Lakhasly

Tumors that are sensitive to steroid hormones may be either 1-hormone responsive, in which the tumor regresses following treatment with a specific hormone; or 2-hormone dependent, in which removal of a hormonal stimulus causes tumor Tumors that are sensitive to steroid hormones may be either 1-hormone responsive, in which the tumor regresses following treatment with a specific hormone; or 2-hormone dependent, in which removal of a hormonal stimulus causes tumor regression; or 3- Both.Etoposide finds its major clinical use in the treatment of lung cancer and in combination with bleomycin and cisplatin for testicular carcinoma.Etoposide finds its major clinical use in the treatment of lung cancer and in combination with bleomycin and cisplatin for testicular carcinoma.D. Leuprolide, goserelin, and triptorelin Gonadotropin-releasing hormone (GnRH) is normally secreted by the hypothalamus and stimulates the anterior pituitary to secrete the gonadotropic hormones:

1-Luteinizing hormone (LH), the primary stimulus for the secretion of testosterone by the testes, and 2-Follicle-stimulating hormone (FSH), which stimulates the secretion of estrogen.D. Leuprolide, goserelin, and triptorelin Gonadotropin-releasing hormone (GnRH) is normally secreted by the hypothalamus and stimulates the anterior pituitary to secrete the gonadotropic hormones:

1-Luteinizing hormone (LH), the primary stimulus for the secretion of testosterone by the testes, and 2-Follicle-stimulating hormone (FSH), which stimulates the secretion of estrogen.Removal of hormonal stimuli from hormone-dependent tumors 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 treatment with the antiestrogen tamoxifen prevents estrogen stimulation of breast cancer cells).As GnRH analogs, 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 synthesis are reduced.Removal of hormonal stimuli from hormone-dependent tumors 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 treatment with the antiestrogen tamoxifen prevents estrogen stimulation of breast cancer cells).As GnRH analogs, 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 synthesis are reduced.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, singlestrand breaks.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, singlestrand breaks.Adverse effects

Adverse effects caused by tamoxifen include : Hot flashes, nausea, vomiting, skin rash, and vaginal bleeding and discharge (due to estrogenic activity of the drug and some of its metabolites in the endometrial tissue).Tamoxifen has the potential to cause endometrial cancer, thromboembolism and effects on vision.This agent blocks cells in the late S to G2 phase of the cell cycle, and 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.Adverse effects

Adverse effects caused by tamoxifen include : Hot flashes, nausea, vomiting, skin rash, and vaginal bleeding and discharge (due to estrogenic activity of the drug and some of its metabolites in the endometrial tissue).Tamoxifen has the potential to cause endometrial cancer, thromboembolism and effects on vision.This agent blocks cells in the late S to G2 phase of the cell cycle, and 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.They compete with the natural hormone for binding to the androgen receptor and prevent its action in the prostate

Adverse effects include : gynecomastia, constipation, nausea, and abdominal pain.They compete with the natural hormone for binding to the androgen receptor and prevent its action in the prostate

Adverse effects include : gynecomastia, constipation, nausea, and abdominal pain.B. Fulvestrant and raloxifene

Fulvestrant is an estrogen receptor antagonist that is given via IM injection to patients with hormone receptor-positive metastatic breast cancer.Exemestane

A steroidal, irreversible inhibitor of aromatase,

Exemestane, is well absorbed after oral administration and widely distributed.The major limiting toxicity is dose-related nephrotoxicity, involving the distal convoluted tubule and collecting ducts.B. Fulvestrant and raloxifene

Fulvestrant is an estrogen receptor antagonist that is given via IM injection to patients with hormone receptor-positive metastatic breast cancer.Exemestane

A steroidal, irreversible inhibitor of aromatase,

Exemestane, is well absorbed after oral administration and widely distributed.The major limiting toxicity is dose-related nephrotoxicity, involving the distal convoluted tubule and collecting ducts.Mechanism of action

Tamoxifen competes with estrogen for binding to estrogen receptors in the breast tissue, and inhibits estrogen induced growth of breast cancer.Raloxifene is an oral SERM that blocks estrogen effects in the uterine and breast tissues, while promoting effects in the bone to inhibit resorption.Platinum Coordination Complexes A. Cisplatin, carboplatin, and oxaliplatin

Cisplatin was the first member of the platinum coordination complex class of anticancer drugs, but because of severe toxicity, carboplatin was developed.It has found wide application in the treatment of solid tumors, such as metastatic testicular carcinoma in combination with VBL and bleomycin, ovarian carcinoma in combination with cyclophosphamide, or alone for bladder carcinoma.Unlike cisplatin, carboplatin causes only mild nausea and vomiting, and it is rarely nephro-, neuro-, or ototoxic.Topoisomerase Inhibitors

These agents exert their mechanism of action via inhibition of topoisomerase enzymes, a class of enzymes that reduce supercoiling of DNA.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.Mechanism of action

Tamoxifen competes with estrogen for binding to estrogen receptors in the breast tissue, and inhibits estrogen induced growth of breast cancer.Raloxifene is an oral SERM that blocks estrogen effects in the uterine and breast tissues, while promoting effects in the bone to inhibit resorption.Platinum Coordination Complexes A. Cisplatin, carboplatin, and oxaliplatin

Cisplatin was the first member of the platinum coordination complex class of anticancer drugs, but because of severe toxicity, carboplatin was developed.It has found wide application in the treatment of solid tumors, such as metastatic testicular carcinoma in combination with VBL and bleomycin, ovarian carcinoma in combination with cyclophosphamide, or alone for bladder carcinoma.Unlike cisplatin, carboplatin causes only mild nausea and vomiting, and it is rarely nephro-, neuro-, or ototoxic.Topoisomerase Inhibitors

These agents exert their mechanism of action via inhibition of topoisomerase enzymes, a class of enzymes that reduce supercoiling of DNA.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.It is an estrogen antagonist in breast tissue and an agonist in other tissues, such as bone and the endometrium.Tamoxifen is used for first-line therapy in the treatment of estrogen receptor-positive breast cancer.The result is

o depletion (down-regulation) of estrogen receptors, and the

o growth-promoting effects of the natural hormone and other growth factors are suppressed.C. Aromatase inhibitors The aromatase reaction is responsible for extra-adrenal synthesis of estrogen from androstenedione, which takes place in liver, fat, muscle, skin, and breast tissues, including breast malignancies. Leuprolide is available as:

1. A subcutaneous daily injection,

2. A subcutaneous depot injection, or

3. An intramuscular depot injection to treat metastatic carcinoma of the prostate.Goserelin acetate is a subcutaneous implant, and triptorelin pamoate is injected intramuscularly.In the high-chloride milieu of the plasma, cisplatin persists as the neutral species, which enters the cell and loses chloride in the low-chloride milieu.1.2.1.2.

Tumors that are sensitive to steroid hormones may be either 1-hormone responsive, in which the tumor regresses following treatment with a specific hormone; or 2-hormone dependent, in which removal of a hormonal stimulus causes tumor Tumors that are sensitive to steroid hormones may be either 1-hormone responsive, in which the tumor regresses following treatment with a specific hormone; or 2-hormone dependent, in which removal of a hormonal stimulus causes tumor regression; or 3- Both.

Removal of hormonal stimuli from hormone-dependent tumors 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 treatment with the antiestrogen tamoxifen prevents estrogen stimulation of breast cancer cells). For a steroid hormone to influence a cell, that cell must have intracellular (cytosolic) receptors that are specific for that hormone. A.

Tamoxifen

Tamoxifen is a selective estrogen modulator (SERM).

It is an estrogen antagonist in breast tissue and an agonist in other tissues, such as bone and the endometrium.Tamoxifen is used for first-line therapy in the treatment of estrogen receptor–positive breast cancer. It is also used for prevention of breast cancer in high-risk women.

Mechanism of action

Tamoxifen competes with estrogen for binding to estrogen receptors in the breast tissue, and inhibits estrogen induced growth of breast cancer.

The result is

• depletion (down-regulation) of estrogen receptors, and the

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

Pharmacokinetics Tamoxifen is effective after oral administration. It is partially metabolized by the liver. Some metabolites possess estrogen antagonist activity, whereas others have agonist activity.

Unchanged drug and metabolites are excreted predominantly through the bile into the feces. Tamoxifen is an inhibitor of CYP3A4 and P-glycoprotein.

Adverse effects

Adverse effects caused by tamoxifen include : Hot flashes, nausea, vomiting, skin rash, and vaginal bleeding and discharge (due to estrogenic activity of the drug and some of its metabolites in the endometrial tissue).Tamoxifen has the potential to cause endometrial cancer, thromboembolism and effects on vision.

B. Fulvestrant and raloxifene

Fulvestrant is an estrogen receptor antagonist that is given via IM injection to patients with hormone receptor–positive metastatic breast cancer. This agent binds to and causes estrogen receptor down regulation on tumors and other targets.

Raloxifene is an oral SERM that blocks estrogen effects in the uterine and breast tissues, while promoting effects in the bone to inhibit resorption. This agent reduces the risk of estrogen receptor–positive invasive breast cancer in postmenopausal women. Both drugs are known to cause hot flashes, arthralgias, and myalgias.

C. Aromatase inhibitors The aromatase reaction is responsible for extra-adrenal synthesis of estrogen from androstenedione, which takes place 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 the production of estrogen in these women.

1. Anastrozole and letrozole

Anastrozole and letrozole are nonsteroidal aromatase inhibitors.

These agents are considered first-line drugs for the treatment of breast cancer in postmenopausal women. They are orally active and cause almost a total suppression of estrogen synthesis.

Anastrozole and letrozole do not predispose patients to endometrial cancer.

Both drugs are extensively metabolized in the liver, and metabolites and parent drug are excreted primarily in the urine.

2. Exemestane

A steroidal, irreversible inhibitor of aromatase,

Exemestane, is well absorbed after oral administration and widely distributed.

Hepatic metabolism occurs via the CYP3A4 isoenzyme. Because the metabolites are excreted in urine, doses of the drug must be adjusted in patients with renal failure.

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

D. Leuprolide, goserelin, and triptorelin Gonadotropin-releasing hormone (GnRH) is normally secreted by the hypothalamus and stimulates the anterior pituitary to secrete the gonadotropic hormones:

1-Luteinizing hormone (LH), the primary stimulus for the secretion of testosterone by the testes, and 2-Follicle-stimulating hormone (FSH), which stimulates the secretion of estrogen. Leuprolide, goserelin, and triptorelin are synthetic analogs of GnRH.

As GnRH analogs, 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 synthesis are reduced. Response to leuprolide in prostatic cancer is equivalent to that of orchiectomy with regression of tumor and relief of bone pain.

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:

1. 
   

   A subcutaneous daily injection,

   
   


2. 
   

   A subcutaneous depot injection, or

   
   


3. 
   

   An intramuscular depot injection to treat metastatic carcinoma of the prostate. Goserelin acetate is a subcutaneous implant, and triptorelin pamoate is injected intramuscularly. Levels of androgen in prostate cancer patients 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.

E. Antiandrogens

Flutamide, nilutamide, bicalutamide, and enzalutamide are oral antiandrogens

used in the treatment of prostate cancer. They compete with the natural hormone for binding to the androgen receptor and prevent its action in the prostate

Adverse effects include : gynecomastia, constipation, nausea, and abdominal pain.

Rarely, liver failure has occurred with flutamide. Nilutamide can cause visual problems.

Platinum Coordination Complexes A. Cisplatin, carboplatin, and oxaliplatin

Cisplatin was the first member of the platinum coordination complex class of anticancer drugs, but because of severe toxicity, carboplatin was developed. Cisplatin has synergistic cytotoxicity with radiation and other chemotherapeutic agents. It has found wide application in the treatment of solid tumors, such as metastatic testicular carcinoma in combination with VBL and bleomycin, ovarian carcinoma in combination with cyclophosphamide, or alone for bladder carcinoma.

Carboplatin is used when patients cannot be vigorously hydrated, as is required for cisplatin treatment, or if they suffer from kidney dysfunction or are prone to neuro- or ototoxicity.

Oxaliplatin is a closely related analog of carboplatin used in the setting of colorectal cancer. Mechanism of action

The mechanism of action of these agents is similar to that of the alkylating agents. In the high-chloride milieu of the plasma, cisplatin persists as the neutral species, which enters the cell and loses chloride in the low-chloride milieu. It then binds to guanine in DNA, forming inter- and intrastrand cross-links. The resulting cytotoxic lesion inhibits both polymerases for DNA replication and RNA synthesis.

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

Pharmacokinetics

These agents are administered via IV infusion. Cisplatin and carboplatin can also be given intraperitoneally for ovarian cancer and intra-arterially to perfuse other organs. The highest concentrations of the drugs are found in the liver, kidney, and intestinal, testicular, and ovarian cells, but little penetrates into the cerebrospinal fluid (CSF). The renal route is the main pathway of excretion.

Adverse effects

Severe nausea and vomiting occurs in most patients after administration of cisplatin and may continue for as long as 5 days. Premedication with antiemetic agents is required. The major limiting toxicity is dose-related nephrotoxicity, involving the distal convoluted tubule and collecting ducts. This can be prevented by aggressive hydration. Other toxicities include ototoxicity with high-frequency hearing loss and tinnitus. Unlike cisplatin, carboplatin causes only mild nausea and vomiting, and it is rarely nephro-, neuro-, or ototoxic. The dose-limiting toxicity is myelosuppression. Oxaliplatin has a distinct adverse effect of coldinduced peripheral neuropathy that usually resolves within 72 hours of administration. It also causes myelosuppression and cumulative peripheral neuropathy. Hepatotoxicity has also been reported. These agents may cause hypersensitivity reactions ranging from skin rashes to anaphylaxis.

Topoisomerase Inhibitors

These agents exert their mechanism of action via inhibition of topoisomerase enzymes, a class of enzymes that reduce supercoiling of DNA.

A. Camptothecins

Camptothecins are plant alkaloids originally isolated from the Chinese tree Camptotheca. Irinotecan and topotecan are semisynthetic derivatives of camptothecin.

Topotecan is used in metastatic ovarian cancer when primary therapy has failed and also in the treatment of small cell lung cancer. Irinotecan is used with 5-FU and leucovorin for the treatment of colorectal carcinoma.

Mechanism of action

These drugs are S-phase specific and 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, singlestrand breaks. Adverse effects: Bone marrow suppression, particularly neutropenia, is the doselimiting toxicity for topotecan. Frequent blood counts should be performed in patients receiving this drug. 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.

B. Etoposide

Etoposide is a semisynthetic derivative of the plant alkaloid, podophyllotoxin.

This agent blocks cells in the late S to G2 phase of the cell cycle, and 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.

Etoposide finds its major clinical use in the treatment of lung cancer and in combination with bleomycin and cisplatin for testicular carcinoma. Etoposide may be administered either IV or orally. Dose-limiting myelosuppression (primarily leukopenia) is the major toxicity. regression; or 3- Both.

Removal of hormonal stimuli from hormone-dependent tumors 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 treatment with the antiestrogen tamoxifen prevents estrogen stimulation of breast cancer cells). For a steroid hormone to influence a cell, that cell must have intracellular (cytosolic) receptors that are specific for that hormone. A.

Tamoxifen

Tamoxifen is a selective estrogen modulator (SERM).

It is an estrogen antagonist in breast tissue and an agonist in other tissues, such as bone and the endometrium.Tamoxifen is used for first-line therapy in the treatment of estrogen receptor–positive breast cancer. It is also used for prevention of breast cancer in high-risk women.

Mechanism of action

Tamoxifen competes with estrogen for binding to estrogen receptors in the breast tissue, and inhibits estrogen induced growth of breast cancer.

The result is

• depletion (down-regulation) of estrogen receptors, and the

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

Pharmacokinetics Tamoxifen is effective after oral administration. It is partially metabolized by the liver. Some metabolites possess estrogen antagonist activity, whereas others have agonist activity.

Unchanged drug and metabolites are excreted predominantly through the bile into the feces. Tamoxifen is an inhibitor of CYP3A4 and P-glycoprotein.

Adverse effects

Adverse effects caused by tamoxifen include : Hot flashes, nausea, vomiting, skin rash, and vaginal bleeding and discharge (due to estrogenic activity of the drug and some of its metabolites in the endometrial tissue).Tamoxifen has the potential to cause endometrial cancer, thromboembolism and effects on vision.

B. Fulvestrant and raloxifene

Fulvestrant is an estrogen receptor antagonist that is given via IM injection to patients with hormone receptor–positive metastatic breast cancer. This agent binds to and causes estrogen receptor down regulation on tumors and other targets.

Raloxifene is an oral SERM that blocks estrogen effects in the uterine and breast tissues, while promoting effects in the bone to inhibit resorption. This agent reduces the risk of estrogen receptor–positive invasive breast cancer in postmenopausal women. Both drugs are known to cause hot flashes, arthralgias, and myalgias.

C. Aromatase inhibitors The aromatase reaction is responsible for extra-adrenal synthesis of estrogen from androstenedione, which takes place 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 the production of estrogen in these women.

1. Anastrozole and letrozole

Anastrozole and letrozole are nonsteroidal aromatase inhibitors.

These agents are considered first-line drugs for the treatment of breast cancer in postmenopausal women. They are orally active and cause almost a total suppression of estrogen synthesis.

Anastrozole and letrozole do not predispose patients to endometrial cancer.

Both drugs are extensively metabolized in the liver, and metabolites and parent drug are excreted primarily in the urine.

2. Exemestane

A steroidal, irreversible inhibitor of aromatase,

Exemestane, is well absorbed after oral administration and widely distributed.

Hepatic metabolism occurs via the CYP3A4 isoenzyme. Because the metabolites are excreted in urine, doses of the drug must be adjusted in patients with renal failure.

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

D. Leuprolide, goserelin, and triptorelin Gonadotropin-releasing hormone (GnRH) is normally secreted by the hypothalamus and stimulates the anterior pituitary to secrete the gonadotropic hormones:

1-Luteinizing hormone (LH), the primary stimulus for the secretion of testosterone by the testes, and 2-Follicle-stimulating hormone (FSH), which stimulates the secretion of estrogen. Leuprolide, goserelin, and triptorelin are synthetic analogs of GnRH.

As GnRH analogs, 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 synthesis are reduced. Response to leuprolide in prostatic cancer is equivalent to that of orchiectomy with regression of tumor and relief of bone pain.

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:

1. 
   

   A subcutaneous daily injection,

   
   


2. 
   

   A subcutaneous depot injection, or

   
   


3. 
   

   An intramuscular depot injection to treat metastatic carcinoma of the prostate. Goserelin acetate is a subcutaneous implant, and triptorelin pamoate is injected intramuscularly. Levels of androgen in prostate cancer patients 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.

E. Antiandrogens

Flutamide, nilutamide, bicalutamide, and enzalutamide are oral antiandrogens

used in the treatment of prostate cancer. They compete with the natural hormone for binding to the androgen receptor and prevent its action in the prostate

Adverse effects include : gynecomastia, constipation, nausea, and abdominal pain.

Rarely, liver failure has occurred with flutamide. Nilutamide can cause visual problems.

Platinum Coordination Complexes A. Cisplatin, carboplatin, and oxaliplatin

Cisplatin was the first member of the platinum coordination complex class of anticancer drugs, but because of severe toxicity, carboplatin was developed. Cisplatin has synergistic cytotoxicity with radiation and other chemotherapeutic agents. It has found wide application in the treatment of solid tumors, such as metastatic testicular carcinoma in combination with VBL and bleomycin, ovarian carcinoma in combination with cyclophosphamide, or alone for bladder carcinoma.

Carboplatin is used when patients cannot be vigorously hydrated, as is required for cisplatin treatment, or if they suffer from kidney dysfunction or are prone to neuro- or ototoxicity.

Oxaliplatin is a closely related analog of carboplatin used in the setting of colorectal cancer. Mechanism of action

The mechanism of action of these agents is similar to that of the alkylating agents. In the high-chloride milieu of the plasma, cisplatin persists as the neutral species, which enters the cell and loses chloride in the low-chloride milieu. It then binds to guanine in DNA, forming inter- and intrastrand cross-links. The resulting cytotoxic lesion inhibits both polymerases for DNA replication and RNA synthesis.

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

Pharmacokinetics

These agents are administered via IV infusion. Cisplatin and carboplatin can also be given intraperitoneally for ovarian cancer and intra-arterially to perfuse other organs. The highest concentrations of the drugs are found in the liver, kidney, and intestinal, testicular, and ovarian cells, but little penetrates into the cerebrospinal fluid (CSF). The renal route is the main pathway of excretion.

Adverse effects

Severe nausea and vomiting occurs in most patients after administration of cisplatin and may continue for as long as 5 days. Premedication with antiemetic agents is required. The major limiting toxicity is dose-related nephrotoxicity, involving the distal convoluted tubule and collecting ducts. This can be prevented by aggressive hydration. Other toxicities include ototoxicity with high-frequency hearing loss and tinnitus. Unlike cisplatin, carboplatin causes only mild nausea and vomiting, and it is rarely nephro-, neuro-, or ototoxic. The dose-limiting toxicity is myelosuppression. Oxaliplatin has a distinct adverse effect of coldinduced peripheral neuropathy that usually resolves within 72 hours of administration. It also causes myelosuppression and cumulative peripheral neuropathy. Hepatotoxicity has also been reported. These agents may cause hypersensitivity reactions ranging from skin rashes to anaphylaxis.

Topoisomerase Inhibitors

These agents exert their mechanism of action via inhibition of topoisomerase enzymes, a class of enzymes that reduce supercoiling of DNA.

A. Camptothecins

Camptothecins are plant alkaloids originally isolated from the Chinese tree Camptotheca. Irinotecan and topotecan are semisynthetic derivatives of camptothecin.

Topotecan is used in metastatic ovarian cancer when primary therapy has failed and also in the treatment of small cell lung cancer. Irinotecan is used with 5-FU and leucovorin for the treatment of colorectal carcinoma.

Mechanism of action

These drugs are S-phase specific and 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, singlestrand breaks. Adverse effects: Bone marrow suppression, particularly neutropenia, is the doselimiting toxicity for topotecan. Frequent blood counts should be performed in patients receiving this drug. 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.

B. Etoposide

Etoposide is a semisynthetic derivative of the plant alkaloid, podophyllotoxin.

This agent blocks cells in the late S to G2 phase of the cell cycle, and 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.

Etoposide finds its major clinical use in the treatment of lung cancer and in combination with bleomycin and cisplatin for testicular carcinoma. Etoposide may be administered either IV or orally. Dose-limiting myelosuppression (primarily leukopenia) is the major toxicity.