Steroid Hormones, Antagonists, and Anticancer Drugs

Steroid Hormones and Antagonists (Antitumor)

• Hormone-dependent tumors can be managed by:

  • Surgery (e.g., orchiectomy for advanced prostate cancer).

  • Drugs (e.g., tamoxifen for breast cancer).

• Steroid hormones influence cells via intracellular (cytosolic) receptors.

• Tumors sensitive to steroid hormones can be:

  • Hormone-responsive: Tumor regresses with specific hormone treatment.

  • Hormone-dependent: Tumor regresses upon removal of hormonal stimulus.

  • Both.

Tamoxifen

• Selective estrogen receptor modulator (SERM).

• Estrogen antagonist in breast tissue; agonist in bone and endometrium.

• Used as first-line therapy for estrogen receptor-positive breast cancer.

• Used for breast cancer prevention in high-risk women.

• Mechanism of Action:

  • Competes with estrogen for binding to estrogen receptors in breast tissue.

  • Inhibits estrogen-induced growth of breast cancer.

  • Depletes (down-regulates) estrogen receptors.

  • Suppresses growth-promoting effects of the natural hormone and other growth factors.

• Pharmacokinetics:

  • Effective after oral administration.

  • Partially metabolized by the liver.

  • Some metabolites have estrogen antagonist activity; others have agonist activity.

  • Unchanged drug and metabolites excreted predominantly through the bile into the feces.

  • Inhibitor of CYP3A4 and P-glycoprotein.

• Adverse Effects:

  • Hot flashes, nausea, vomiting, skin rash, vaginal bleeding and discharge (due to estrogenic activity in the endometrial tissue).

  • Potential to cause endometrial cancer, thromboembolism, and effects on vision.

Fulvestrant and Raloxifene

• Fulvestrant:

  • Estrogen receptor antagonist.

  • Administered via IM injection.

  • Used for hormone receptor-positive metastatic breast cancer.

  • Causes estrogen receptor down-regulation on tumors and other targets.

• Raloxifene:

  • Oral SERM.

  • Blocks estrogen effects in uterine and breast tissues.

  • Promotes estrogen effects in bone, inhibiting resorption.

  • Reduces the risk of estrogen receptor-positive invasive breast cancer in postmenopausal women.

• Adverse Effects (Both Drugs):

  • Hot flashes, arthralgias, and myalgias.

Aromatase Inhibitors

• Aromatase reaction is responsible for extra-adrenal synthesis of estrogen from androstenedione in liver, fat, muscle, skin, and breast tissues, including breast malignancies.

• Peripheral aromatization is an important source of estrogen in postmenopausal women.

• Aromatase inhibitors decrease estrogen production in these women.

Anastrozole and Letrozole

• Nonsteroidal aromatase inhibitors.

• First-line drugs for breast cancer in postmenopausal women.

• Orally active and cause almost total suppression of estrogen synthesis.

• Do not predispose patients to endometrial cancer.

• Extensively metabolized in the liver.

• Metabolites and parent drug are excreted primarily in the urine.

Exemestane

• Steroidal, irreversible inhibitor of aromatase.

• Well absorbed after oral administration and widely distributed.

• Hepatic metabolism occurs via the CYP3A4 isoenzyme.

• Doses must be adjusted in patients with renal failure (metabolites excreted in urine).

• Major toxicities: nausea, fatigue, and hot flashes. Alopecia and dermatitis have also been noted.

Leuprolide, Goserelin, and Triptorelin

• Synthetic analogs of GnRH.

• Occupy the GnRH receptor in the pituitary, leading to desensitization and inhibition of FSH and LH release.

• Reduces both androgen and estrogen synthesis.

• Response to leuprolide in prostatic cancer is equivalent to that of orchiectomy.

• Benefit in premenopausal women with advanced breast cancer.

• Largely replaced estrogens in therapy for prostate cancer.

• Leuprolide is available as:

  • A subcutaneous daily injection

  • A subcutaneous depot injection

  • An intramuscular depot injection to treat metastatic carcinoma of the prostate.

• Goserelin acetate is a subcutaneous implant.

• Triptorelin pamoate is injected intramuscularly.

• Levels of androgen in prostate cancer patients may initially rise, but then fall to castration levels.

• Adverse effects: impotence, hot flashes, and tumor flare are minimal compared to those experienced with estrogen treatment.

Antiandrogens

• Flutamide, nilutamide, bicalutamide, and enzalutamide are oral antiandrogens used in the treatment of prostate cancer.

• Compete with the natural hormone for binding to the androgen receptor and prevent its action in the prostate.

• Adverse effects: gynecomastia, constipation, nausea, and abdominal pain. Rarely, liver failure has occurred with flutamide; nilutamide can cause visual problems.

Platinum Coordination Complexes

Cisplatin, Carboplatin, and Oxaliplatin

• Cisplatin:

  • First member of the platinum coordination complex class of anticancer drugs.

  • Synergistic cytotoxicity with radiation and other chemotherapeutic agents.

  • Used in the treatment of solid tumors, such as metastatic testicular carcinoma (with VBL and bleomycin), ovarian carcinoma (with cyclophosphamide), or alone for bladder carcinoma.

• Carboplatin:

  • Developed because of severe toxicity of cisplatin.

  • Used when patients cannot be vigorously hydrated or if they suffer from kidney dysfunction or are prone to neuro- or ototoxicity.

• Oxaliplatin:

  • Closely related analog of carboplatin; used in the setting of colorectal cancer.

• Mechanism of Action:

  • Similar to alkylating agents.

  • Cisplatin persists as the neutral species in the high-chloride milieu of the plasma.

  • Enters the cell and loses chloride in the low-chloride milieu.

  • Binds to guanine in DNA, forming inter- and intrastrand cross-links.

  • Inhibits polymerases for DNA replication and RNA synthesis.

  • Cytotoxicity can occur at any stage of the cell cycle, but cells are most vulnerable in the G1 and S phases.

• Pharmacokinetics:

  • Administered via IV infusion.

  • Cisplatin and carboplatin can be given intraperitoneally for ovarian cancer and intra-arterially to perfuse other organs.

  • Highest concentrations in the liver, kidney, and intestinal, testicular, and ovarian cells; little penetrates into the cerebrospinal fluid (CSF).

  • Renal route is the main pathway of excretion.

• Adverse Effects:

  • Cisplatin: severe nausea and vomiting, dose-related nephrotoxicity (prevented by aggressive hydration), ototoxicity with high-frequency hearing loss and tinnitus.

  • Carboplatin: mild nausea and vomiting, rarely nephro-, neuro-, or ototoxic; the dose-limiting toxicity is myelosuppression.

  • Oxaliplatin: cold-induced peripheral neuropathy (usually resolves within 72 hours), myelosuppression, and cumulative peripheral neuropathy; hepatotoxicity has also been reported.

  • Hypersensitivity reactions can occur with these agents.

Topoisomerase Inhibitors

• Exert their mechanism of action via inhibition of topoisomerase enzymes (enzymes that reduce supercoiling of DNA).

Camptothecins

• Plant alkaloids originally isolated from the Chinese tree Camptotheca.

• Irinotecan and topotecan are semisynthetic derivatives of camptothecin.

• Topotecan:

  • Used in metastatic ovarian cancer when primary therapy has failed and also in the treatment of small cell lung cancer.

• Irinotecan:

  • Used with 5-FU and leucovorin for the treatment of colorectal carcinoma.

• Mechanism of Action:

  • S-phase specific; inhibit topoisomerase I, which is essential for the replication of DNA in human cells.

  • SN-38 (the active metabolite of irinotecan) is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I.

  • The topoisomerases relieve torsional strain in DNA by causing reversible, single-strand breaks.

• Adverse effects:

  • Bone marrow suppression, particularly neutropenia, is the dose-limiting toxicity for topotecan; frequent blood counts should be performed.

  • Myelosuppression is also seen with irinotecan.

  • Acute and delayed diarrhea with irinotecan may be severe and require treatment with atropine during the infusion or high doses of loperamide in the days following the infusion.

Etoposide

• Semisynthetic derivative of the plant alkaloid, podophyllotoxin.

• Blocks cells in the late S to G2 phase of the cell cycle; the major target is topoisomerase II.

• Binding of the drug to the enzyme–DNA complex results in persistence of the transient, cleavable form of the complex and, thus, renders it susceptible to irreversible double-strand breaks.

• Major clinical use in the treatment of lung cancer and in combination with bleomycin and cisplatin for testicular carcinoma.

• May be administered either IV or orally.

• Dose-limiting myelosuppression (primarily leukopenia) is the major toxicity.

Monoclonal Antibodies

• Active area of drug development for anticancer therapy and other nonneoplastic diseases.

• Directed at specific targets and often have different adverse effect profiles compared to traditional chemotherapy agents.

• All of these agents are administered intravenously, and infusion-related reactions are common.

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.

• Administered orally, and these agents have a wide variety of applications in the treatment of cancer.

Abiraterone Acetate

• Oral agent used in the treatment of metastatic castration–resistant prostate cancer.

• Used in conjunction with prednisone to inhibit the CYP17 enzyme (required for androgen synthesis), resulting in reduced testosterone production.

• Coadministration with prednisone is required to help lessen the effects of mineralocorticoid excess resulting from CYP17 inhibition.

• Adverse events include diarrhea, colitis, pneumonitis, hepatitis, nephritis, neurotoxicity, dermatologic toxicity (severe skin rashes), and endocrinopathies (hypo- or hyperthyroidism).

• Closely monitor for toxicity and treat with corticosteroids if necessary.

Immunotherapy

• Intravenous immune checkpoint inhibitors are a rapidly evolving option for cancer treatment.

• Goal of immune checkpoint inhibitors is to block the checkpoint molecules, such as the programmed death (PD-1) receptor, that normally help to keep the immune system in check.

• By blocking these molecules, the immune system is better able to attack the tumor and cause destruction.

• The two most commonly used checkpoint inhibitors are pembrolizumab and nivolumab.

• The adverse reaction profiles of these agents consist of potentially severe and even fatal immune-mediated adverse events.

• Turning off the immune checkpoints allows attack of the tumor but can also lead to an unchecked autoimmune response to normal tissues.

Immuno-modulating Agents

• Thalidomide, lenalidomide, and pomalidomide are oral agents used in the treatment of multiple myeloma.

• Their exact mechanism of action is not clear, but they possess antimyeloma properties including antiangiogenic, immune-modulation, anti-inflammatory and antiproliferative effects.

• These agents are often combined with dexamethasone or other chemotherapeutic agents.

• Adverse effects include thromboembolism, myelosuppression fatigue, rash, and constipation.

• Thalidomide:

  • Previously given to pregnant women to prevent morning sickness; caused severe birth defects.

• Lenalidomide and pomalidomide:

  • Contraindicated in pregnancy due to structural similarities to thalidomide.

Proteasome inhibitors

• Bortezomib, Ixazomib, and Carfilzomib are proteasome inhibitors commonly used as backbone therapy in the treatment of multiple myeloma.

• Work by inhibiting proteasomes, which in turn prevents the degradation of proapoptotic factors, thus leading to a promotion in programmed cell death (apoptosis).

• Malignant cells readily depend on suppression of the apoptotic pathway; therefore, proteasome inhibition works well in multiple myeloma.

• Bortezomib:

  • Can be administered IV, but the subcutaneous route is preferred because it is associated with less neuropathy.

  • Other adverse effects include myelosuppression, diarrhea, nausea, fatigue, and herpes zoster reactivation.

  • Patients should receive antiviral prophylaxis if they are receiving therapy with bortezomib.

• Ixazomib:

  • Oral agent with an adverse effect profile similar to bortezomib.

• Carfilzomib:

  • Administered intravenously, and common adverse effects include myelosuppression, fatigue, nausea, diarrhea, and fever.