Chemotherapy tyrosine kinase inhibitors

Chemotherapy agents, such as DNA alkylators (see Chapter 6), have traditionally been administered intravenously because of their high chemical reactivity and low bioavailability. During the past decade, a new class of oral anticancer drug, the tyrosine kinase inhibitors, has been developed. These inhibitors bind membrane-bound tyrosine kinase-linked receptors (TKLR) (see Chapter 5). 

Erlotinib is an epidermal growth factor receptor inhibitor that inhibits intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor. It is indicated in the treatment of locally advanced or metastatic non-small-cell lung cancer after failure of at least 1 prior chemotherapy regimen. Erlotinib (Tarceva) is a human HER 1/EGER tyrosine kinase inhibitor with the following chemical formula A-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. It is indicated in treatment of patients with locally advanced or metastatic non-small-cell lung cancer. 

The extracellular domain of the HER-2 neu molecule is the therapeutic target for the specific IgGlx humanized chimeric monoclonal antibody Trastuzumab (Herceptin ), approved 1998 and found to be effective in malignancies with HER-2 overexpression. An important aspect of this specific immunotherapy includes the efficiency against non-proliferating disseminated tumor cells (dormant cells), which are usually in the GO phase of the cell cycle, where conventional chemotherapy is less effective. The HER-2 neu molecule is also the target for specific tyrosine kinase inhibitors such as Tykerb (lapatinib ditosylate), which block the kinase-substrate interaction and the extracellular tyrosine kinase receptors on tumor cells. 

Kloth JS, Pagani A, Verboom MC et al (2015) Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors. Br 1 Cancer 112 1011-1016 Korzeniowska K, Jankowski J, Cie lewicz A, JaWeeka A (2015) Current approcich for detection of sub-cfinical left ventricirlar dysfimetion associated with chemotherapy. Pharmacol Rep 67 1098-1102... 

Lenihan DJ (2014) Reversibility of effectively treated chemotherapy-related heart failure raising our awareness and a call to action for cardiology. J Card Fail 20 159-160 Lenihan DJ, Kowey PR (2013) Overview and management of cardiac adverse events associated with tyrosine kinase inhibitors. Oncologist 18 900-908 Lenihan DJ, Westcott G (2015) Cardio-oncology a tremendous opportunity to improve patient care. Future Oncol 11 2007-2010... 

The proportion of ALL in patients older than age 60 years constitutes between 16% and 31% of all adult leukemias. Treatment of adults largely has followed the conventional chemotherapeutic regimes used in childhood ALL. However, the intensification regimens common in childhood are not suitable for this population because of their associated toxic-ities in older patients. The adverse prognostic factor, the Philadelphia chromosome, occurs in 15% to 30% of adults and thus is more common in the over 60 age group.17 Based on the experience achieved in CML, the use of imatinib, a potent inhibitor of the Ph+-associated BCR-ABL tyrosine kinase, is becoming a common practice for these older adults. Results show that the combination of imatinib with conventional chemotherapy has improved remission rates compared with the use of conventional chemotherapy alone,... 

Fry DW. Inhibition of the epidermal growth factor receptor family of tyrosine kinases as an approach to cancer chemotherapy progression from reversible to irreversible inhibitors. Pharmacol Ther 1999 82 207-218. 

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