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Phase II trials of thalidomide have shown potential activity against some solid tumors.[35,36,37] While the mechanism is unclear, it is thought to involve both immunomodulatory and non-immunomodulatory activities. These tumors produce immunologic suppressive factors that prevent priming and activation of CD4+ and CD8+ T cells of the lymph nodes.[3]Other immune cells such as NK and macrophages are also inhibited and are therefore unable to respond to and destroy tumor cells. Thalidomide and the IMiDs’ costimulatory action on primary human T cells enhance antitumor activity mediated by the Th-1 cytokines IL-2 and IFN-γ. The costimulation is thought to overcome the T cell unresponsiveness and prevent the release of suppressive factors, thereby enabling tumor-specific cells to kill tumor cells.[38] Thalidomide and the IMiDs are also thought to costimulate macrophages and NK cells leading to antitumor activity as discussed earlier. Anti-angiogenic and pro-apoptotic activities of thalidomide and the IMiDs are also thought to play a role in the apparent efficacy seen in various highly vascularized solid tumors through inhibition of VEGF and induction of growth arrest respectively.[34]

Thalidomide has re-surfaced in the field of oncology, despite its troubled history as a teratogen. The increasing realization of its potential clinical utility in different neoplasms make the study of thalidomide and its  analogues very promising.It has yet to be approved for multiple myeloma. Recent reports of potential efficacy in other solid tumors have increased its experimental use and initiation of further clinical trials.  The development of the IMiDs is an example of how active research efforts contribute to the synthesis of new thalidomide analogues that provide improved efficacy and/or reducing toxicity. Particulary lenalidomide has significantly higher immunomodulatory and anti-angiogenic potency then thalidomide and  also has less side effects then thalidomide. These properties of IMiDsmade them potentially important therapeutics in cancer.While the IMiDs have shown encouraging results in both animal models and have successfully entered clinical trials, efforts are still underway to improve the toxicity profile as well as understanding further and identifying specific molecular targets that would also help delineate the neoplasms for which it may exhibit clinical potency.

The rehabilitation of thalidomide has increased its experimental use in numerous oncologic and inflammatory conditions and its analogues also shows a promising result in different malignancies but the exact mechanism of anti tumour activity of thalidomide is unknown. Thalidomide possesses many properties that can help us to explain its anti tumour activity but these are not so specific in explaining about targets. Therefore, despite the success of these agents in certain types of neoplasms, the specific molecular mechanisms and targets are still incompletely understood. Understanding of the precise mechanisms of action will help in the rational design of better thalidomide analogues, optimizing clinical applications, and ultimately translating into beneficial activity in specific neoplasms.

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