1|Page

Introduction
Cancer is the abnormal growth of normal cells that typically grow beyond their original boundaries, invade surrounding
areas, spread to other organs, and result in metastasis, which is one of the main causes of cancer-related death, the second
most common cause of deaths across the globe [1]

Around 10.0 million cancer-related fatalities (9.9 million excluding squamous cell carcinoma) and 19.3 million new cases
of cancer (18.1 million excluding squamous cells carcinoma) were estimated globally by 2020. Up to 25% of cancer cases
are caused by cancer-causing illnesses such as hepatitis as well as human papillomavirus infections.

The most common malignancies in both genders are breast, lung, stomach, colorectal, thyroid, liver, and ovarian. The most
fatal cancers are lung (1.8 million), liver (830,000), stomach (769,000), breast cancer (627,000), and colorectal (935,000).
The most commonly diagnosed cancers worldwide are lung (2.2 million), breast (2.09 million), colorectal (1.9 million),
prostate (1.28 million), skin (1.04 million), and stomach (1.04 million).[2-5]

Cancer classifications by tissue type include:

1. Carcinoma: Cancer starts in epithelial tissue.

2. Myeloma: Cancer starts in plasma cells that are inside bone marrow.
3. Leukemia: Cancer starts in the bone marrow, where blood cells are made.
4. Lymphoma: Cancer starts in the lymphatic system (ex., lymph nodes, spleen, etc.).
5. Sarcoma: Cancer starts in connective and supportive tissue (ex., muscle, bone,
cartilage, etc.).
6. Mixed types: Cancer starts in more than one tissue type.

As carcinoma cells grow and multiply, they form solid masses called tumors. Cancer cells
can break away from tumors and spread to other parts of your body (metastasize). Labels
for carcinoma describe how much it has spread.
2|Page

There are multiple cancers classified as carcinomas. The most common carcinoma
types include the following:

1. Adenocarcinoma

starts in the glands that line your organs (glandular epithelial

cells). Glandular epithelial cells secrete fluids, like mucus and
digestive juices. Most prostate cancers, breast cancers, colorectal
cancers and pancreatic cancers are adenocarcinoma. Renal cell
carcinoma (RCC) is a type of adenocarcinoma responsible for
85% of all kidney cancer. Hepatocellular carcinoma (HCC) is an
adenocarcinoma and the most common form of liver cancer.

2.Basal cell carcinoma (BCC)

starts in the basal cell layer of your epidermis. The epidermis

is your top layer of skin. A layer of basal cells lines the bottom
of your epidermis. These cells replace the cells in the top layer
of your epidermis (squamous cells) when they die. Basal cell
carcinoma is the most common type of skin cancer.

3.Squamous cell carcinoma (SCC)

starts in your epidermis's squamous cell layer (top layer). It

usually appears in those parts of your skin that receive the
most sun exposure, like your face, ears, neck, arms, legs, etc.
SCC can also form in the mucous membranes lining your
lungs, esophagus, head and neck. It's the second most
common type of skin cancer. Squamous cell carcinoma
generally spreads faster than basal cell carcinoma

4. Ductal carcinoma in situ (DCIS)

starts in your breast milk ducts. Milk flows through your milk
ducts and to your nipple during breastfeeding (chest feeding).
Being "in situ" means that the carcinoma hasn't spread to cells
outside your milk ducts. DCIS is considered noninvasive or pre-
invasive breast cancer and is highly treatable.
3|Page

5. Invasive (infiltrating) ductal carcinoma

starts in your breast milk ducts, like DCIS. Unlike DCIS,

invasive ductal carcinoma has spread to nearby tissue.
Untreated, it has the potential of spreading to other parts of
your body via your lymphatic system and bloodstream. It's the
most common type of breast cancer

Symptoms and Causes

Carcinoma, like all cancer, begins when a genetic mutation (change) transforms a normal,
healthy cell into a cancer cell. That cancer cell keeps multiplying and making more cancer cells.
Untreated, the cancer cells can invade nearby healthy tissue. Eventually, the cancer cells may
travel through your bloodstream or lymphatic system to invade other parts of your body
(metastasize).

Risk factors for adenocarcinoma are significantly varied since these types of carcinoma may
present in multiple organs, including your breast, prostate, pancreas, esophagus, colon/rectum,
stomach, lungs, etc. Common risk factors include:

 Tobacco use.
 Drinking alcohol.
 Exposure to harmful toxins.
 Previous radiation therapy.
 Genetic mutations such as BRCA, HNPCC, FAP, etc.

Basal and squamous cell carcinoma

 Excessive exposure to UV radiation (from the sun or tanning beds).

 Light-colored skin that burns or freckles easily.
 Blue or green eyes, blonde or red hair.
 An infection with a high-risk strain of HPV.
 Previous radiation therapy.
 Exposure to harmful toxins.
4|Page

Diagnosis and Tests

 Physical exam. Your provider will examine skin changes that may indicate basal cell
carcinoma or squamous cell carcinoma. Breast exams allow your provider to identify
abnormal growths or symptoms that may be signs of ductal carcinoma, like skin changes or
nipple discharge.

 Blood tests. Blood tests can detect protein levels, enzyme levels, tumor markers and other
indicators that may help your provider get closer to a diagnosis.

 Imaging. Routine imaging procedures, like a mammogram or colonoscopy, can help detect
carcinoma early. Imaging can also help your provider get closer to a diagnosis or see if your
cancer's spread. Imaging may include ultrasounds, mammograms, MRIs, CT scans, PET
scans and X-rays. Your provider may recommend specialized imaging procedures to
identify tumors impacting specific organs.

 Biopsy. A biopsy is the only way to confirm a carcinoma diagnosis. Biopsies used to
diagnose carcinoma include a shave biopsy, punch biopsy, fine-needle aspiration biopsy,
core needle biopsy, surgical lymph node biopsy, incisional biopsy and excisional biopsy.
Though the specific technique is different, all biopsies involve your provider removing
tissue that's later tested in a lab for cancer cells.

carcinoma stage
 stage 0: Cancer hasn't spread beyond where it formed. Stage 0 cancer is in situ and is
often curable with prompt treatment.
 Stage 1: The tumor is more pronounced than in stage 0. Cancer hasn't spread to nearby
tissues, organs or lymph nodes.
 Stage 2: The tumor is bigger than in stage 1 and may or may not have spread to your
lymph nodes.
 Stage 3: The tumor is larger and has spread to nearby tissues or lymph nodes.
 Stage 4: The cancer is metastatic, which means it's spread to other organs or parts of your
body.
5|Page

1.1 Management and Treatment

How is carcinoma treated?

Carcinoma treatment depends on various factors, including your overall health, stage of the
tumor, details of the biopsy report such as pathology, your age and what you want out of
treatment. Your provider will discuss a care plan with you that matches your unique situation.

a) Surgery: Your provider may remove the cancer cells or tumor and nearby healthy tissue for
safe measures. They may recommend surgery if the carcinoma is confined to one area (it
hasn't metastasized).
b) Chemotherapy: You may receive drugs that kill cancer cells or prevent them from
multiplying. Chemotherapy may accompany other treatments, like surgery or radiation. It
may be used before surgery to shrink cancer cells so that they're easier to remove (neo
adjuvant chemotherapy). It may be used afterward to prevent cancer cells from returning
(adjuvant chemotherapy).
c) Radiation therapy: Radiation uses targeted energy beams, like X-rays, to kill cancer cells or
prevent them from multiplying. It's often used in combination with surgery and
chemotherapy. Similar to chemotherapy, radiation can be used to shrink a tumor before
surgery or to kill remaining cancer cells afterward. Radiation can also help relieve
symptoms depending on the type of carcinoma.
d) Targeted therapy: This treatment uses drugs that target specific weaknesses or genetic
changes in cancer cells. Targeted therapy can zero in on these weaknesses, killing the cancer
cells or stopping them from multiplying.
e) Immunotherapy: Immunotherapy helps your immune system identify cancer cells and
eliminate them. Your provider may recommend immunotherapy alongside other treatments,
like chemotherapy.

f). Hormone therapy: Reducing the amounts of certain sex hormones circulating in your body
can slow carcinoma growth. For example, long-term exposure to estrogen has been linked to
breast cancer risk. Exposure to androgens has been linked to prostate cancer. Hormone therapy
can lessen the impacts these hormones have on cancer growth.

Depending on your diagnosis, treatment may be curative, palliative or both. The goal of curative
treatment is remission. Complete cancer remission means that the signs and symptoms of the
cancer are no longer present. Palliative care can help you manage cancer symptoms. It can also
empower you to feel more comfortable and confident with care decisions as you navigate life
with a cancer diagnosis.
6|Page

Pharmacognostic study of anti cancer drug :

Fig : anti cancer drug plant

7|Page

1.2 VINCA
Synonyms:

Vinca rosea, Catharanthus, Madagascar periwinkle. Barmasi.

Biological Source
Vinca is the dried entire plant of Catharanthus roseus Linn., belonging to family Apocynaceae.

Geographical Source

The plant is a native of Madagascar and is found in many tropical and subtropical countries especially in
India, Australia, South Africa and North and South America. The plant is cultivated as garden plant in
Europe and India.[25]

Cultivation and Collection

The plant is perennial and retains its glossy leaves throughout the winter. The plant prefers light
(sandy), medium (loamy) and heavy (clay) soils and can grow in heavy clay soil. The plant
prefers acid, neutral and basic (alkaline) soils. It can grow in full shade (deep woodland) semi
shade (light woodland) or no shade. It requires dry or moist soil and can tolerate drought. It is
cultivated either by directly sowing the seeds or sowing the seeds in nursery. Nursery sowing
method is found to be economical and the fresh seeds are sown in nursery in the month of
February or March. The seedlings attain a height of 5–8 cm after two months and then they are
transplanted in to the field at a distance of 45 cm × 30 cm. Proper fertilization and weeding is
done timely and leaves are stripped after nine months. In order to collect the whole plant, the
stems are first cut about 10 cm above the grounds and the leaves, seeds, stems are separated and
dried. The roots are collected by plugging which are later washed and dried under shade and
packed.

Characteristics

The leaves are green in colour, flowers are either violet, pinkish white or carmine red and roots are pale
grey in colour. It has characteristic odour and bitter taste. The flowers are hermaphrodite (have both male
and female organs) and are pollinated by bees. Leaves are petiolate, entire margin, ovate or oblong, glossy
appearance and with acute apex. Fruit is follicles with numerous black seeds.
8|Page

Microscopy

Vinca has dorsiventral leaf structure. Epidermis is a single layer of rectangular cells covered with thick
cuticle. It consists of uni-cellular covering trichome and cruciferous stomata. In the mesophyll region
single layer of elongated and closely packed palisade parenchyma cells are present just below the upper
epidermis. In the midrib region two to three layers of collenchyma is present, both below the upper
epidermis and above the lower epidermis. Vascular bundle consisting of xylem and phloem is present in
the middle of midrib region and rest of the intercellular spacis covered by five to eight layers of
spongy parenchyma. Calcium oxalate crystals are absent.

Chemical Constituents

Alkaloids are present in entire shrub but leaves and roots contain more alkaloids. About 90
alkaloids have been isolated from Vinca from which some like Ajmalicine, Serpentine and
Tetrahydroalstonine are known and are present in other species of Apocynaceae. The important
alkaloids in Catharanthus are the dimer indole indoline alkaloids Vinblastine and Vincristine and
they possess definite anticancer activity. Vindoline and Catharanthine are indole monomeric
alkaloids. It also contains monoterpenes, sesquiterpene, indole and indoline glycoside.

Uses

Vinblastin is an antitumour alkaloid used in the treatment of Hodgkin’s disease. Vincristine is a

cytotoxic compound and used to treat leukaemia in children. Vinca is used in herbal practice for
its astringent and tonic properties in menorrhagia and in haemorrhages generally. In cases of
scurvy and for relaxed sore throat and inflamed tonsils, it may also be used as a gargle. For
bleeding piles, it may be applied externally, as well as taken internally. It is also used in the
treatment of diabetes. The flowers of the Periwinkle are gently purgative, but lose their effect on
drying. If gathered in the spring and made into a syrup, they impart all their virtues, and this, it is
stated, is excellent as a gentle laxative for children and also for overcoming chronic constipation
in grown persons.[25]
 9|Page

Nitrogen-containing FDA-approved drugs

Table 1.1

S.N Name of drug structure Mode of action Drug

o. Target
1. Alectinib It prevents the Anaplastic
Hydrochloride multiplication of cancer lymphoma
cells by blocking the kinase
[5]
action of abnormal (ALK)
proteins Inhibitor

2. Brigatinib[6] It inhibits the ability of Anaplastic

the phosphate group to lymphoma
bind ALK and inhibits kinase
the activity of proteins (ALK)
STAT3, A.K.T., Inhibitor
ERK1/2, and S6 both in
vitro and in vivo

3. Lorlatinib[7] Inhibits will disrupt the Anaplastic

ALK and ROS1- lymphoma
mediated signaling, kinase
further inhibiting the (ALK)
growing tumor cells in Inhibitor
ALK and ROS1 cells.

4. Entrectinib[8] It interferes with the Anaplastic

growth of cancer lymphoma
cells, which are kinase
eventually
destroyed. (ALK)
Inhibitor
 10 | P a g e

5. Midostaurin It Prevents the Fms-

multiplication of cancer tyrosinekinas
cells by blocking the e (FLT3)
[9-10] action of abnormal inhibitor
proteins.

6. Osimertinib The abnormal Epidermis

protein’s ability to growth factor
mesylate [11] (EGF)
cause cancer cells to
grow is blocked, receptor
which may also help inhibitors
tumors get smaller
and slow down the
spread of cancer
cells.

7. Fruquintinib It prevents the Vascular

VEGF from causing endothelial
[12] the phosphorylation growth
of V.E.G.F.R.s 1, 2, factor
and 3, which may (VEGF)
reduce the inhibitors
proliferation,
migration, and
survival of
endothelial cells,
the development of
microvessels, and
the proliferation and
death of tumor cells.
 11 | P a g e

8. Acalabrutinib Bruton Tyrosine Kinase Tyrosine

inhibitor that stops B kinase
cells from chemotactic, inhibitor(TKI
[13] proliferating, moving, )
and adhesion of B cells

9. Trabectedin Inhibition of trans- Alkylating

activated agent
[14,15] transcription and
the interaction with
D.N.A. repair
proteins

Resistance of Tyrosine
kinase
V.E.G.F.R. inhibitor
10. Cabozantinib inhibitor
via the c-MET axis is
[16-17] decreased by
inhibiting

V.E.G.F.R. and
c-MET
12 | P a g e

2.1Alectinib Hydrochloride
Alectinib is a second generation oral drug that selectively inhibits the activity of anaplastic
lymphoma kinase (ALK) tyrosine kinase. It is specifically used in the treatment of non-small cell
lung cancer (NSCLC) expressing the ALK-EML4 (echinoderm microtubule-associated protein-
like 4) fusion protein that causes proliferation of NSCLC cells. Inhibition of ALK prevents
phosphorylation and subsequent downstream activation of STAT3 and AKT resulting in reduced
tumor cell viability.[17]

Approved under accelerated approval in 2015, alectinib is indicated for use in patients who have
progressed on or were not tolerant of crizotinib, which is associated with the development of
resistance.

Chemical properties
Alectinib hydrochloride is a white to yellow-white powder with a molecular formula of
C30H35ClN4O2 HCl. It has a pKa of 7.05 and is poorly soluble in aqueous buffers but soluble
in organic solvents.

Side effects
Apart from unspecific gastrointestinal effects such as
 Constipation (in 34% of patients)
 Nausea (22%),
Common adverse effects in studies included
 Edema (swelling; 34%),
 Myalgia (muscle pain; 31%),
 Anemia (low red blood cell count)
Sight disorders,
Light sensitivity and rashes (all below 20%).
Serious side effects occurred in 19% of patients; fatal ones in 2.8%

Interactions
Alectinib has a low potential for interactions. While it is metabolised by the liver
enzyme CYP3A4, and blockers of this enzyme accordingly increase its concentrations in the
body, they also decrease concentrations of the active metabolite M4, resulting in only a small
overall effect. Conversely, CYP3A4 inducers decrease alectinib concentrations and increase M4
concentrations. Interactions via other CYP enzymes and transporter proteins cannot be excluded
but are unlikely to be of clinical significance.
13 | P a g e

Mechanism of action
The substance potently and selectively blocks two receptor tyrosine kinase enzymes:

Anaplastic lymphoma kinase (ALK) and the RET proto-oncogene. The active metabolite M4 has
similar activity against ALK. Inhibition of ALK subsequently blocks cell signalling pathways,
including STAT3 and the PI3K/AKT/mTOR pathway, and induces death (apoptosis) of tumour
cells.

Pharmacokinetics
Proposed metabolism of alectinib. Alectinib itself and the active metabolite M4 are the main
compounds found in the circulation, while the others are minor metabolites.

When taken with a meal, the absolute bioavailability of the drug is 37%, and highest blood
plasma concentrations are reached after four to six hours. Steady state conditions are reached
within seven days. Plasma protein binding of alectinib and M4 is over 99%. The enzyme mainly
responsible for alectinib metabolism is CYP3A4; other CYP enzymes and aldehyde
dehydrogenases only play a small role. Alectinib and M4 account for 76% of the circulating
substance, while the rest are minor metabolites.[13][14]

Plasma half-life of alectinib is 32.5 hours, and that of M4 is 30.7 hours. 98% are excreted via the
faeces, of which 84% are unchanged alectinib and 6% are M4. Less than 1% are found in the
urine.

uses
In the European Union, alectinib is indicated for the first-line treatment of adults with anaplastic
lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)

In the United States, it is indicated for the treatment of people with anaplastic lymphoma kinase
(ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved
test

In April 2024, the US Food and Drug Administration (FDA) expanded the indication of
alectinib to include adjuvant treatment following tumor resection in people with anaplastic
lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), as detected by an FDA-
approved test.[21]
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2.2 Lorlatinib
Lorlatinib as an anti-cancer medication used for the treatment of non-small cell lung cancer. It
is an orally administered inhibitor of anaplastic lymphoma kinase (ALK) and C-ros oncogene
1 (ROS1), two enzymes that play a role in the development of cancer[28]

Lorlatinib is an oral inhibitor of ALK and C-rosoncogene 1 (ROS1) kinases, which disrupts
signaling and stops tumor cell growth. It can cross the blood-brain barrier, which is important
because ALK-positive lung cancers often spread to the brain.

Adverse effect
 The most common adverse reactions include
 Edema
 peripheral neuropathy
 weight gain
 cognitive effects
 Fatigue
 Dyspnea
 Arthralgia
 Diarrhea
 Mood effects
 hypercholesterolemia
 hypertriglyceridemia, and cough.

Contraindications
Lorlatinib must not be combined with strong inducers (i.e. activators) of the liver
enzymes CYP3A4/5 if it can be avoided, as serious cases of liver toxicity have been observed
under combination with the CYP3A4/5 inducer rifampicin [23]

Side effects
 The most common side effects in studies were
 High blood cholesterol (84% of patients)
 High blood triglycerides (67%)
 Edema (55%)
 Peripheral neuropathy (48%)
 Cognitive effects (29%)
 Fatigue (28%)
 Weight gain (26%)
 Mood effects (23%)
 Serious side effects led to dose reduction in 23% of patients and to termination of
lorlatinib treatment in 3% of patients
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2.3 Interactions
Lorlatinib is metabolized by the enzymes CYP3A4/5. Therefore, CYP3A4/5 inducers such
as

Rifampicin, carbamazepine or St John's wort decrease its concentrations in the blood plasma and
can reduce its effectiveness. Additionally, the combination of lorlatinib with rifampicin showed
liver toxicity in studies. Inhibitors of these enzymes such as ketoconazole or grapefruit
juice increase lorlatinib plasma concentrations, leading to higher toxicity. Lorlatinib is also a
(moderate) CYP3A4/5 inducer, so that drugs that are metabolized by these enzymes are broken
down more quickly when combined with lorlatinib. Examples
include midazolam and ciclosporin.

Interactions via other enzymes have only been studied in vitro. According to these findings,
lorlatinib may inhibit CYP2C9, UGT1A1 and several transport proteins, induce CYP2B6, and
has probably no relevant effect on CYP1A2 .

Mechanism of action
Lorlatinib is a small molecule kinase inhibitor of ALK and ROS1 as well as a number of
other kinases. It is active in vitro against many mutated forms of ALK

Pharmacokinetics
Lorlatinib is cleaved to the metabolite M8 (top left), which makes up 21% of the circulating
substance, and an undetected metabolite (given in brackets). Other phase I metabolites are given
in the bottom row. Most of these metabolites, as well as the original substance,
undergo glucuronidation.

Lorlatinib is taken by mouth and reaches highest blood plasma concentrations 1.2 hours after a
single dose, or 2 hours after ingestion when taken regularly. Its absolute bioavailability is 80.8%.

Intake with fatty food increases its availability by 5%, which is not considered clinically
significant When in the bloodstream, 66% of the substance are bound to plasma proteins.
Lorlatinib is able to cross the blood–brain barrier.

Lorlatinib is inactivated by oxidation, mainly through CYP3A4, and by glucuronidation, mainly

through UGT1A4. Other CYPs and UGTs play a minor role. Lorlatinib and its metabolites are
excreted with a half-life of 23.6 hours after a single dose; 47.7% into the urine (of which less
than 1% in unchanged form), and 40.9% into the faeces (9.1% unchanged).[28]

uses
Lorlatinib is indicated for the treatment of adults with metastatic non-small cell lung cancer
whose tumors are anaplastic lymphoma kinase (ALK)-positive
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2.4 Trabectedin
Trabectedin belongs to a group of medicines known as 'anti-cancer' used to treat various cancers,
including ovarian cancer and soft tissue sarcoma. Cancer is a condition where cells in a specific
body part grow and reproduce uncontrollably. Breast cancer is cancer that forms in the cells of
the breasts. A liposarcoma is a rare cancer that develops in your fatty tissue.[31,32]

Trabectedin contains Trabectedin, which works by sticking to the DNA in cells and damaging it.
This stops the cancer cells from growing and multiplying.

Trabectedin, sold under the brand name Yondelis, is an antitumor chemotherapy medication for
the treatment of advanced soft-tissue sarcoma and ovarian cancer[29-30]

The most common adverse reactions include

 Nausea
 Fatigue
 Vomiting
 Constipation
 decreased appetite
 diarrhea
 peripheral edema
 dyspnea, and headache.

Mechanism of Action

Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which
bends towards the major groove. In this manner, it is thought that the drug affects various transcription
factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair
system.

Trabectedin blocks the cell cycle at the G2 phase, while cells at the G1 phase are most sensitive to the
drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-
glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is
also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it
could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as
lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these
indications.
17 | P a g e

Pharmacodynamics

Two of the rings in the drug's structure allows it to covalently bind to the minor groove of DNA.
The third ring protrudes from the DNA which lets it interact with nearby nuclear proteins. This
has the additive effect of blocking cell division at the G2 phase
Drug Interactions
Drug-Drug Interactions: Trabectedin interacts with immunomodulatory medication (e.g.
baricitinib, fingolimod), antifungal infections (e.g. ketoconazole), vaccinations (e.g. BCG
Vaccine, mumps virus vaccine, rotavirus vaccine), and antipsychotic medications (e.g.
Clozapine).
Drug-Food Interactions: Do not drink grapefruit juice or alcoholic beverages while you are being
treated with Trabectedin. It can affect the way the medicine works.
Drug-Disease Interactions: Trabectedin may potentially interact with various disease conditions,
including infections (bacterial/fungal/protozoal/viral) and severe hepatic and renal impairment.

Trabectedin, also known as Yondelis, is a chemotherapy drug used to treat certain types of
cancer:
Soft tissue sarcoma
Trabectedin is used to treat liposarcoma or leiomyosarcoma that has spread to other parts of the
body or cannot be removed by surgery. It's used in patients who have already been treated with
anthracycline chemotherapy.
Ovarian cancer
Trabectedin is used to treat relapsed ovarian cancer in combination with another chemotherapy
drug called liposomal doxorubicin.
Trabectedin is an alkylating agent that slows or stops the growth of cancer cells. It works by
binding to DNA, which blocks cell division at the G2 phase.

Storage
Store in a cool and dry place away from sunlight
18 | P a g e

2.5 Cabozantinib
A drug used alone or with other drugs under the brand name Cabometyx to treat certain types of
hepatocellular carcinoma (a type of liver cancer), renal cell carcinoma (a type of kidney cancer),
and differentiated thyroid cancer and under the brand name Cometriq to treat certain types of
medullary thyroid cancer. Cabozantinib-s-malate is also being studied in the treatment of other
types of cancer. It blocks certain proteins, which may help keep cancer cells from growing. It
may also prevent the growth of new blood vessels that tumors need to grow. Cabozantinib-s-
malate is a type of tyrosine kinase inhibitor and a type of angiogenesis inhibitor.[33]

Pharmacodynamics

Cabozantinib is a potent inhibitor of VEGFR 2 and MET in multiple tumor models in vivo, and it
results in blockade of phosphorylation of oncogenic mutant RET in human xenografts models of
medullary thyroid cancer . It also inhibits ROS1, FLT3 and AXL

In preclinical models cabozantinib blocked angiogenesis, metastasis and induced tumor

regression in multiple tumor models including RCC, MTC, lung cancer, breast cancer,
neuroblastoma, hepatocellular carcinoma, colorectal carcinoma and gastrointestinal stromal
cancers.

In the phase III MTC trial the effect of cabozantinib at the 140 mg daily dose on the QTc interval
was evaluated. A mean increase in QTc of 10 – 15 ms was observed at 4 weeks after initiating
cabozantinib. A concentration and QTc relationship could not be definitively established.
Changes in cardiac wave form morphology or new rhythms were not observed. No cabozantinib
treated patients in this study had a confirmed QTc > 500 ms and nor did any cabozantinib-treated
patients in the RCC study (at a dose of 60 mg.)
Pharmacokinetics

Cabozantinib is commercially available in 2 formulations; the capsule called Cometriq is

approved for medullary thyroid cancer and the tablet called Cabometyx is approved for
metastatic RCC. Cabometyx (tablet, used in RCC) did not meet bioequivalence criteria of 80–
125% of Cmax level achieved by Cometriq (capsule used in medullary thyroid cancer). This is
likely secondary to differences in rates of absorption in healthy volunteers which were noted to
be higher in the tablet formulation than in the capsule by 19% and the upper limit of the
confidence interval was 131.5% which lay beyond the range of 125% [32]. In a subsequent study
a dose proportional increase in levels was observed with dose escalation ranging from 20mg,
40mg to 60mg daily dose tablets.
19 | P a g e

Single dose pharmacokinetics were evaluated in 8 patients with mild or moderate liver
dysfunction and in 10 patients with mild or moderate renal impairment [33]. Comparisons of
levels to matched controls with normal function showed an increase of upto 31% in renal
impairment cases and 81% in hepatic dysfunction. No clear trends for increased risk of toxicities
were noted but extreme caution and close monitoring for adverse events is advised if
cabozantinib is used in patients with mild or moderate renal or liver impairment. In severe
hepatic or renal dysfunction, no safety data is available.

A food effect study revealed that a high fat meal can increase the Cmax by about 40% and hence
administration in a fasting state (at least 2 hours after and 1 hour before a meal) is recommended.

Proton pump inhibitors did not significantly impact drug levels and hence can be used in
conjunction with cabozantinib . Cabozantinib was shown to be substrate for CYP3A4. It was
studied with a strong CYP3A4 inhibitor; ketoconazole which led to significantly increased
plasma levels of cabozantinib. Thus a reduced starting dose is recommended when concurrently
administered with a potent CYP3A4 inhibitor. Examples of potent inhibitors are protease
inhibitors such as antivirals atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir,
saquinavir and tipranavir and antifungals like ketoconazole and itraconazole. Of note other
moderate inhibitors of CYP3A4 include amiodarone and grape fruit juice. A dose decrease of 20
mg is advised if these medications have to be administered concurrently with Cabozantinib.

Strong inducers of CYP3A4 like rifampin and phenytoin also have a significant effect on
reducing cabozantinib levels and possibly decreasing its efficacy. A dose increase by 20 mg in
the daily dose is recommended when the patient is anticipating receiving cabozantinib is treated
with a concurrent CYP3A4 inducer. Dexamethasone, St Johns wort, nafcillin and carbamazepine
are among the other most notable examples of inducers.

Dose modification with co administration of strong inhibitors and inducers of CYP3A4 is

specific for the US labeling of Cabozantinib but these drug interactions should be considered
during clinical management worldwide.

USES:

This medication is used to treat various types of cancer (including kidney, thyroid, liver cancer).
Cabozantinib belongs to a class of drugs known as tyrosine kinase inhibitors. It works by
slowing or stopping the growth of cancer cells.[34]
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2.6 Fruquintinib

Colorectal cancer (CRC) is the third most common malignant tumor worldwide, and its
mortality is second only to lung cancer
(1). More than 20% of patients have metastasis at the time of initial diagnosis, most of them have
unrespectable tumors, and 25% of patients will develop metastasis after radical surgery .
(2). Standard treatment for these patients includes chemotherapy based on cytotoxic drugs (fluorouracil,
oxaliplatin, irinotecan) and targeted therapy for vascular endothelial growth factor (VEGF; bevacizumab)
and epidermal growth factor receptor (EGFR; cetuximab)
(3). However, it is a pity that most patients with MCRC still have disease progression after first-or
second-line standard treatment. At present, the choice of drugs for third-line or post-line treatment of
MCRC is very limited[35]

Fruquintinib, sold under the brand name Fruzaqla, is an anti-cancer medication used for the treatment
of colorectal cancer.[6] Fruquintinib is a kinase inhibitor. It is taken by mouth.

The most common adverse reactions include

a) Hypertension
b) Palmar-plantar erythrodysesthesia
c) Proteinuria
d) Dysphonia
e) Abdominal pain
f) Diarrhea, and asthenia.

Mechanism of action

Fruquintinib is a tyrosine kinase inhibitor (TKI) that works by blocking the VEGF-1, -2, and -3
receptors:
Fruquintinib is a highly selective oral TKI that targets the VEGF receptors. It inhibits the
activity of these receptors, which are involved in tumor angiogenesis, growth, and progression.
Pharmacodynamics
In vitro studies showed fruquintinib inhibited VEGF-mediated endothelial cell proliferation and tubular
formation, while in vivo studies demonstrated fruquintinib-mediated tumor growth inhibition in a tumor
xenograft mouse model of colon cancer. Inhibition of VEGF-induced VEGFR-2 phosphorylation was
illustrated in both in vitro and in vivo studies. Fruquintinib exposure-response relationships and the time
course of pharmacodynamic response are unknown. A mean increase in QTc interval >20 milliseconds
(ms) was not observed at the approved recommended dosage.
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Pharmacokinetics
The fruquintinib steady-state geometric mean (% coefficient of variation [CV]) maximum
concentration (Cmax) is 300 ng/mL (28%) and area under the concentration-time curve for the
dosing interval (AUC0-24h) is 5880 ng∙h/mL (29%) at the recommended dosage. The
fruquintinib Cmax and AUC0-24h are dose-proportional across the dosage range of 1 to 6 mg
(0.2 to 1.2 times the recommended dosage). Fruquintinib steady state is achieved after 14 days
with a mean AUC0-24h accumulation of 4-fold. Absorpt.

USES

FRUZAQLA is a kinase inhibitor indicated for the treatment of adult patients with metastatic
colorectal cancer (MCRC) who have been previously treated with fluoropyrimidine-,
oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type
and medically appropriate, an anti-EGFR therapy

DOSAGE AND ADMINISTRATION

The recommended dose of FRUZAQLA is 5 mg orally once daily, with or without food for the first
21 days of each 28-day cycle.

DRUG INTERACTIONS

Effects of Other Drugs on FRUZAQLA Strong CYP3A Inducers Avoid concomitant use of drugs
that are strong CYP3A inducers with FRUZAQLA.
Concomitant use with a strong CYP3A inducer may decrease fruquintinib Cmax and AUC
which may reduce the efficacy of FRUZAQLA.
Moderate CYP3A Inducers If possible, avoid concomitant use of drugs that are moderate
CYP3A inducers with FRUZAQLA. If it is not possible to avoid concomitant use of a moderate
CYP3A inducer and fruquintinib, continue to administer FRUZAQLA at the recommended dosage.
Concomitant use with a moderate CYP3A inducer may decrease fruquintinib Cmax and AUC
which may reduce the efficacy of FRUZAQLA.
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