Palbociclib: A breakthrough in breast carcinoma in women.

Breast cancer (BC) is the most common cancer and leading cause of death in women worldwide. Cellular proliferation, growth, and division are tightly controlled by the cell-cycle regulatory machinery. An important pathway is cyclin-dependent kinases (CDKs) which regulate cell cycle and thus control transcriptional processes. In human cancer, multiple CDK family members are commonly deregulated. The cyclin D-CDK4/6-retinoblastoma (RB) protein-INK4 axis is particularly affected in many solid tumors which leads to cancer cell proliferation. This has led to long-standing interest in targeting CDK4/6 as an anticancer strategy. Different investigational agents that have been tested which inhibit multiple cell cycle and transcriptional CDKs but have carried excessive toxicity thus failed to stand the rational of human use. Amongst several selective and potent inhibitors of CDK4/6, palbociclib is the first to be accessed suitable for human use having explicit selectivity toward CDK4/6. Its mechanism is to arrest cells in G1 phase by blocking RB phosphorylation at CDK4/6-specfic sites without affecting the growth of cells which are RB-deficient. Studies conducted in patients of BC having cells with advanced RB-expression demonstrated acceptable side effects but dose-limiting toxicities primarily neutropenia and thrombocytopenia, with prolonged stable disease in patients.

Denosumab: A bone antiresorptive drug.

Bone remodeling is the continuous process by which old bone is removed by bone-resorbing cells, the osteoclasts and replaced by new bone synthesized by bone forming cells, the osteoblasts. Osteoporosis is characterized by a progressive loss of bone mass and microarchitecture, which leads to increased fracture risk. Denosumab, a human monoclonal antibody resembling natural IgG2 immunoglobulin, has antiresorptive activity and is distinguished from other antiresorptive drugs. It mimics osteoprotegerin (OPG) that binds to RANKL and hence does not allow RANKL to bind with RANK receptor, thereby inhibiting osteoclast differentiation, activation and survival exerting primarily antiresorptive action. Denosumab trials have shown its efficacy in postmenopausal women with osteoporosis, unresectable giant cell tumor of bone and significant effect in non-metastatic prostate cancer and delay in the time-to-first skeletal related events (SRE) and subsequent SRE with denosumab than zoledronic acid in patients. It is available as 60 mg/ml in pre-filled syringes and approved for osteoporosis in postmenopausal women (60 mg s.c. twice yearly), unresectable giant cell tumor of bone in adults and skeletally mature adolescents (120 mh s.c. monthly), prevention of skeletal-related events and to increase bone mass in patients at high risk for fracture including androgen deprivation therapy for non-metastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer. Denosumab offers advantages of twice yearly dosing in osteoporosis and monthly dosing in giant cell tumor of bone with its novel mechanism of action and better tolerability.