Antitumor effects of bisphosphonates:
Promising preclinical evidence
Theresa A. Guise *

Summary:

The majority of patients with advanced cancer will ultimately develop bone metastases. The bone microenvironment provides fertile soil for a cycle of tumor growth and bone destruction that increases the risk of debilitating and potentially life-limiting skeletal-related events. Therefore, developing appropriate strategies to prevent bone metastases is critical. Bisphosphonates used to treat and prevent skeletal-related events resulting from multiple myeloma and bone metastases secondary to solid tumors, may also have direct and indirect antitumor effects. Emerging evidence from in vitro and in vivo preclinical studies in several tumor types suggests that bisphosphonates can reduce tumor burden in bone and soft tissue, inhibit angiogenesis, prevent tumor cell invasion and adhesion in bone, and induce tumor cell apoptosis.

The powerful antiresorptive properties of bisphosphonates appear to directly prevent tumor cell growth and angiogenesis; in addition, combining bisphosphonates with cytotoxic chemotherapy may provide further antitumor synergies. Sequential application of cytotoxic chemotherapy (e.g., doxorubicin, paclitaxel, and gemcitabine) followed by bisphosphonates has been shown to induce significantly more tumor cell apoptosis than either agent alone in vitro and effectively inhibits tumor growth in vivo. Furthermore, in vivo data suggest that optimizing the dosing schedule may significantly increase survival.

Overall, preclinical data suggesting that bisphosphonates have antitumor potential are promising and have provided the impetus for several ongoing clinical studies.

Conclusions: The available preclinical evidence suggests that the antitumor potential of bisphosphonates is achieved through several direct and indirect mechanisms that inhibit multiple steps in the pathways of tumor progression and metastasis. It is well understood that tumor-induced bone resorption causes the release of  a variety of growth factors from the bone matrix that further stimulate tumor growth, thereby creating an endless positive feedback loop. Bisphosphonates may prevent tumor growth indirectly by inhibiting bone resorption and the subsequent release of tumor- stimulatory growth factors, interrupting the viscous cycle of bone loss and tumor growth. Second, inhibition of angiogenesis appears to be another indirect mechanism by which bisphosphonates prevent tumor growth. Furthermore, bisphosphonate-mediated activation of the innate immune response against malignant cells may provide additional clinical efficacy. Finally, the direct cytotoxic effects of bisphosphonates alone or in combination with other established chemotherapy agents add to the possibility that the variety of antitumor effects may offer additional clinical benefit, especially in the adjuvant therapy setting. The data presented herein provide the rationale for investigating the potential antitumor and bone metastasis prevention activities of bisphosphonates in the clinical setting. Data from preliminary and ongoing large, randomized clinical trials will provide important insight into these emerging roles of bisphosphonates.

Courtesy: Guise TA, Antitumor effects of bisphosphonates: Promising preclinical evidence, Cancer Treat Rev (2008), doi:10.1016/j.ctrv.2008.03.006.

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Stem Cell Transplantation BMT
Center proposed at PIMS

ISLAMABAD: Lawrence Faulkner, a world renowned Pediatric Hematologist  Oncologist who was the member of Dr. Lucarelli team, which first carried out World's first ever Bone Marrow Transplant, gave a very illuminating lecture on Stem Cell Transplantation at Pakistan Institute of Medical Sciences recently. The lecture was well attended by consultants and postgraduate doctors.

Dr. Lawrence gave the technical details how to carry out the stem cell transplantation. The talk was followed by discussion with Dr. Majeed Rajput, Director of Pakistan Institute of Medical Sciences. Dr. Abdul Majeed gave several practical suggestions and assured his full support to the project.

 PIMS being the premier medical institute of the country has the need and all the provisions for establishment of bone marrow transplant and stem cell transplant center After establishment of Burn Center with infection free environment, it will be easy to establish Stem cell and Bone marrow Transplant Center. For this we would need a State of the Art Centralized Blood Bank and the Laboratory says Prof. Anwarul Haque Consultant Pathologist at PIMS. The laboratory will cater in addition to the routine patients for the patients of Liver Transplantation the project which is now in the pipeline. Burn Center, Cardiac Center and in future Stem Cell & Bone Marrow Transplantation will also be used for the future Medical College and Medical University at PIMS.  Prof. Anwar Ul Haque, Prof. Mumtaz, Prof. Khalid Hassan and Dr. Lubna Naseem participated in the discussion. Mr. Khliad and his wife Dr. Sadaf who had created a bridge between Dr. Faulkner and Pakistan, were also in the meeting. Dr. Lawrenece also visited Children Hospital at PIMS. (PR)