DOXIL (doxorubicin hcl liposome injection)

DOXIL (doxorubicin hcl liposome injection) is doxorubicin HCl encapsulated in long-circulating STEALTH® liposomes. Liposomes are microscopic vesicles composed of a phospholipid bilayer that are capable of encapsulating active drugs. The STEALTH® liposomes of DOXIL (doxorubicin hcl liposome injection) are formulated with surface-bound methoxypolyethylene glycol (MPEG), a process often referred to as pegylation, to protect liposomes from detection by the mononuclear phagocyte system (MPS) and to increase blood circulation time.

It is an anthracyclic antibiotic, closely related to the daunomycin, and like all anthracyclines, it works by intercalating DNA, with the most serious adverse effect being life-threatening heart damage. It is commonly used in the treatment of a wide range of cancers, including hematological malignancies, many types of carcinoma, and soft tissue sarcomas.

Molecular mechanism:

1. Doxorubicin helps to stabilize complexes containing double-stranded DNA and the enzyme topoisomerase II: this enzyme then cuts both of the DNA strands, which leads to the death of both normal cells (predominantly via topoisomerase IIβ) and in tumour cells that are susceptible to the drug (predominantly via topoisomerase IIα), thus accounting for both the toxicity and anti-tumour efficacy of doxorubicin.

2. Doxorubicin increases the production of ceramides inside cells, which leads to the latent transcription factor CREB3L1 translocating from the endoplasmic reticulum to the Golgi apparatus. Two proteases (S1P and S2P) then cut the CREB3L1 protein; and its amino-terminal fragment then migrates into the nucleus, where it acts as a transcription factor to activate the CDNK1A locus and additional genes. This leads to increased expression of the p21 protein along with other proteins that inhibit the proliferation of tumour cells.

Reference:
1. http://elife.elifesciences.org/content/1/e00387
2. http://www.rxlist.com/doxil-drug/clinical-pharmacology.htm
3. www.doxil.com

IMATINIB in Chronic myeloid leukemia

 

 


Reference:
www.gleevec.com

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Cancer stem cells; novel target for cancer treatment

Cancer stem cells are an underlying cause of tumor recurrence and metastasis. The majority of cancer drugs, while killing the bulk of tumor cells, ultimately fail to induce durable clinical responses because these cells develop a resistance to treatment over time. A reason for this acquired resistance may be the presence of small minority of cells in the tumor called cancer stem cells (CSC). These CSCs are often resistant to existing cancer therapies including targeted drugs, chemo- and radiation therapy.

The ability of CSCs to move to other sites in the body, combined with the capability to initiate a new tumor mass, may implicate CSCs as an important factor in the formation of metastases. Metastatic tumor sites are the cause of death in more than 90% of human cancer patients. Cancer stems cells have been found in many types of tumors, including leukemia, myeloma, breast, prostate, colon, brain, lung and other cancer. 

In order to develop truly effective treatments that can create a durable clinical response it is important to develop drugs that can target and kill CSCs. A major factor that has prevented the discovery of drugs targeting CSCs is that isolated CSCs rapidly differentiate in culture, yielding the non-CSCs that represent the majority of cells in tumors.

Reference

1. http://www.verastem.com/research/

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mechanism of soliris