CONVENTIONAL

ANTICANCER
CHEMOTHERAPY (PART 2)

John Tiong
Platinum-based antineoplastic agents
 Cisplatin
 Cisplatin (cis-platinum (II) diaminedichloride) was the first platinum-
based drug with antitumour activity introduced clinically.
 Applications:
 First line: Cisplatin, usually in combination with other drugs, is being used
against cancers of the lung, head-and-neck, colon, testis, ovaries, uterus.
 E.g: Bleomycin, in combination with cisplatin is important as part of the
potentially curative combination chemotherapy of advanced testicular
carcinomas.
 E.g. Paclitaxel in combination with cisplatin is used in the treatment of
ovarian and lung cancers
 Second-line treatment: Against most other advanced cancers such as cancers
of the breast, pancreas, liver, kidney, prostate as well as against metastatic
melanomas.
 Cisplatin
Pharmacokinetics:
 The hydrolysis of cisplatin to the
active aquated species is
significantly inhibited in the
plasma due to the relatively high
concentration of chloride ions
present in the plasma.
 Cisplatin enters the cell by
passive diffusion and undergoes
hydrolysis to the active aquated
species due to the low
intracellular concentration of
chloride ions.
 The aquated form can then
chemically react with nuclear
DNA.
Cisplatin
 The in vivo antitumour activity of cisplatin is not mediated directly by
the cisplatin molecule itself but rather by the active aquated species
cis-[Pt(NH3)2Cl(OH2)]+ formed once the cisplatin enters the cell.
 The reactive form of cisplatin, cis-[Pt(NH3)2Cl(OH2)]+, preferentially
reacts with the N7 position of the imidazole ring of guanine or
adenine to form a mono-adduct.
 The second chlorine group is then subsequently hydrolysed in situ
and 1,2-intrastrand guanine-platinum-guanine or guanine-platinum-
adenosine adducts are formed that can block replication and/or
prevent transcription.
 A small percentage of other adducts are also formed by the
aquated cisplatin species (e.g. 1,3-intrastrand, inter-strand and
mono-platinum adducts) but these are not thought to be of clinical
importance.
Cisplatin
Cisplatin
 Despite its clinical success against a range of tumour types, a
number of clinical limitations have become apparent. Cisplatin
is toxic and causes:
 Severe nephrotoxicity if the patient is not adequately
hydrated prior to therapy (hydration promotes diuresis and
minimises toxicity monitoring of renal function is essential)
 Severe nausea and vomiting

 Neurotoxicity

 Ototoxicity

 Myelosuppression.
Lipoplatin
 Lipoplatin is a liposomal preparation of cisplatin using
nanoparticle technology. The Lipoplatin formulation is based
on the formation of reverse micelles between cisplatin and
dipalmitoyl phosphatidyl glycerol (DPPG)

 It has enhanced therapeutic efficacy compared to cisplatin due

to maximized tumour uptake and penetration.

 It has reduced side effects due to minimal toxic exposure of

normal tissues to its cytotoxic properties. The toxicities, in
particular nephrotoxicity, neurotoxicity and myelotoxicity, was
significantly lower with lipoplatin compared to cisplatin.
 Factors contributing to enhanced therapeutic effect
and reduced toxicity:

 Longer half life due to the liposomal preparation which evade immune
destruction of the drug.

 The tumour uptake of lipoplatin results from the preferential

extravasation of the 100-nm liposome nanoparticles through the leaky
vasculature of tumours. This will result in 2- to 40-fold higher
concentrations compared to the adjacent normal tissue in human
studies.

 One additional mechanism for the higher accumulation of lipoplatin in

tumour tissue, compared to normal tissue, arises from the higher uptake
of lipoplatin nanoparticles by tumours presumably arising from a more
avid phagocytosis by tumour cells. This second mechanism results in an
average of 5- to 10-fold higher uptake of lipoplatin by tumour cells,
compared to normal cells in human studies giving an overall 10 to
400-fold higher tumour cell uptake and binding to macromolecules.
Carboplatin
 Carboplatin was the second platinum (II) analogue to enter
clinical practice.

 Carboplatin has been shown to have comparable activity to

cisplatin in ovarian cancer and it is widely used in the
treatment of ovarian cancer and lung cancer. However,
cisplatin still has superior activity against testicular cancer
and head and neck cancers.

 Most tumors that are resistant to cisplatin are cross-resistant

to carboplatin.
Carboplatin vs cisplatin
 The slower formation of the aquated species from carboplatin
appears to significantly reduce its clinical toxicity and it is
better tolerated than cisplatin.

 At therapeutic doses:
 Less nausea, vomiting, nephrotoxicity (no pre-hydration is necessary),
neurotoxicity, ototoxicity compared with cisplatin
 More pronounced myelosuppression

 The reduced toxicity of carboplatin means that more aggressive

treatment regimens can be pursued compared to cisplatin.

 The main clinical limitation of carboplatin is that it is still only

active against the same range of tumours as cisplatin.
 Oxaliplatin
 Oxaliplatin (oxalatoplatinum (II)) represents the last platinum (II)
compound to enter clinical practice.

 It has extended antitumour activity compared to cisplatin, particularly

against colorectal cancers where in combination with 5-fluorouracil
and folinic acid it has doubled the response rate.

 The toxicity profile of oxaliplatin is dramatically different to that of

cisplatin and carboplatin:
 Oxaliplatin does not exhibit nephrotoxicity and myelosuppression.
 Nausea and vomiting is minimal and can be readily controlled by antiemetics.
 The major side-effect observed is its ability to cause neurological toxicity,
specifically cold-related dysaesthesia (impairment of sensitivity especially to
touch) and paraesthesia (pins and needles). However these appear largely
reversible upon cessation of therapy.

Anticancer antibiotics
 Anticancer antibiotics
 Clinically useful cytotoxic drugs of microbial origin, sometimes called
‘cytotoxic antibiotics’ (even though they are not used as antiinfectives!),
originate from Streptomyces spp. They are generally classified as cell
cycle non-specific.

 They are vesicant  administered via intravenous infusion (cause tissue

necrosis therefore must not be injected intramuscularly or subcutaneously)

 Daunorubicin was the first anthracycline isolated from S. peucetius in

1962. Five years later, another natural product, doxorubicin (the 14-
hydroxy derivative of daunorubicin) was isolated. This apparently minor
chemical difference transformed it into the most widely used
anthracycline used today.
 Anticancer antibiotics
 Doxorubicin
 extensively employed against leukaemias, lymphomas and a
variety of solid tumours (e.g. ovarian cancer, metastatic breast
cancer).
 Mechanism of action:
 Doxorubicin binds tightly to DNA strands by its ability to intercalate between base
pairs via a methylene bridge formed from formaldehyde generated in the cell. The
DNA intercalating agent forms a stable ternary DNA– topoisomerase II – drug
complex, that results in inhibition of topoisomerase-catalysed DNA relaxation,
diminishing DNA synthesis  causing cell death
 Intercalation also results in steric hindrance, hence production of single-strand breaks
in DNA and inhibition of DNA synthesis and DNA-dependent RNA synthesis.
 Other action: Interacts with molecular oxygen, producing superoxide ions and
hydrogen peroxide, which cause single-strand breaks in DNA. In particular, the
cardiac toxicity of anthracyclines may result from the generation of free radicals of
oxygen.
Anticancer antibiotics
 Doxorubicin:
 Doxorubicin is known to cause myelosuppression.
 Acutely, doxorubicin may cause irreversible dose-
dependent cardiac arrhythmias and depression of
myocardial function. Patients who have received a total
cumulative dose over 450mg/m2 body surface area are at
greater risk of having a potentially fatal heart failure
induced by the affinity of the drug for the cardiac muscle.
This effect is less common in idarubicin and epirubicin
Anticancer antibiotics
 Idarubicin
 Its mechanisms of action and adverse effects are similar to those
of doxorubicin and daunorubicin.
 It is used in acute leukaemias and for advanced breast cancer.

 Epirubicin
 This has led to anticancer activity similar to doxorubicin but with
less cardiotoxicity.
 Epirubicin is used in breast cancer and the maximum
recommended cumulative dose is 900-1000mg/m2 body surface
area.
Anticancer antibiotics
 Dactinomycin
 It is known to bind non-covalently to double-strand DNA by
partial intercalation, inhibiting DNA-directed RNA synthesis
 Therapeutic applications:
 It is used in combination with surgery and vincristine for the treatment
of Wilms tumor.
 In combination with MTX, dactinomycin is effective in the treatment of
gestational choriocarcinoma.
 The major side effects of dactinomycin are severe nausea,
vomiting, and dose-limiting myelosuppression.
 The drug is carcinogenic
 Anticancer antibiotics
 Bleomycin
 Mechanism of action:
 Bleomycin binds to DNA via intercalation
mechanism
 The drug produces both single- and double-
strand scission and fragmentation of DNA.
 It is thought that the bleomycins, which are
avid metal-chelating agents, form a
bleomycin–Fe2+ complex that can donate
electrons to molecular oxygen, thus forming
the superoxide and hydroxyl free radicals.
It is these highly reactive intermediates that
attack DNA and produce DNA strand
breakage and maximum cytotoxicity in the
late G2 and early M-phases of the cell cycle.
Anticancer antibiotics
 Bleomycin
 Therapeutic applications:
 Bleomycin is important as part of the potentially curative combination
chemotherapy for advanced testicular carcinomas.
 Bleomycin is used in some regimens for the treatment of Hodgkin’s
and non-Hodgkin’s lymphomas
 Bleomycin hydrolase, which inactivates bleomycin is an enzyme
that is abundant in liver and kidney but virtually absent in
lungs and skin; the latter two organs are the major targets of
bleomycin toxicity. It is thought that bleomycin-induced dermal
and pulmonary toxicities are related to the persistence of
relatively high local concentrations of active drug.
 A potentially fatal lung toxicity occurs in 10 to 20% of patients
receiving bleomycin.
 Bleomycin is unusual in the sense that mylosuppression is rare
Tyrosine kinase inhibitors
Tyrosine kinase inhibitors
 The tyrosine kinases are a family of enzymes that are involved
in several important processes within a cell, including signal
transduction and cell division.
 Tyrosine kinase inhibitors can inhibit the growth of cancers
associated with deregulated tyrosine kinases.

 Imatinib, dasatinib, and nilotinib

 Indicated for treatment of chronic myelogenous leukemia

 Erlotinib
 It is approved for the treatment of non–small cell lung cancer and
pancreatic cancer
Hormonal therapy in cancer
Hormonal therapy in cancer
 Hormonal therapy is one of the major modalities of medical
treatment for cancer, others being cytotoxic chemotherapy and
targeted therapy (biotherapeutics).

 Tumours that are steroid hormone-sensitive may be either:

 hormone responsive, in which the tumour regresses following treatment
with a specific hormone
 hormone dependent, in which removal of a hormonal stimulus causes
tumour regression

 Removal of hormonal stimuli from hormone-dependent tumours can

be accomplished by surgery (for example, in the case of
orchiectomy -surgical removal of one or both testes for patients with
advanced prostate cancer) or by drugs (for example, in breast
cancer, for which treatment with the antiestrogen, tamoxifen is used
to prevent estrogen stimulation of breast cancer cells)
Prednisone
 Prednisone is a potent, synthetic, anti-inflammatory
corticosteroid.

 The use of this compound in the treatment of lymphomas arose

when it was observed that patients with Cushing syndrome,
which is associated with hypersecretion of cortisol, have
lymphocytopenia and decreased lymphoid mass.

 Prednisone is primarily employed to induce remission in

patients with acute lymphocytic leukemia and in the treatment
of both Hodgkin and non-Hodgkin lymphomas.
Prednisone
Mechanism of action:
 Prednisone itself is inactive and must first be reduced to
prednisolone by 11-ß-hydroxysteroid dehydrogenase.
 This steroid then binds to steroid receptor that causes a

decrease in eosinophils, basophils, monocytes, and

lymphocytes in the circulation.
 The decrease in circulating lymphocytes and
macrophages compromises the body’s ability to fight
infections. However, this property is important in the
treatment of leukemia.
Prednisone
Resistance
 Resistance is associated with an absence of the receptor protein or a
mutation that lowers receptor affinity for the hormone.
 However, in some resistant cells, a receptor-hormone complex is formed,
although a stage of gene expression is apparently affected.

Adverse effects:
 It can predispose to infection (due to its immunosuppressant action) and to
ulcers.
 Other effects include hyperglycemia, cataract formation, glaucoma,
osteoporosis, and change in mood (euphoria or psychosis).
 HPA-axis suppression
Estrogen receptors targeted therapeutics
Estrogen receptor targeted
therapeutics
 Estrogens are implicated in the development or progression
of numerous diseases, which include but are not limited to:
 various types of cancer (breast, ovarian, endometrial etc),
 osteoporosis,
 cardiovascular disease,
 insulin resistance,
 endometriosis, and
 etc

 In many of these diseases, estrogens mediate their effects

through the estrogen receptor (ER), which serves as the basis
for many therapeutic interventions.
Mechanism of action of estrogen
 After dissociation from their binding sites on sex hormone–
binding globulin or albumin in the plasma, steroid hormones
diffuse across the cell membrane and bind with high affinity to
specific nuclear-receptor proteins.

 The activated steroid-receptor complex interacts with nuclear

chromatin to initiate hormone-specific RNA synthesis.

 This results in the synthesis of specific proteins that mediate a

number of physiologic functions
Selective Estrogen-Receptor
Modulators (SERMs)
 SERMs are a class of estrogen-related compounds that
interact at estrogen receptors but have different effects
depending on the tissues i.e. exhibiting selective agonism
or antagonism according to the tissue type.

 Anticancer hormones used include:

 Tamoxifen
 Toremifene
 Raloxifene
 Tamoxifen
 Normal breast growth is stimulated by estrogen

 Tamoxifen is an anti-estrogen used for first line therapy in the treatment of

estrogen receptor-positive breast cancer.

 Tamoxifen has weak estrogenic activity, and it is classified as a selective

estrogen-receptor modulator (SERM).

 It also finds use prophylactically in reducing breast cancer occurrence in women

who are at high risk. However, because of possible effects stimulating
premalignant lesions due to its estrogenic properties, tamoxifen is currently
approved only for 5 years of use.

 Another SERM that has been approved for advanced breast cancer in
postmenopausal women is toremifene which has similar efficacy and side effects
to tamoxifen
Tamoxifen
Mechanism of action:
 Tamoxifen binds to the estrogen receptor, but the complex fails to
induce estrogen-responsive genes, and RNA synthesis does not ensue.
 The result is a depletion (down-regulation) of estrogen receptors,
and the growth-promoting effects of the natural hormone and other
growth factors are suppressed.
 The action of tamoxifen is not related to any specific phase of the
cell cycle.
Tamoxifen
 The presence of estrogen receptors (ER) in biopsies of
breast cancers is a good predictor of responsiveness to
tamoxifen therapy:
 60% of women with ER-positive tumors will have a remission,
as opposed to fewer than 10% with ER-negative tumours.
 Overall, 35 to 40% of women with breast cancer will
respond to some degree, with antitumor effects lasting an
average of 9 to 12 months.
 Complete remissions may occur in 10 to 15% of patients
and may last several months to a few years.
 Therapy should be continued for at least 6 weeks to
establish efficacy.
Tamoxifen
Resistance:
 Resistance is associated with a decreased affinity for the receptor or
the presence of a dysfunctional receptor.

Adverse effects:
 Side effects caused by tamoxifen are similar to the effects of
natural estrogen, including hot flashes, skin rash, vaginal bleeding,
and discharge (due to some slight estrogenic activity of the drug
and some of its metabolites).
 Tamoxifen has the potential to cause endometrial cancer.

 Because of a more favourable adverse effect profile, aromatase

inhibitors are making an impact in the treatment of breast cancer
Raloxifene
 Raloxifene is a second-generation SERM that is related to tamoxifen.

 Like tamoxifen, raloxifene also exhibits antagonism of estrogen

receptors in the breast tissue.

 In addition, raloxifene decreases bone resorption and overall bone

turnover.

 Bone density is increased, and vertebral fractures are decreased.

 Unlike estrogen and tamoxifen, raloxifene apparently has little to no

effect on the endometrium and, therefore, may not predispose to
uterine cancer.
Raloxifene
 It is indicated for the treating and preventing of osteoporosis
(bone thinning) in postmenopausal women. It is also used to
reduce the risk of invasive breast cancer in postmenopausal
women.

 The use of raloxifene is associated with the risk of thrombosis.

Aromatase inhibitors
 Aromatase
 Before menopause, ovarian aromatase is responsible for the majority of
circulating estrogen and is exquisitely sensitive to changes in luteinising
hormone (LH). Following menopause, aromatase in fat and muscle may be
responsible for much of the circulating estrogen.

 Aromatase in highly estrogen-sensitive tissues, such as the breast, uterus,

vagina etc provides local estrogen in an autocrine fashion

 The exquisite sensitivity of the ovarian aromatase promoter to gonadotrophins,

which increase dramatically after aromatase inhibitor (AI) administration,
makes AIs less effective in inhibiting ovarian estrogen production. Thus, AIs are
generally not given to premenopausal women for breast cancer treatment
without the addition of a medication to suppress the rise in gonadotrophins
and subsequent increase in hormone levels
 Anastrozole and letrozole
 The imidazole aromatase inhibitors, such as anastrozole and letrozole are
nonsteroidal.
 They inhibit aromatization by greater than 96 percent.
 They are devoid of the androgenic side effects that occur with the steroidal
aromatase inhibitors.

 Although anastrozole and letrozole are considered to be second-line

therapy after tamoxifen for hormone-dependent breast cancer in the
United States, they have become first-line drugs in other countries for the
treatment of breast cancer in post-menopausal women.

 They are orally active and cause almost a total suppression of estrogen
synthesis.

 They are cleared primarily by liver metabolism.

Exemestane
 A steroidal, irreversible inhibitor of aromatase, exemestane, is
orally well absorbed and widely distributed.

 Because the metabolites are excreted in urine, doses of the

drug must be adjusted in patients with renal failure.

 Its major toxicities are nausea, fatigue, and hot flashes. Acne
and hair changes also occur.
Progestins
Megestrol
 Megestrol acetate was formerly the progestin used most
widely in treating metastatic hormone-responsive breast and
endometrial neoplasms.

 It is orally effective.

 Other agents are usually compared to it in clinical trials.

 However, the aromatase inhibitors are replacing it in therapy.

Leuprolide and goserelin
 GnRH is normally secreted by the hypothalamus and stimulates the
anterior pituitary to secrete the gonadotropic hormones; luteinizing
hormone (LH), the primary stimulus for the secretion of testosterone
by the testes; LH and follicle-stimulating hormone (FSH), which
stimulates the secretion of estrogen.

 The synthetic nonapeptides, leuprolide and goserelin are analogs of

GnRH.

 As GnRH agonists, they occupy the GnRH receptor in the pituitary,

which leads to its desensitization and, consequently, inhibition of
release of FSH and LH. Thus, both androgen and estrogen syntheses
are reduced
Leuprolide and goserelin
 Response to leuprolide in prostatic cancer is equivalent to that
of orchiectomy with regression of tumour

 These drugs have some benefit in premenopausal women with

advanced breast cancer and have largely replaced estrogens
in therapy for prostate cancer.

 Leuprolide is available as:

 sustained-release preparation,
 subcutaneous,
 depot intramuscular injection to treat metastatic carcinoma of the
prostate.
Leuprolide and goserelin
 Goserelin acetate is implanted intramuscularly.

 Levels of androgen may initially rise but then fall to castration

levels.

 The adverse effects of these drugs, including impotence, hot

flashes, and tumor flare, are minimal compared to those
experienced with estrogen treatment.
 Estrogens
 Estrogens, such as ethinyl estradiol or diethylstilbestrol, had been used in
the treatment of prostatic cancer. However, they have been largely
replaced by the GnRH analogs because of fewer adverse effects.

 Estrogens inhibit the growth of prostatic tissue by blocking the production

of LH, thereby decreasing the synthesis of androgens in the testis. Thus,
tumours that are dependent on androgens are affected.

 Estrogen treatment can cause serious complications, such as

thromboemboli, myocardial infarction, strokes, and hypercalcemia.

 Men who are taking estrogens may experience gynecomastia and

impotence.
 Estramustine
 Estramustine phosphate sodium (Emcyt) is a hybrid structure combining
estradiol and a nitrogen mustard in a single molecule.

 The drug has been approved for use in prostatic carcinomas and will
produce clinical remissions in one-third of patients who have failed to
respond to previous estrogen therapy.

 The mechanism of action of estramustine is not well defined, but it does not
appear to require either alkylation of DNA or the presence of estrogen
receptors in tumor cells.

 The toxicities of the drug are similar to those of estrogen therapy: breast
tenderness and enlargement (gynecomastia), fluid retention and an
increased risk of thrombophlebitis and pulmonary embolism. The drug is
not myelosuppressive
Flutamide, nilutamide, and
bicalutamide
 Flutamide, nilutamide and bicalutamide are synthetic, nonsteroidal
antiandrogens used in the treatment of prostate cancer.

 They compete with the natural hormone for binding to the androgen
receptor and prevent its translocation into the nucleus.

 Flutamide is metabolized to an active hydroxy derivative that binds

to the androgen receptor. Flutamide blocks the inhibitory effects of
testosterone on gonadotropin secretion, causing an increase in serum
LH and testosterone levels.

 Therefore, flutamide is always administered in combination with

leuprolide or goserelin, which can desensitize the hypothalamus-
pituitary axis.
Flutamide, nilutamide, and
bicalutamide
 Nilutamide and bicalutamide have similar action to flutamide.

 These antiandrogens are taken orally. [Note: Flutamide

requires dosing three times a day and the others once a day.]

 These agents are cleared through the kidney. Side effects

include gynecomastia and GI distress, and, in the case of
flutamide, liver failure could occur.

 Nilutamide can cause visual problems

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