynska, 2002). Several reports have indicated treatment of multiple myeloma in combination with dexamethasone have shown activity in about 50% patients with a reduced median time to response and daily dose of Thalidomide which in turn reduced the drug-related side-effects (Dimopoulos, 2001). This combination has been widely used in newly diagnosed young patients in induction treatment before autologous stem cell transplantation. In newly diagnosed elderly patients an oral combination of melphalan and prednisone with Thalidomide has shown better response than the standard melphalan and prednisone (Palumbo et al., 2003). Combinations of thalidomide with a number of drugs like dexamethasone, doxorubicin, melphalan or cyclophosphamide have been extensively investigated in refractory-relapsed disease. However the use of thalidomide in combination with other drugs increases the risk of side effects, the major concerns being thromboembolism and peripheral neuropathy. Countries like Australia, South Korea, Turkey, New Zealand and Israel has licensed thalidomide for relapsed-refractory multiple myeloma treatment. The Food and Drug Administration of the United States has also approved thalidomide in combination with dexamethasone for newly diagnosed multiple myeloma patents (Palumbo et al, 2008). High risk myelodysplasia, acute and chronic myeloid leukaemia are other haematological malignancies in which Thalidomide maybe effective. A published trial by Raza et al. (2001) showed almost 31% patients with refractory anaemia, a secondary condition to myelodysplasia completed treatment with 19% independent of transfusion. Thalidomide in the treatment of acute myeloid leukaemia has also been investigated with very few patients' showing positive response. However the results indicated particularly no positive effect of Thalidomide making further studies necessary to confirm any correlation between thalidomide and the response (Thomas et al.,2003). Thalidomide in solid tumours Thalidomide has been evaluated in a number of solid organ malignancies because of the role of angiogenesis in the metastasis of these conditions. The thalidomide action data on solid tumours are however limited when compared to haematological malignancies. Thalidomide monotherapy was studies in three phase II trials of patients with glioma, glioblastoma and astrocytoma, highly vascularised tumours in which angiogenic factors are overexpressed. A daily dose administration of 100 to 1200 mg in patients with these diseases most of who had previously received some treatment in the form of radiotherapy, chemotherapy or surgery was well tolerated but showed rare objective responses. The data however showed minimal activity of single agent thalidomide in high grade gliomas necessitating further study of thalidomide in combination with other drugs (Fine et al., 2000; Short et al., 2001; Marx et al.,2001). Thalidomide mono therapy in renal cell carcinoma also showed modest response and combination studies of thalidomide with IFN- and IL-2 in metastatic condition shows some promising results which require further studies (Eleutherakis-Papaiakovou, 2004) Thalidomide in low doses shows activity in hormone refractory prostate cancer. 37.5% patients showed a decrease in prostate-specific antigen in a phase II study in which low-dose thalidomide was administered (Drake et al., 2003). Another phase II study showed an increased response rate on administering thalidomide in combination with docetaxel supporting the role of thalidomide in the prostate cancer chemotherapy (Figg et al., 2001) The negligible effect of thalidomide in the treatment of advanced melanoma was seen to improve when it was combined with temozolomide (Hwu et al.,2001). Thalidomide has also shown some activity against Kaposi sarcoma when administered to HIV patients during clinical trials. In a phase II trial conducted by Fife et al. (1998) on 17 patients, six showed partial response when thalidomide was administered at 100 mg per day for 8 weeks. Another dose escalation study in which initial dose of 200mg per day was increased to 1000 mg per day for a duration of upto an year showed partial response in eight of 17 patients. Side-effects in the form of depression and drowsiness were noted (Little et al., 200). Activity of thalidomide on other solid tumours has had not much positive response so far. Single agent thalidomide therapy showed no effect on metastatic breast, head and neck carcinoma s well as pretreated metastaic colorectal cancer. However a study has shown promising results of the treatment of advanced colorectal cancer pretreated with fluorouracil with thalidomide in combination with irinotecan (Govindarajan, 2000). These studies have shown that though thalidomide shows some activity against solid tumours, the benefits when compared to accompanying side effect are marginal when used as a single agent. Its potential in the use of combination therapy is being evaluated in ongoing research of thalidomide with other cytotoxic drugs (Eleutherakis-Papaiakovou, 2004). Results of thalidomide action on non haematological tumours from selected published trials. Tumour Number of patients therapy Thalidomide dose Response rate % Gliomas 1. Fine et al., 2000 2. Marx et al., 2001 3. Bell et al., 2000 39 42 37 Single agent phase II Single agent phase II Single agent phase II 800-1200 mg 100-500 mg 100-500 mg 6 5 15 Kaposi sarcoma 1. Fife et al., 1998 2. Little et al., 2000 17 20 Single agent phase II Single agent phase II 100 mg 200-1000 mg 35 40 Renal cell carcinoma 1. Eisen et al., 2000 2. Stebbing et al., 2001 3. Escudier et al., 2002 18 25 40 Single agent phase II Single agent phase II Single agent phase II 100 mg 600 mg 400-1200 mg(escalating) 17 9 5 Prostate cancer 1. Figg et al., 2001 2. Dixon et al., 1999 63 59 Single agent phase II Docetaxel +/thalidomide - 200 vs1200 mg(random) 200 mg 18/0 53/35 Melanoma 1. Hwu et al., 2001 2. Pavlick et al., 2002 12 10 Temozolomide + thalidomide phase I DTIC + thalidomide phase II 100-400 mg 200-400 mg 42 30 Thalidomide in osteosarcoma Osteosarcoma is the most common malignancy of the bone that generally occurs during the rapid growth period as a teenager matures into an adult. Adjuvant or neoadjuvant chemotherapy and removal of the primary tumour in patients whom pulmonary metastasis has not occurred are effective treatment strategy (Raymond et al., 2002). However substantial changes in survival have not been observed over the last couple of years although systemic chemotherapy and modern surgery has improved treatment dramatically. This makes novel therapeutic strategies imperative for osteosarcoma patients with fatal metastases to be treated successfully. Antiangiogenic and immunomodulatory drugs are emerging compounds for the treatment of soft tissue sarcomas including osteosarcoma. Thalidomide is one of the first drugs to have shown antiangiogenic properties. However data on the efficacy of Thalidomide in osteosarcoma are few. An interesting case report by Tsai et al. showed that refractory osteosarcoma patients treated with 200 mg Thalidomide per day in combination with 200 mg celecoxib twice a day resulted in persisted remission after a year of treatment (Tsai et al., 2005). Derivatives of thalidomide The re-emergence of thalidomide has propelled scientific research towards the development of structural analogues of Thalidomide with its immunomodulatory properties intact without its associated side effects. A number of such compounds have been developed recently with a potency of more than 50 000 fold at a molar base inhibition of TNF-. Depending upon their biological effects, they are broadly classified into two groups. The first is a group of immunomodulatory drugs which shows strong inhibitory action on TNF-, IL-1, IL-6 and IL-12 while stimulating IL_10 production. They augment T-cell proliferation when activated through receptors of T cells and refrain from inhibiting phosphodiesterase-4. The second is a group of selective cytokine inhibitory drugs which inhibit TNF- potently yet much more selectively without having considerable effect on other cytokines or T-cell activation. These derivatives however strongly inhibit phosphodiesterase-4 the contribution of which to the biological effect is not yet clear (Corral, 1999). IMiDs-A novel class of thalidomide analogues as anti cancer agents IMiDs are a novel class of thalidomide analogues with increased immunomodulatory effects and an increased safety profile. These compounds are amino-phthaloyl -substituted thalidomide analogues in which the fourth carbon of phtahloyl ring of thalidomide has an amino group added to it (Aragon-Ching et al., 2007). The potent immunomodulatory activity of IMiD was demonstrated by the inhibition of TNF- in lipopolysaccharide induced human peripheral blood mononuclear cell both in vivo and in vitro . The analogue was shown to inhibit TNF- more potently than the parent drug. It also showed inhibitory effect on IL-1 and IL 12 and partial inhibitory effect on IL-6 as well as augmented the production of IL-10. Multiple myeloma cell lines had been used for earlier studies using IMiD. The potential targets of the IMiD TNF-, NF-B and IL-6 are all involved in the trigger, activation and subsequent survival signal of Multiple myeloma (Corral et al., 1996; Corral and Kaplan, 1999). The pro-apoptic properties of thalidomide and its analogues were first demonstrated by Hidshima et al. (2000). By demonstrating a raise in sub G1 cells and p21 induction related to G1 growth arrest. IMiDs demonstrated properties such as caspase-8 activation enhancement, increased fas induction sensitivity, reduction in the expression of apoptosis protein-2 cellular inhibitor and stimulation of activities of other inducers of apoptosis such as TNF-related apoptosis-inducing ligand (TRAIL) (Mitsiades et al.,2002). IMiDs also act as costimulators of Tcells and was seen to induce proliferation of T cells as well as IL-2 and IFN- in multiple patients without being cytotoxic to the multiple myeloma cells. The drugs also enhanced the lysis of autologous tumour cells mediated by natural killer cells. One study showed greater costimulation of the CD8 T cell subset when compared to Cd4 (Corral and Kaplan, 1999) T cell subset another study showed similar costimulation of both the subsets in correlation with TNFR2 inhibition (Marriott et al., 2002). This costimulatory effect of IMiD represent a paradox to ligand stimulated apoptotic and inflammatory cytokine suppression which like the effect of thalidomide leads to clinically divergent effects with regard to particular pathways involved during a clinical condition (Bartlett et al., 2004; List, 2005). IMiDs have demonstrated antiangiogenic properties by inhibiting the secretion of VEGF and bFGF from both tumour and stromal cells. IMiD analogues exhibited an antiangiogenic property of 100-fold increase in potency when compared to thalidomide using human umbilical artery explants assay. IMiD analogues have also been shown to act in the inhibition of endothelial cell migration and adhesion possibly due to endothelial cell integrin downregulation (Bartlett et al., 2004; Dredge et al., 2002; Knight, 2005). The US FDA has approved one of the IMiD lead compounds lenalidomide in treatment of 5q-myelodysplasia and multiple myeloma and another lead compound which has also undergone studies and clinical trials in multiple myeloma is Actimid. The review on the two analogues by Aragon-Ching et al. (2007) is summarised in the following paragraphs. Lenalidimide ( -(3-aminophthalimido) glutarimide) is an analogue of thalidomide that has shown higher potency in the proliferation and tube formation assays of human umbilical vein endothelial cells (HUVEC) in a dose-dependent manner(Tohnya et al., 2004). In vivo studies also showed inhibition of tumour growth and anti-migratory effects. Studies with lenalidomide demonstrated no effect on the activity of cytochrome P-450 or phase I and II metabolism by liver microsomes and supersomes in humans. Rats and monkeys tested showed 50% excreted unchanged and the rest metabolised to hydrolysis metabolites. Humans showed a rapid absorption of lenalidimide following oral administration and about 67% was excreted in urine unchanged in less than 24 hours time (Knight, 2005). Lenalidomide is being evaluated in a numer of haematological as well as solid tumours. Lenalidomide trials in multiple myeloma has shown a response rate of over 90% and has emerged with great potential in induction regimen of newly diagnosed multiple myeloma patients in front-line chemotherapy. Lenalidomide is also being evaluated with combination of other drugs like bortezomib and low-dose dexamethasone (Richardson et al., 2005). Positive response in trials with lenalidomide in myelodysplasia characterised by del5q31 has helped gain approval for the drug to be used in low and intermediate risk category of the disease as well as for the management of myelodysplastic syndromes (List et al, 2005). Lenalidomide has also shown potential in solid tumours especially prostate cancer. In a study conducted for determination of the maximum tolerated dose and characterisation of pharmacokinetics and side effects demonstrated good tolerance in patients with mostly grade 1 or 2 side effects (Tohnya et al., 2006). Actimid is another costimulatory analogue of thalidomide that has demonstrated long-lasting tumour specific Th-1 type in vivo response (Dredge et al., 2002). A dose escalation trial on multiple myeloma patients showed increased IL-2 levels consistent with T cells monocyte and macrophage activation. Treatment related side effects were similar to that of single agent thalidomide treatment (Schey et al., 2004). ENMD-0995 is an S enantiomer 3-amino thalidomide which has shown improved antiangiogenesis without related side effects in animal models. It has been granted Orphan Drug designation from FDA following clinical trials to treat patients with multiple myeloma (Aragon-Ching et al., 2007). A number of thalidomide analogues are currently under trial of which N-substituted and tetrafluorinated classes were seen to significantly inhibit microvessel growth in rat aortic ring assay which was subsequently confirmed by HUVEC proliferation and tube formation experiments. The therapeutic potential of these thalidomide analogues were evaluated in vivo following promising results in vitro and ex vivo (Aragon-Ching et al., 2007). These efforts are an example of what active research can do in developing analogues that improve efficacy and reduce side effects. Though promising results in animal models and clinical trials are encouraging, much work remains to be done to improve the toxicity profile and identify particular molecular targets to help in delineating the neoplasm for which it exhibits potency. Although the revived interest in the potential of thalidomide has opened up much about the action mechanism of thalidomide and its analogues, the precise molecular targets of these agents are yet to be identified. The most important factor in the development of new analogues is the retention of the bioactivity of thalidomide with the removal or reduction in the accompanying side effects. Very simple modifications in the chemical structure can alter the mechanism of action significantly and might differ in the activity profile from that of the parent compound. And in analogues that demonstrate activity in experimental models, exact molecular targets are unclear. Hence these compounds are best considered as new drugs, despite their similarity to thalidomide, as its analogue. However the promising results shown by these compounds in clinical trials require continued research to translate them into beneficial treatment agents in specific neoplasms (Aragon-Ching et al., 2007). CONCLUSION Despite its troubled history, thalidomide has re-surfaced in the field of cancer research by demonstrating great potential in inflammatory and malignant disorders where conventional treatments have failed. The significant side effect profile of the drug poses a great risk of treatment cessation in patients. Research is underway to develop potentially safe derivatives of thalidomide with immunomodulatory analogues like lenalidomide and actmid being approved for use in treatment of multiple myeloma. 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