By

Dr. Gaurav KumarPGT, Radiation OncologyMedical College, Kolkata

In Order to effectively combat cancers we must underatand the process.

~ 1% neonatal Cord blood Collection contains malignant clones

1/3rd of Adults possess-IgH-BCL2 translocationResponsible for follicular leukemia

Its Tumor Suppressor Mechanisms

By- 1) Apoptosis 2) Senescence

P 16-Rb pathwayARF- P53 pathway

Telomeres

Senescence It Is the process by which a primary cultured cell undergo permanent growth arrest after a f inite replicative l i fespan or in response to certain stressor.

Causes•*Telomere Erosion•* DNA damage•* Activat ion of Oncogene

Chromosome – 9p21

INH 4a/ARF/INH 4b locus

p16 , p15 ,ARF

Telomere dysfunction - Principle effector of tumor suppressor mechanism.

Telomeres – * TTAGGG (G-rich repeats) * 5-15 bp at end of each

chromosome. * Forms T-LOOPS near

chromosomal ends.

T – loops

Capping of chromosomal ends

Prevents from DNA-DNA interaction&

Genetic alteration

NUTLINS -Stabilises ARF & Mdm2, prevents p53 degradation

Reactvation of p53 – Growth Arrest (Sarcoma & HCC)

DNA Methy transferase Inhibitors – Reactivates

P15 & p16 (Induce Senescence)

Telomerase directed Immunotherapy

Telomerase peptide vaccines

(GV 1001 & HR 2822) – Metastatic lung Ca Advanced pancreatic Ca Advanced HCC

Telomerase deficient Cells – More sensitive to Ionising radiation & DNA DSB CT agents

CT induced senescence – Responsible for long term toxicities of therapy

Lymphocyte telomere length – Predicts risk of Atherosclerosis Alzheimer Premature MI CAD

Germline Telomere mutation – Risk of early BM failure (Aplastic Anemia)