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A Textbook of Clinical Pharmacology and Therapeutics

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384 CANCER CHEMOTHERAPY<br />

OESTROGENS<br />

Oestrogens are little used in the current management <strong>of</strong> prostatic<br />

carcinoma, because <strong>of</strong> the availability <strong>of</strong> gonadotrophinreleasing<br />

hormone (GnRH) analogues to suppress testosterone.<br />

ANTI-OESTROGENS<br />

Therapy for hormone receptor-positive breast cancers includes<br />

the use <strong>of</strong> selective oestrogen receptor modulators (SERM),<br />

selective oestrogen receptor downregulators (SERD) <strong>and</strong> aromatase<br />

inhibitors.<br />

Selective oestrogen receptor modulators (SERMs)<br />

<strong>and</strong> selective oestrogen receptor downregulators<br />

(SERDs)<br />

Tamoxifen (Chapter 41) is the lead compound in the SERM<br />

class (others include raloxifene). It is used to treat oestrogen<br />

receptor-positive breast cancer <strong>and</strong> may be used as prophylaxis<br />

against breast cancer in high-risk patients. It is given<br />

orally once or twice a day <strong>and</strong> metabolized by CYP2D6 <strong>and</strong> 3A<br />

to active metabolites (e.g. endoxifen). Tamoxifen <strong>and</strong> its<br />

metabolites are competitive inhibitors <strong>of</strong> oestrogen binding to<br />

its receptor. Adverse effects include hot flushes, hair loss, nausea<br />

<strong>and</strong> vomiting, menstrual irregularities, an increased incidence<br />

<strong>of</strong> thrombo-embolic events, <strong>and</strong> a two- to three-fold<br />

increased incidence <strong>of</strong> endometrial cancer in post-menopausal<br />

women.<br />

Fulvestrant is one example <strong>of</strong> the SERD class. It purportedly<br />

has an improved safety pr<strong>of</strong>ile, faster onset <strong>and</strong> longer<br />

duration <strong>of</strong> action than SERMs. It is given as a monthly injection.<br />

Common adverse effects are nausea, fatigue, injection<br />

reactions <strong>and</strong> hot flushes.<br />

Aromatase inhibitors<br />

This class <strong>of</strong> agents, for example anastrazole (letrozole), is<br />

used to treat early <strong>and</strong> advanced-stage oestrogen receptorpositive<br />

breast cancer. Original members <strong>of</strong> this class were<br />

aminoglutethimide <strong>and</strong> formestane. Anastrazole is given<br />

orally <strong>and</strong> metabolized by CYP3A <strong>and</strong> glucuronidation to<br />

inactive metabolites. Anastrazole acts by reversibly binding<br />

to the haem moiety <strong>of</strong> the CYP19 gene product. This is the aromatase<br />

enzyme responsible in many tissues (including breast<br />

tissue) for converting <strong>and</strong>rostenedione <strong>and</strong> testosterone to<br />

oestrogen. Adverse effects are less frequent than with tamoxifen,<br />

but include hot flushes, menstrual irregularities,<br />

thrombo-embolic events <strong>and</strong> endometrial cancer.<br />

PROGESTOGENS<br />

Endometrial cells normally mature under the influence <strong>of</strong><br />

progestogens <strong>and</strong> some malignant cells that arise from the<br />

endometrium respond in the same way. About 30% <strong>of</strong> patients<br />

with disseminated adenocarcinoma <strong>of</strong> the body <strong>of</strong> the uterus<br />

respond to a progestogen, such as megestrol. Progestogen<br />

bound to its receptor impairs the regeneration <strong>of</strong> oestrogen<br />

receptors <strong>and</strong> also stimulates 17-β-oestradiol dehydrogenase,<br />

the enzyme that metabolizes intracellular oestrogen. These<br />

actions may deprive cancer cells <strong>of</strong> the stimulatory effects <strong>of</strong><br />

oestrogen. There is also probably a direct cytotoxic effect at high<br />

concentrations. Other progestogens that are used include<br />

norethisterone <strong>and</strong> hydroxyprogesterone. There are no important<br />

toxic effects <strong>of</strong> progestogens that are relevant to cancer<br />

chemotherapy (Chapter 41).<br />

GLUCOCORTICOSTEROIDS<br />

Glucocorticosteroids (see Chapters, 33, 40 <strong>and</strong> 50) are cytotoxic<br />

to lymphoid cells <strong>and</strong> are combined with other cytotoxic<br />

agents to treat lymphomas <strong>and</strong> myeloma, <strong>and</strong> to induce<br />

remission in acute lymphoblastic leukaemia.<br />

HORMONAL MANIPULATION THERAPY IN ADVANCED<br />

PROSTATE CANCER<br />

In advanced prostate cancer, manipulation <strong>of</strong> the <strong>and</strong>rogen<br />

environment <strong>of</strong> the tumour cells can control the disease.<br />

Gonadotrophin-releasing hormone (GnRH) analogues (longacting<br />

preparations <strong>of</strong> drugs, such as leuprolide/goserelin<br />

(Chapter 42) initially stimulate <strong>and</strong> then reduce pituitary<br />

FSH/LH release. These desensitize <strong>and</strong> suppress testosterone<br />

production <strong>and</strong> have superseded the use <strong>of</strong> oestrogens to antagonize<br />

the <strong>and</strong>rogen dependency <strong>of</strong> prostate cancer cells. They<br />

are given with an <strong>and</strong>rogen receptor antagonist (e.g. flutamide,<br />

bicalutamide, cyproterone) to block the intracellular receptors<br />

for dihydrotestosterone <strong>and</strong> prevent flare <strong>of</strong> the disease.<br />

Aminoglutethimide (an aromatase inhibitor) <strong>and</strong> high-dose<br />

ketoconazole (Chapter 45) block the synthesis <strong>of</strong> testicular<br />

testosterone, adrenal <strong>and</strong>rogens <strong>and</strong> other steroids. They are<br />

given orally to patients with refractory prostate cancer.<br />

BIOLOGICAL RESPONSE MODIFIERS<br />

These agents influence the biological response to the tumour.<br />

They may act indirectly to mediate anti-tumour effects, e.g<br />

stimulate the immune response against the transformed neoplastic<br />

cells or directly on the tumour (e.g. by modulating<br />

tumour differentiation). Drugs with proven anti-cancer clinical<br />

efficacy in this class are interleukin-2 <strong>and</strong> interferon-alfa 2b.<br />

INTERLEUKIN-2 (ALDESLEUKIN)<br />

Interleukin-2 (IL-2, aldesleukin) is a human recombinant form<br />

<strong>of</strong> the native IL-2 produced by T helper cells. It differs from<br />

native IL-2 in that it is not glycosylated, has no terminal alanine<br />

<strong>and</strong> a serine substituted at amino acid 125. It is used to treat<br />

metastatic malignant melanoma <strong>and</strong> renal cell carcinoma. In<br />

these patients with advanced cancer, response rates <strong>of</strong> as high as<br />

20–30%, with durable complete responses in 5–10% have been<br />

observed. IL-2 is not a direct cytotoxic, but it induces/exp<strong>and</strong>s<br />

cytolytic T cells against tumours. It is administered intravenously.<br />

Toxicity is the major determinant <strong>of</strong> the duration <strong>of</strong><br />

treatment. Common toxicities are <strong>of</strong>ten dose-limiting due to the<br />

activation <strong>of</strong> T cells <strong>and</strong> release <strong>of</strong> other cytokines (TNF, interleukins<br />

<strong>and</strong> interferon). They include hypotension, capillary<br />

leak syndrome with pulmonary oedema, cardiac dysrhythmias,<br />

prerenal uraemia, abnormal transaminases, anaemia-thrombocytopenia,<br />

nausea, vomiting, diarrhoea, confusion, rashes <strong>and</strong><br />

fever.

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