alkylating agents & anti-metabolites chemotherapy

ALKYLATING AGENTS

DR. AADITYA PRAKASH

DNB RT , RESIDENT

BMCHRC , JAIPUR

CLASSIFICATION

MECHANISM OF ACTION

• Alkylating agents target DNA and are cytotoxic, mutagenic, and carcinogenic.

• All agents produce alkylation through the formation of intermediates.

• Alkylating agents impair cell function by transferring alkyl groups to amino, carboxyl, sulfhydryl, or phosphate groups of biologically important molecules.

MECHANISM OF ACTION

• Most important, nucleic acids (DNA and RNA) and proteins are alkylated.

• The number 7 (N-7) position of guanine in DNA and RNA is the most actively alkylated site; the O-6 group of guanine is alkylated by nitrosoureas.

• Alkylation of guanine results in abnormal nucleotide sequences, miscoding of messenger RNA, cross-linked DNA strands that cannot replicate, breakage of DNA strands, and other damage to the transcription and translation of genetic material.

MECHANISM OF ACTION

• Cross-linking of DNA appears to be of major importance to the cytotoxic action of alkylating agents, and replicating cells are most susceptible to these drugs.

• Alkylating agents are cell cycle-non specific.

• The drugs kill a fixed percentage of cells at a given dose.

A bis(chloroethyl)amine forms an ethyleneimonium ion that reacts with a base such as N7 of guanine in DNA, producing an alkylated purine.

Alkylation of a second guanine residue, through the illustrated mechanism, results in cross-linking of DNA strands.

RESISTANCE• Increased capability to repair DNA lesions

• Decreased transport of the alkylating drug into the cell

• Increased expression or activity of glutathione and glutathione-associated proteins, which are needed to conjugate the alkylating agent, or increased glutathione S-transferase activity, which catalyzes the conjugation

• Increased scavenging of drug species by nonessential cellular nucleophiles

• Increased enzymatic detoxification of drug species

• Altered expression of genes coding for cellular commitment to apoptosis

ADVERSE EFFECTS

• NAUSEA AND VOMITING

• BONE MARROW TOXICITY

• HEMORRHAGIC CYSTITIS :–

• Unique to the oxazaphosphorines (cyclophosphamide and ifosfamide)

• Caused by the excretion of toxic metabolites (particularly acrolein)

• Incidence and severity can be lessened by:-

1. Adequate hydration and continuous irrigation of the bladder with a solution containing 2-mercaptoethane sulfonate (MESNA) and frequent bladder emptying.

2. MESNA Is given in divided doses every 4 hours in dosages of 60% of those of the alkylating agent.

ADVERSE EFFECTS • INTERSTITIAL PNEUMONITIS AND PULMONARY FIBROSIS

• GONADAL TOXICITY :-

1. Depletion of testicular germ (but not sertoli) cells

2. Patients in remission and off alkylating agents for 2 to 7 years show complete spermatogenesis, indicating that testicular damage is reversible.

• TERATOGENESIS :-

• Administration of alkylating agents during the first trimester of pregnancy presents a definitive risk of a malformed fetus

• But the administration of such drugs during the second and third trimesters does not increase the risk of fetal malformation above normal.

• CARCINOGENESIS : e.g fulminant acute myeloid leukemia

• ALOPECIA

• ALLERGIC REACTIONS

• IMMUNOSUPPRESSION

IMPORTANT CLINICALLY USEFUL ALKYLATING AGENTS

CISPLATINTRADE NAME :- CIS-DIAMMINEDICHLOROPLATINUM, CDDP, PLATINOL

ABSORPTION: • Not absorbed orally.

• Systemic absorption is rapid and complete after intraperitoneal (IP) administration

INDICATIONS:

1. TESTICULAR CANCER.

2. OVARIAN CANCER.

3. BLADDER CANCER.

4. HEAD AND NECK CANCER.

5. ESOPHAGEAL CANCER.

6. SMALL CELL AND NON–SMALL CELL LUNG CANCER.

7. NON-HODGKIN’S LYMPHOMA.

8. TROPHOBLASTIC NEOPLASMS.

DOSAGE RANGE:

• OVARIAN CANCER—

1. 75 mg/m2 IV on day 1 every 21 days as part of the cisplatin/paclitaxel regimen

2. 100 mg/m2 on day 1 every 21 days as part of the cisplatin/cyclophosphamide regimen.

• TESTICULAR CANCER— 20 mg/m2 IV on days 1–5 every 21 days as part of the PEB regimen

• HEAD AND NECK CANCER— 100 mg/m2/day IV on day 1 every 21 days

• NON–SMALL CELL LUNG CANCER— 60–100 mg/m2 IV on day 1 every 21 days as part of the cisplatin/etoposide or cisplatin/gemcitabine regimens

• METASTATIC BREAST CANCER- 20 mg/m2 (IV, days 1–5 every 3 wks)

• CERVICAL CANCER- 70 mg/m2 (IV, dosing cycled every 4 wks)

• ESOPHAGEAL CANCER- 75 mg/m2 on day 1 of wks 1, 5, 8, and 11 (IV)

SPECIAL CONSIDERATIONS:

• Contraindicated in patients with known hypersensitivity to cisplatin or other platinum analogs

• Creatinine clearance should be obtained at baseline and before each cycle of therapy

• Patients must be hydrated before, during, and post-drug administration

• Baseline audiology exam and periodic evaluation during therapy are recommended to monitor the effects of drug on hearing.

• Contraindicated in patients with pre-existing hearing deficit

• Prophylaxis against delayed emesis (>24 hours after the drug administration) is also recommended.

• A combination of a 5-HT3 antagonist (e.g., Ondansetron or Granisetron) and dexamethasone is standard therapy for prevention of nausea and vomiting.

• Avoid aluminum needles when administering the drug because precipitate may form, resulting in decreased potency

TRADE NAME:- PARAPLATIN, CBDCA

ABSORPTION:

Not absorbed by the oral route. Only I/V

INDICATIONS:

1. OVARIAN CANCER.

2. GERM CELL TUMORS.

3. HEAD AND NECK CANCER.

4. SMALL CELL AND NON–SMALL CELL LUNG CANCER.

5. BLADDER CANCER.

6. RELAPSED AND REFRACTORY ACUTE LEUKEMIA.

7. ENDOMETRIAL CANCER.

DOSAGE RANGE:

• Usually calculated to a target area under the curve (AUC) based on the glomerular filtration rate (GFR)

• Calvert formula is used to calculate dose—total dose (mg) 5 (target AUC) 3 (GFR 1 25). Note: dose is in mg NOT mg/m2.

• Target AUC is usually between 5 and 7 mg/ml/min for previously untreated patients.

• Previously treated patients, lower AUCS (between 4 and 6 mg/ml/min) are recommended.

SPECIAL CONSIDERATIONS:• Contraindicated in patients with known hypersensitivity to cisplatin or

other platinum analogs

• Creatinine clearance should be obtained at baseline and before each cycle of therapy

• Pregnancy category D. Breastfeeding should be avoided

• Avoid aluminum needles when administering the drug because precipitate may form, resulting in decreased potency

• Myelosuppression is significant and dose-limiting. Thrombocytopenia is most commonly observed, with nadir by day 21.

OXALIPLATIN• TRADE NAME:- ELOXATIN, DIAMINOCYCLOHEXANE

PLATINUM

ABSORPTION

• Not orally bioavailable.

INDICATIONS

• METASTATIC COLORECTAL CANCER— FDA -Approved in combination with infusional 5-FU/LV in patients with advanced, metastatic disease.

• EARLY-STAGE COLON CANCER—FDA -Approved as adjuvant therapy in combination with infusional 5-FU/LV in patients with stage III and with high-risk stage II colon cancer.

• METASTATIC PANCREATIC CANCER.

• METASTATIC GASTRIC CANCER and GASTROESOPHAGEAL CANCER.

DOSAGE RANGE:

• Recommended dose is 85 mg/m2 IV over 2 hours, on an every 2-week &/OR 100–130 mg/m2 IV on an every 3-week SCHEDULE.

SPECIAL CONSIDERATIONS

• Use with caution in patients with abnormal renal function

• Careful neurologic evaluation should be performed before starting therapy.

• Caution patients to avoid exposure to cold following drug administration:- worsen acute neurotoxicity.


• Calcium/magnesium infusions (1 gm calcium gluconate/1 gm magnesium sulfate) prior to and at the completion of the oxaliplatin infusion can be used to reduce the incidence of acute neurotoxicity.

• Oxaliplatin should not be administered with basic solutions (e.g., Solutions containing 5-FU), as it may be partially degraded.

• Pregnancy category D. Breastfeeding should be avoided.

• Unlike cisplatin, oxaliplatin does not accumulate to any significant level after multiple courses of treatment. This may explain why neurotoxicity associated with oxaliplatin is reversible.

CYCLOPHOSPHAMIDE

• TRADE NAME:- CYTOXAN, CTX

ABSORPTION

• Well-absorbed by the GI tract with a bioavailability of nearly 90%

INDICATIONS

1. BREAST CANCER.


3. CHRONIC LYMPHOCYTIC LEUKEMIA.

4. OVARIAN CANCER.

5. BONE AND SOFT TISSUE SARCOMA.

6. RHABDOMYOSARCOMA.

7. NEUROBLASTOMA

8. WILMS’ TUMOR.

DOSAGE RANGE:

• BREAST CANCER—

1. Orally, the usual dose is 100 mg/m2 PO on days 1–14 given every 28 days.

2. IV, the usual dose is 600 mg/m2 given every 21 days as part of the AC or CMF regimens.

• NON-HODGKIN’S LYMPHOMA—750 mg/m2 on day 1 every 21 days, as part of the CHOP regimen.

• HIGH-DOSE BONE MARROW TRANSPLANTATION— Usual dose in the setting of bone marrow transplantation is 60 mg/kg IV for 2 days.


• Use with caution in patients with abnormal RFT

• Administer oral form of drug during the daytime

• Encourage fluid intake of at least 2–3 L/day to reduce the risk of hemorrhagic cystitis.

• Encourage patients to empty bladder several times daily (on average, every 2 hours) to reduce the risk of bladder toxicity.


• Myelosuppression is dose-limiting.

CARMUSTINE

• TRADE NAME:- BCNU, BISCHLOROETHYLNITROSOUREA

ABSORPTION

• Not absorbed via the oral route.

INDICATIONS

1. BRAIN TUMORS— Glioblastoma Multiforme, Brain Stem Glioma, Medulloblastoma,astrocytoma, And Ependymoma.

2. HODGKIN’S LYMPHOMA.


4. MULTIPLE MYELOMA.

5. GLIOBLASTOMA MULTIFORME— Implantable BCNU -impregnated wafer (GLIADEL).

6. CUTANEOUS T-CELL LYMPHOMA

DOSAGE RANGE:

• Usual dose is 150-200 mg/m2 IV every 6 weeks.

• Implantable BCNU -impregnated wafers– up to eight wafers (61.6 mg) are placed into the surgical resection site after excision of the primary brain tumor.

• Cutaneous t-cell lymphoma 200–600 mg (topical solution)


• PFTs should be obtained at baseline and monitored periodically during therapy.

• At cumulative doses greater than 1400 mg/m2 interstitial lung disease and pulmonary fibrosis develops.

• Administer carmustine slowly over a period of 1–2 hours to avoid intense pain and/or burning at the site of injection.

• Monitor CBC while on therapy.


TEMOZOLOMIDE

• TRADE NAME:- TEMODAR

MECHANISM OF ACTION

• Methylates guanine residues in DNA and inhibits DNA, RNA, and protein synthesis synthesis and function

• Does not cross-link DNA strands

MECHANISM OF RESISTANCE

• Increased activity of DNA repair enzymes such as O6-alkylguanine DNA alkyltransferase.

ABSORPTION

• Rapidly and completely absorbed with an oral bioavailability approaching 100%. Maximum plasma concentrations are reached within 1 hour after administration.

• Food reduces the rate and extent of drug absorption.

INDICATIONS

• For refractory anaplastic astrocytomas at first relapse

• Newly diagnosed glioblastoma multiforme (GBM)

• Metastatic melanoma.

DOSAGE RANGE:

• Temozolomide is given at 75 mg/m2 PO daily for 42 days along with radiotherapy (60 Gy in 30 fractions) for newly diagnosed GBM.

• During the maintenance phase, which is started 4 weeks after completion of the combined modality therapy, Temozolomide is given on cycle 1 at 150 mg/m2 PO daily for 5 days followed by 23 days without treatment.

RESULTS• 2 YR OS –– 27% VS 10%

• STUPP R. et al RADIOTHERAPY PLUS CONCOMITANT AND ADJUVANT TEMOZOLOMIDE FOR GLIOBLASTOMA. N . ENGL J MED 2005 352(10):987––996.


• Monitored closely for the development of PCP. Require PCP prophylaxis.

• Prophylaxis with Trimethoprim/Sulfamethoxazole (Bactrim DS) 1 tablet PO bid, 3 times per week to reduce the risk of Pneumocystis jiroveci infection.

• Increased risk for myelosuppression.

• To avoid sun exposure.

• Pregnancy category D. Breastfeeding should be discontinued.

OTHER USEFUL ALKYLATING AGENTS

ANTI-METABOLITESDR. AADITYA PRAKASH

DNB RT , RESIDENT

BMCHRC , JAIPUR

MECHANISM OF ACTION• Antifolate compounds are tight-binding inhibitors of DHFR

(dihydrofolate reductase), enzyme in folate metabolism.

• Results in inhibition of the synthesis of tetrahydrofolate (THF)- key one-carbon carrier for enzymatic processes involved in denovo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine.

• Thereby interferes with the formation of DNA, RNA, and key cellular proteins.

• Their activity is greatest in the S phase of the cell cycle.(CCS)

MECHANISM OF ACTION• PURINE ANTAGONISTS inhibit enzymes involved in de novo purine

synthesis and purine interconversion reactions.

RESISTANCE• Alteration in antifolate transport.

• Increased expression of the catabolic enzyme γ-glutamyl hydrolase.

• Alterations in the target enzymes DHFR and/or thymidylate synthase (TS) through increased expression of wild-type protein or overexpression of a mutant protein.

• Gene amplification.

• Decreased expression of mismatch repair enzymes.(hMLH1, hMSH2)

ADVERSE EFFECTS

• Dose-limiting myelosuppression

• Gastro-intestinal (GI) toxicity

• Acute elevations in hepatic enzyme levels and hyperbilirubinemia (with high doses)

• Mucositis, skin rash (hand-foot syndrome)

METHOTREXATE

• TRADE NAME:- MTX, AMETHOPTERIN

ABSORPTION

• Oral bioavailability is saturable and erratic at doses greater than 25 mg/m2.

• Methotrexate is completely absorbed from parenteral routes.

• At conventional doses, CSF levels are only about 5%–10% of those in plasma.

• High-dose MTX yields therapeutic concentrations in the CSF.

• Distributes into third-space fluid collections such as pleural effusion and ascites.

INDICATIONS

• Breast cancer.

• Head and neck cancer.

• Osteogenic sarcoma.

• Acute lymphoblastic leukemia

• Non-hodgkin’s lymphoma

• Primary CNS lymphoma.

• Meningeal leukemia and carcinomatous meningitis.

• Bladder cancer.

• Gestational trophoblastic cancer.

DOSAGE RANGE

• Low dose: 10–50 mg/m2 IV every 3–4 weeks

• Low dose weekly: 25 mg/m 2 IV weekly

• Moderate dose: 100–500 m/m2 IV every 2–3 weeks

• High dose: 1–12 gm/m2 IV over a 3- to 24-hour period every 1–3 weeks

• Intrathecal (IT): 10–15 mg IT 2 times weekly until CSF is clear, then weekly dose for 2–6 weeks, followed by monthly dose.


• Methotrexate enhances the antitumor activity of 5-fluorouracil when given 24 hours before fluoropyrimidine treatment.

Antifolate analogs ( like MTX) increase the formation of 5-FU nucleotide metabolites when given 24 hours before 5-FU.

• Leucovorin rescues the toxic effects of methotrexate and may also impair the antitumor activity. The active form of leucovorin is the L-isomer.

Leucovorin is normally started 24 hours after methotrexate is given. This delay gives the methotrexate a chance to exert its anti cancer effects.


• Thymidine—thymidine rescues the toxic effects of methotrexate and may also impair the antitumor activity.

• Proton pump inhibitors—proton pump inhibitors may reduce the elimination of methotrexate, which can then result in increased serum methotrexate levels, leading to increased toxicity.

• Use with caution in patients with abnormal RFT.

• Instruct patients to stop folic acid supplements during therapy.


• With high-dose therapy, methotrexate blood levels should be monitored every 24 hours starting at 24 hours after methotrexate infusion.

• With high-dose therapy, methotrexate doses >1 grams/m2 important to vigorously hydrate the patient with 2.5–3.5 liters/m2/day of IV 0.9% sodium chloride starting 12 hours before and for 24–48 hours after methotrexate infusion.

• Patients should be instructed to lie on their side for at least 1 hour after intrathecal administration of methotrexate. This will ensure adequate delivery of drug throughout the CSF.


• Instruct patients to avoid sun exposure for at least 1 month after therapy

• Caution patients about drinking carbonated beverages as they can increase the acidity of urine, resulting in impaired drug elimination.


5-FLUOROURACIL

• TRADE NAME:- 5-FU, EFUDEX

ABSORPTION

• Oral absorption is variable and erratic with a bioavailability that ranges from 40% to 70%.

• After IV administration, 5-FU is widely distributed to tissues tissues with highest concentration in GI mucosa, bone marrow, and liver.

• Because of its extremely short half-life, on the order of 10-15 minutes, infusional schedules of administration have been generally favored over bolus schedules.

INDICATIONS:

• Colorectal cancer—adjuvant setting and advanced disease.

• Breast cancer—adjuvant setting and advanced disease.

• GI malignancies, including anal, esophageal, gastric, and pancreatic cancer.

• Head and neck cancer.

• Hepatoma.

• Ovarian cancer.

• Topical use in basal cell cancer of skin and actinic keratoses.

DOSAGE RANGE

• Bolus monthly schedule: 425–450 mg/m2 IV on days 1–5 every 28 days.

• Bolus weekly schedule: 500–600 mg/m2 iv every week for 6 weeks every 8 weeks.

• 24-hour infusion: 2400–2600 mg/m2 iv every week.

• 96-hour infusion: 800–1000 mg/m2/day iv.

• 120-hour infusion: 1000 mg/m2/day iv on days 1–5 every 21–28 days.

• Protracted continuous infusion: 200–400 mg/m2/day iv.


• 5FU alone stays in the body for only a short time.

• Leucovorin can enhance the binding of fluorouracil to an enzyme inside of the cancer cells. As a result fluorouracil may stay in the cancer cell longer and exert its anti cancer effect on the cells

• Contraindicated in patients with bone marrow depression, poor nutritional status, infection, active ischemic heart disease, or history of myocardial infarction within previous 6 months.

• Monitored closely for mucositis and/or diarrhea as there is increased potential for dehydration, fluid imbalance, and infection.

• Vistonuridine, at a dose of 10 g PO every 6 hr, may be used in patients overdosed with 5-FU or in those who experience severe toxicity.

• Vitamin B6 (pyridoxine 50 mg PO bid) may be used to prevent and/or reduce the incidence and severity of hand-foot syndrome.

CAPECITABINE

• TRADE NAME:- XELODA

ABSORPTION :

• Capecitabine is readily absorbed by the GI tract.

• The rate and extent of absorption are reduced by food.

INDICATIONS

• Stage III colon cancer- XELOX(XELoda+OXaliplatin)

• Metastatic breast cancer— FDA -approved when used in combination with docetaxel, after failure of prior anthracycline-containing chemotherapy.

• Metastatic breast cancer—FDA -approved as monotherapy in patients refractory to both paclitaxel- and anthracycline-based chemotherapy.

• Metastatic colorectal cancer—FDA -approved as first-line therapy when fluoropyrimidine therapy alone is preferred. XELOX combination is also FDA proved.

DOSAGE RANGE

• Recommended dose for monotherapy is 1,250 mg/m2 PO BID for 2 weeks with 1 wk rest .May decrease dose of capecitabine to 850–1,000 mg/m2 BID on days 1–14 to reduce risk of toxicity without compromising efficacy.

• An alternative dosing schedule for monotherapy is 1,250–1,500 mg/m2 PO BID for 1 week on and 1 week off; this schedule appears to be well tolerated, with no compromise in clinical efficacy.

• Capecitabine should be used at lower doses (850–1,000 mg/m2 bid on days 1–14) when used in combination with other cytotoxic agents, such as oxaliplatin and lapatinib.


• Capecitabine should be taken with a glass of water within 30 minutes after a meal.

• Contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency-> result in a clinically dangerous increase in the anabolic products of 5-FU.

• Patients should be monitored for diarrhea.

• Drug therapy should be stopped immediately in the presence of grades 2 to 4 hyperbilirubinemia.

• Vitamin B6 (pyridoxine 50 mg PO bid) may be used to prevent and/or reduce the incidence and severity of hand-foot syndrome.

• Celecoxib at a dose of 200 mg PO BID may be effective in preventing and/or reducing the incidence and severity of hand-foot syndrome.

• Diltiazem can prevent capecitabine-induced coronary vasospasm and chest pain.

GEMCITABINE

• TRADE NAME:- GEMZAR

ABSORPTION :

• Administered by the IV route.

• Poor oral bioavailability as a result of extensive deamination within the GI tract

INDICATIONS

• Pancreatic cancer— FDA -approved as monotherapy or in combination with erlotinib for first-line treatment of locally advanced or metastatic disease.

• Non–small cell lung cancer—FDA -approved in combination with cisplatin for first-line treatment of inoperable, locally advanced, or metastatic disease.

• Breast cancer—FDA -approved in combination with paclitaxel for first-line treatment of metastatic breast cancer

• Ovarian cancer—FDA -approved in combination with carboplatin for with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

• Bladder cancer.

• Soft tissue sarcoma.

• Hodgkin’s lymphoma

• Non-hodgkin’s lymphoma.

DOSAGE RANGE

• Pancreatic cancer: 1,000 mg/m2 IV every week for 7 weeks with 1 week rest treatment then continues weekly for 3 weeks followed by 1 week off

• Bladder cancer: 1,000 mg/m2 IV on days 1, 8, and 15 every 28 days

• Non–small-cell lung cancer: 1,000-1,200 mg/m2 IV on days 1 and 8 every 21 days


• Gemcitabine is a potent radiosensitizer.

• Monitor CBCS on a regular basis during therapy.

• Myelosuppression is dose-limiting.


OTHER USEFUL ANTI-METABOLITES

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alkylating agents & anti-metabolites chemotherapy

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