8. newer chemical entities for cancer treatment

Recent development in cancer research; A critical review on new chemical Entities New Chemical Entities

NEW DRUGS OF CANCER IN THE RECENT YEAR [10]

1) Ibrutinib

This drug used for the treatment of patients with chronic lymphocytic leukemia

(CLL). Treatment of activated CLL cells with ibrutinib resulted in inhibition of Btk

tyrosine phosphorylation and also effectively abrogated downstream survival

pathways activated by this kinase including ERK, PBK and Nf-KB. It also inhibited

proliferation of CLL cells invitro.[11] This drug is used for the treatment of

chronic lymphocytic leukemia.

2) Avastin

This drug used for treatment of renal cell carcinoma. Avastin is a recombinant

humanized monoclonal antibody that produces angiogenesis. Acts by inhibiting

vascular endothelial growth factor (VEGF-A). VEGF-A is a chemical signal that

stimulates angiogenesis in variety of disease especially cancer. [12]

APSC, Pariyaram 28


3) Nolvadex (Tamoxifen)

This drug used for breast cancer. Tamoxifen itself is a prodrug. It is

metabolized in liver cytochrome p450 isoform CYP2D6 and CYP3A4 in to active

metabolites such as 4-hydroxy tamoxifen. It acts as estrogen receptor antagonist so

that transformation of estrogen responsive gene is inhibited. 4-hydroxy tamoxifen

bind to ER, the ER / tamoxifen complex recruits other protein known as co-repressor

and then bind to DNA to gene expression.[13]

4) Mozobil

This drug is used for treatment of non-Hodgkin’s lymphoma and multiple

myeloma. Mozobil is a hematopoietic stem cell mobilizer and inhibitor of the CXCR4

chemokine receptor. It blocks the binding of the CXCR4 cognate ligand, stromal cell-

derived factor-1a (SDF-1a). SDF-1a and CXCR4 are recognized to play a role in the

trafficking and homing of human hematopoietic stem cells to the marrow

compartment. Once in the marrow, stem cell CXCR4 can act to help anchor these

cells to the marrow matrix, either directly via SDF-1a or through the induction of

other adhesion molecules. [14]

APSC, Pariyaram 29


5) Xeloda

This drug is used for the treatment of metastatic colorectal

cancer .Capecitabine is metabolized to 5-FU which in turn is a thymidylate synthase

inhibitor, hence inhibiting the synthesis of thymidine monophosphate (ThMP), the

active form of thymidine which is required for the de novo synthesis of DNA and

RNA during gene expression. [15]

6) Jevtana (cabazitaxel)

This drug is used for the treatment of prostate cancer. They bind to

tubulin and promote its assembly into microtubules while simultaneously inhibiting

disassembly. Stabilizes microtubules, which results in the inhibition of mitotic and

interphase cellular function.

APSC, Pariyaram 30


7) Femara (Letrozole)

This drug is used for treatment of breast cancer. Estrogens are

produced by the conversion of androgens through the activity of the aromatase

enzyme. Estrogens then bind to an estrogen receptor, which causes cells to divide.

Letrozole prevents the aromatase from producing estrogens by competitive, reversible

binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole

does not reduce production of mineralocorticosteroids. [16]

8) Sutent (Sunitinib)

This drug is used for treatment of kidney cancer and GI stromal tumors.

Sunitinib inhibits cellular signaling by targeting multiple receptor tyrosine kinases

(RTKs). These include all receptors for platelet-derived growth factor (PDGF-Rs) and

vascular endothelial growth factor receptors (VEGFRs), which play a role in both

tumor angiogenesis and tumor cell proliferation. The simultaneous inhibition of these

targets therefore leads to both reduced tumor vascularization and cancer cell death,

and ultimately tumor shrinkage. Sunitinib also inhibits KIT (CD117) the RTK that

(when improperly activated by mutation) drives the majority of gastrointestinal

stromal cell tumors.

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9) Camptosar (Iriotecan)

This drug is used for the treatment of colon of rectal cancer. Iriotecan

is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then

inactivated by glucouridination by uridine diphosphate glucoronosyltransferase 1A1

(UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38

eventually leads to inhibition of both DNA replication and transcription.

10) Zytiga (Abiraterone acetate)

This drug is used for the treatment of prostate cancer. Abiraterone

inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1), an enzyme which is expressed in

testicular, adrenal, and prostatic tumor tissues. CYP17 catalyzes two sequential

reactions: (a) the conversion of pregnenolone and progesterone to their 17-α-hydroxy

derivatives by its 17 α-hydroxylase activity, and (b) the subsequent formation of

dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its C17,20

lyase activity.

11) Sensipar (Cinacalcet)

This drug is used for the treatment of secondary hyper parathyroidism and

hyper calcemia in parathyroid carcinoma patients. The calcium-sensing receptors

onthe surface of the chief cell of the parathyroid gland is the principal regulator of

parathyroid hormone secretion (PTH). Cinacalcet increases the sensitivity of calcium

APSC, Pariyaram 32


receptors on parathyroid cells to reduce parathyroid hormone (PTH) levels and thus

decrease serum calcium levels.

12) Ethyol (Amifostine)

This drug is used for the treatment for xerostomia (dry mouth) due to

radiation. Instead cells, amifostine detoxifies reactive metabolites of platinum and

alkylating agents, as well as scavenges free radicals. Other possible effects include

accelerated DNA repair, induction of cellular hypoxia, inhibition of apoptosis,

alteration of gene expression and modification of enzyme activity.

13) Gemzar ( gemcitabine Hcl)

This drug is used for the treatment of lung cancer. Gemcitabine is

metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate

(dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an

enzyme responsible for catalyzing the reactions that generate deoxynucleoside

triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide

concentrations, including dCTP.

APSC, Pariyaram 33


14) Pomalidomide

This drug is used for the treatment of patients with multiple myeloma.

Pomalidomide directly inhibits angiogenesis and myeloma cell growth. This dual

effect is central to its activity in myeloma, rather than other pathways such as TNF

alpha inhibition, since potent TNF alpha inhibitors including rolipram and

pentoxifylline do not inhibit myeloma cell growth nor angiogenesis.

NEW FDA APPROVED DRUGS IN RECENT YEAR

FDA APPROVED DRUGS IN 2014[17]

1) Beleodaq (belinostat) :

This drug is used for the treatment of relapsed or refractory

peripheral T-cell lymphoma. This drug is approved by FDA in 2014.

2) Cyramza (ramucirumab) :

This drug is used for the treatment of gastric cancer. This

drug is approved by FDA in 2014 .

APSC, Pariyaram 34


3) Zydelig (idelalisib):

This drug is used for the treatment of relapsed CLL,

follicular B-cell NHL and small lymphocytic lymphoma .This drug

approved in 2014.

4) Zykadia (ceritnib) :

This drug is used for the treatment of ALK+ metastatic

non-small cell lung cancer. This drug approved in 2014.


1) Gazyva (obintuzumab) :

This drug is used in combination with chlorambucil to treat

patients with previously untreated chronic lymphocytic leukemia (CLL).

This drug approved in 2013.

APSC, Pariyaram 35


2) Gilotrif (afatinib) :

This drug is used for patients with late stage (metastatic) non-

small cell lung cancer (NSCLC) whose tumors express specific types of

epidermal growth factor receptor (EGFR) gene mutations, as detected by

an FDA-approved test.

3) Mekinist (trametinib) :

This drug is used to treat patients whose tumors express the

BRAF V600E or V600K gene mutations. This drug is approved in 2013.

APSC, Pariyaram 36


4) Tafinlar (dabrafenib) :

This drug is used to treat patients with melanoma whose

tumors express the BRAF V600E gene mutation.This drug approved in

2013.

5) Xofigo :

This drug is used o treat men with symptomatic late-stage

(metastatic) castration-resistant prostate cancer that has spread to bones

but not to other organs. This drug approved in 2013.

FDA APPROVED DRUGS IN 2012 [19]

1) Cometriq (cabozantinib) :

This drug is used To treat medullary thyroid cancer that

has spread to other parts of the body.This drug approved in 2012.

APSC, Pariyaram 37


2) Stirvarga (regorafenib) :

This drug is used to treat patients with colorectal cancer

that has progressed after treatment and spread to other parts of the body.

This drug approved in 2012.

3) Xtandi (enzalutamide) :

This drug is used to treat men with late-stage (metastatic)

castration-resistant prostate cancer that has spread or recurred, even with

medical or surgical therapy to minimize testosterone. This drug approved

in 2012.

APSC, Pariyaram 38


4) Perjeta (pertuzumab) :

This drug is used to treat patients with HER2-positive

late-stage (metastatic) breast cancer. This drug approved in 2012.

5) Erivedge (vismodegib) :

This drug is used to treat adult patients with basal cell

carcinoma, the most common type of skin cancer.This drug approved in

2012.

6) Lnlyta (axitinib):

This drug is used to treat patients with advanced kidney

cancer (renal cell carcinoma) who have not responded to another drug for

this type of cancer. This drug approved in 2012.

APSC, Pariyaram 39



1) Adcetris (brentuximab vedotin) :

This drug is used For the treatment of Hodgkin lymphoma and

anaplastic large cell lymphoma.

2) Yervoy (ipilimumab) :

This drug is used for the treatment of metastatic

melanoma. This drug approved in 2011.

3) Abstral (fentanyl sublingual tablet) :

This drug is used for the treatment of breakthrough cancer

pain in opioid-tolerant patients.

APSC, Pariyaram 40


4) Afinitor (everolimus) :

This drug is used for the treatment of advanced pancreatic

neuroendocrine tumors. This drug is approved in 2011.

5) Vandetanib :

This drug is used for the treatment of thyroid cancer.

6) Xalkori (crizotinib) :

This drug is used for the treatment of ALK+ non-

small cell lung cancer.

APSC, Pariyaram 41

8. newer chemical entities for cancer treatment

Health & Medicine