Nilesh Kucha, profile picture
Uploaded byNilesh Kucha
PPT, PDF5,295 views

Chapter 20 alkylating agent extra

This document describes alkylating agents, a class of chemotherapy drugs that work by alkylating DNA and proteins. It discusses their mechanism of action, including how they crosslink DNA and cause DNA damage, leading to cell death. It also covers resistance mechanisms, adverse effects like bone marrow toxicity and nausea/vomiting, and important alkylating agents like cisplatin, carboplatin, oxaliplatin, cyclophosphamide, and carmustine. For each drug, it provides absorption, indications, dosage ranges, and special considerations.

Embed presentation

Downloaded 57 times
ALKYLATING AGENTS
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 CISPLATIN TRADE 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
CARBOPLATIN 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.
SPECIAL CONSIDERATIONS • 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. 2. NON-HODGKIN’S LYMPHOMA. 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.
SPECIAL CONSIDERATIONS: • 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. • Pregnancy category D. Breastfeeding should be avoided. • 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. 3. NON-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)
SPECIAL CONSIDERATIONS: • 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. • Pregnancy category D. Breastfeeding should be avoided.
TEMOZOLOMIDE • TRADE NAME:- TEMODAR
MECHANISM OFACTION • 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.
SPECIAL CONSIDERATIONS • 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
OTHER USEFUL ALKYLATING AGENTS
OTHER USEFUL ALKYLATING AGENTS
ANTI-METABOLITES
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.
SPECIAL CONSIDERATIONS • 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.
SPECIAL CONSIDERATIONS • 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.
SPECIAL CONSIDERATIONS • 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.
SPECIAL CONSIDERATIONS • 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. • Pregnancy category D. Breastfeeding should be avoided.
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.
SPECIAL CONSIDERATIONS • 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.
SPECIAL CONSIDERATIONS • 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
SPECIAL CONSIDERATIONS • Gemcitabine is a potent radiosensitizer. • Monitor CBCS on a regular basis during therapy. • Myelosuppression is dose-limiting. • Pregnancy category D. Breastfeeding should be avoided.
OTHER USEFUL ANTI- METABOLITES
OTHER USEFUL ANTI- METABOLITES
THANKS

More Related Content

PPTX
Anticancer drugs 2 alkylating agents
bySubramani Parasuraman
 
PPTX
Microtubule inhibitors
byLAKSHMI DEEPTHI GEDELA
 
PPTX
Chapter 24.1 kinase inhibitors and monoclonal antibodies
byNilesh Kucha
 
PPTX
Anthracyclines
byDr. Chinmayee Agrawal
 
PPTX
Anthracyclines dr. varun
byVarun Goel
 
PPTX
Antitumor antibiotics
byMohammed Fathy
 
PPTX
TDM OF DOXORUBICIN
byGayatri Peruri
 
PPTX
Chemotherapy
bydas nelaturi
 
Anticancer drugs 2 alkylating agents
bySubramani Parasuraman
 
Microtubule inhibitors
byLAKSHMI DEEPTHI GEDELA
 
Chapter 24.1 kinase inhibitors and monoclonal antibodies
byNilesh Kucha
 
Anthracyclines
byDr. Chinmayee Agrawal
 
Anthracyclines dr. varun
byVarun Goel
 
Antitumor antibiotics
byMohammed Fathy
 
TDM OF DOXORUBICIN
byGayatri Peruri
 
Chemotherapy
bydas nelaturi
 

What's hot

PPTX
Alkylating Agents & Anti-metabolites Chemotherapy
byAaditya Prakash
 
PPTX
BASIC PRINCIPLES OF CANCER CHEMOTHERAPY- THIRD PHARM.D
byAPOLLO JAMES
 
PDF
Anticancer drugs REVISION NOTES
byTONY SCARIA
 
PPTX
Vinca Alkaloids as Anticancer Agents (Looking back and peering ahead)
byMohammad Abrar Khan
 
PPTX
Chapter 22 vinka alkaloids
byNilesh Kucha
 
PDF
Alkylating agents -Medicinal Chemistry
byNarminHamaaminHussen
 
PPTX
Alkylating agents
byMoney Kalash
 
PPTX
Introduction to chemotherapy of cancer
bySubramani Parasuraman
 
PPTX
Antimetabolites
bySabaMustafa11
 
PPTX
Anticancer drugs 1 introduction and classification
bySubramani Parasuraman
 
PPTX
Chemotherapy induced nausea and vomiting
byswathisravani
 
PPTX
Anti tubercular drugs
bySneha Gogineni
 
PPTX
Antimetabolites in cancer chemotherapy
byOriba Dan Langoya
 
PPTX
Anticancer drugs 3 antimetabolites
bySubramani Parasuraman
 
PPTX
Cyclophosphamide ppt
byFerdie Fatiga
 
PPT
Anti metabolites
byDr VARUN RAGHAVAN
 
PPTX
Polyene and polypeptide antibiotics
byNarasimha Kumar G V
 
PPT
Antineoplastic agents(ravisankar)
byDr. Ravi Sankar
 
PPTX
Antineoplastic agents
byDr. Koppala R.V.S. Chaitanya
 
PPTX
Cotrimoxazole
byVijay Kevlani
 
Alkylating Agents & Anti-metabolites Chemotherapy
byAaditya Prakash
 
BASIC PRINCIPLES OF CANCER CHEMOTHERAPY- THIRD PHARM.D
byAPOLLO JAMES
 
Anticancer drugs REVISION NOTES
byTONY SCARIA
 
Vinca Alkaloids as Anticancer Agents (Looking back and peering ahead)
byMohammad Abrar Khan
 
Chapter 22 vinka alkaloids
byNilesh Kucha
 
Alkylating agents -Medicinal Chemistry
byNarminHamaaminHussen
 
Alkylating agents
byMoney Kalash
 
Introduction to chemotherapy of cancer
bySubramani Parasuraman
 
Antimetabolites
bySabaMustafa11
 
Anticancer drugs 1 introduction and classification
bySubramani Parasuraman
 
Chemotherapy induced nausea and vomiting
byswathisravani
 
Anti tubercular drugs
bySneha Gogineni
 
Antimetabolites in cancer chemotherapy
byOriba Dan Langoya
 
Anticancer drugs 3 antimetabolites
bySubramani Parasuraman
 
Cyclophosphamide ppt
byFerdie Fatiga
 
Anti metabolites
byDr VARUN RAGHAVAN
 
Polyene and polypeptide antibiotics
byNarasimha Kumar G V
 
Antineoplastic agents(ravisankar)
byDr. Ravi Sankar
 
Antineoplastic agents
byDr. Koppala R.V.S. Chaitanya
 
Cotrimoxazole
byVijay Kevlani
 

Similar to Chapter 20 alkylating agent extra

PPT
Cisplatin (Anti-cancer Drug)
byAsthaNeupane
 
PPTX
Cytotoxic Drug.pptx
byTabel el
 
PPTX
CYTOTOXIC DRUGS - Dr Apurva.pptx
byapurvap23
 
PPTX
2. alkylating & anti-metabolite drugs
byHarshikaPatel6
 
PPTX
platinum containing compounds
bywaqas ahmad
 
PPTX
Chemotherapy of Malignancy -Anticancer.pptx
byMayuri Chavan
 
PPTX
Anticancer drugs
byArsi University, Asella, Ethiopia
 
PPTX
Chapter 21 alkylating agents,platins,antimetabolites
byNilesh Kucha
 
PPTX
Basic considerations of chemotherapy
byRajib Bhattacharjee
 
PPTX
carboplatin
byKalpanaKawan1
 
PPTX
ANTI-CANCER DRUGS: All you need to know by RxVichuz!
byRxVichuZ
 
PPT
Anticancer agents in medicinal chemistry
bymuthulakshmi623285
 
PPTX
Cancer & Cancer Drug
byMd. Shariful Islam
 
PPTX
Chemotherapy drugs in gynecological oncology
bySravanthi Nuthalapati
 
PPTX
Alkylating agents
byMohammed Fathy
 
PPTX
Alkylating agents by Dr.Neenu Thomas
bymammenchrn
 
PPTX
chemotherapyagents .pptx
byJuma675663
 
PPTX
alkylating agents.pptx
byAkashVigneshwar
 
PPT
Anticancer agents
bymuthulakshmi623285
 
PPTX
Chemotherapy in head and neck
bySREENIVAS KAMATH
 
Cisplatin (Anti-cancer Drug)
byAsthaNeupane
 
Cytotoxic Drug.pptx
byTabel el
 
CYTOTOXIC DRUGS - Dr Apurva.pptx
byapurvap23
 
2. alkylating & anti-metabolite drugs
byHarshikaPatel6
 
platinum containing compounds
bywaqas ahmad
 
Chemotherapy of Malignancy -Anticancer.pptx
byMayuri Chavan
 
Anticancer drugs
byArsi University, Asella, Ethiopia
 
Chapter 21 alkylating agents,platins,antimetabolites
byNilesh Kucha
 
Basic considerations of chemotherapy
byRajib Bhattacharjee
 
carboplatin
byKalpanaKawan1
 
ANTI-CANCER DRUGS: All you need to know by RxVichuz!
byRxVichuZ
 
Anticancer agents in medicinal chemistry
bymuthulakshmi623285
 
Cancer & Cancer Drug
byMd. Shariful Islam
 
Chemotherapy drugs in gynecological oncology
bySravanthi Nuthalapati
 
Alkylating agents
byMohammed Fathy
 
Alkylating agents by Dr.Neenu Thomas
bymammenchrn
 
chemotherapyagents .pptx
byJuma675663
 
alkylating agents.pptx
byAkashVigneshwar
 
Anticancer agents
bymuthulakshmi623285
 
Chemotherapy in head and neck
bySREENIVAS KAMATH
 

More from Nilesh Kucha

PPT
Chapter 24 tyrosine kinase inhibitors
byNilesh Kucha
 
PPTX
Chapter 35 tumor lysis syndrome
byNilesh Kucha
 
PPT
Chapter 24.3 metronomic chemotherapy
byNilesh Kucha
 
PPTX
Chapter 27 chemotherapy side effects dr lms
byNilesh Kucha
 
PPTX
Chapter 32 invasion and metastasis
byNilesh Kucha
 
PPTX
Chapter 26 chemoprevention of cancer
byNilesh Kucha
 
PPTX
Chapter 30 febrile neutropenia
byNilesh Kucha
 
PPTX
Chapter 24.2 lmwh in cancer asso thrombosis
byNilesh Kucha
 
PPTX
Chapter 25 assessment of clincal responses
byNilesh Kucha
 
PDF
Chapter 39 role of radiotherapy in benign diseases.pptx [read only]
byNilesh Kucha
 
PPTX
Chapter 33 isolated tumor cells
byNilesh Kucha
 
PPTX
Chapter 31 genetic counselling
byNilesh Kucha
 
PPTX
Chapter 38 role of surgery in cancer prevention
byNilesh Kucha
 
PPTX
Chapter 34 medical stat
byNilesh Kucha
 
PPTX
Chapter 37 svco
byNilesh Kucha
 
PPTX
Chapter 29 dendritic cells
byNilesh Kucha
 
PPTX
Chapter 39 role of radiotherapy in benign diseases
byNilesh Kucha
 
PDF
Chapter 39 role of radiotherapy in benign diseases
byNilesh Kucha
 
PPTX
Chapter 36 t reg cells
byNilesh Kucha
 
PPT
Chapter 28 clincal trials
byNilesh Kucha
 
Chapter 24 tyrosine kinase inhibitors
byNilesh Kucha
 
Chapter 35 tumor lysis syndrome
byNilesh Kucha
 
Chapter 24.3 metronomic chemotherapy
byNilesh Kucha
 
Chapter 27 chemotherapy side effects dr lms
byNilesh Kucha
 
Chapter 32 invasion and metastasis
byNilesh Kucha
 
Chapter 26 chemoprevention of cancer
byNilesh Kucha
 
Chapter 30 febrile neutropenia
byNilesh Kucha
 
Chapter 24.2 lmwh in cancer asso thrombosis
byNilesh Kucha
 
Chapter 25 assessment of clincal responses
byNilesh Kucha
 
Chapter 39 role of radiotherapy in benign diseases.pptx [read only]
byNilesh Kucha
 
Chapter 33 isolated tumor cells
byNilesh Kucha
 
Chapter 31 genetic counselling
byNilesh Kucha
 
Chapter 38 role of surgery in cancer prevention
byNilesh Kucha
 
Chapter 34 medical stat
byNilesh Kucha
 
Chapter 37 svco
byNilesh Kucha
 
Chapter 29 dendritic cells
byNilesh Kucha
 
Chapter 39 role of radiotherapy in benign diseases
byNilesh Kucha
 
Chapter 39 role of radiotherapy in benign diseases
byNilesh Kucha
 
Chapter 36 t reg cells
byNilesh Kucha
 
Chapter 28 clincal trials
byNilesh Kucha
 

Recently uploaded

PPTX
Urinary tract infection- sample collection , transport and processing
byBilalMaheen
 
PPTX
NATURAL HISTORY OF DISEASE : Definitions , key terms & Example
byZoha Sajjad Hussain
 
PDF
Presentation HTN pregnancy (ANAESTHESIA IN HYPERTENSIVE DISORDERS OF PREGNANCY)
bybezupasana3
 
PDF
spirometry workshop, physiology department, GMC surat.pdf
bydralpnamathur
 
PPTX
Physiotherapy Case Presentation of Left-Sided Subdural Hematoma (SDH)
byFarseen Mohammed P
 
PPTX
Vaccine Preventable Diseases and immunization.pptx
byBilaspaBashyal
 
PDF
MCQ of 10th NHPC Masters of Optometry.pdf
byBipin Koirala
 
PPTX
intracanal medicaments and in endodontics
byvarunrajarn
 
PPTX
Imaging approach to Intraventricular tumors
byDr. Aryan (Anish Dhakal)
 
PPTX
Tourniquet, Types and it's application in a clinical setting.pptx
byNandhakumar S
 
PDF
Hip Joint -Prof.Dr.N.Mugunthan. KMMC Medical College.pdf
byKanyakumari Medical Mission Research Center, Muttom
 
PDF
lec3.Triangles of the neck...... (1).pdf
byeimili1234err
 
PPTX
Safe Water, Sanitation, and Hygiene (WASH).pptx
byDr.Bharti Koria
 
PPTX
Anatomy of respiratory system in Pediatrics View.pptx
bydoshiharsh814
 
PDF
A BRIEF STUDY ON MENINGITIS WITH HOMOEOPATHIC APPROACH
bysadanandarya1
 
PPTX
Journey of HFPEF diagnosis to treatment.pptx
byGauravVerma555753
 
PPTX
WCPCCS 2025 Intelligent Digital Agents Final.pptx
byJAI NAHAR, MD MBA
 
PPTX
Spirituality and Mental Health - therapy perspectives and formulation pptx
bySaju Pj
 
PDF
Public Health Status of Nepal: Data, Facts, and Resources
byPublic Health Concern Nepal
 
PDF
Ayurvedic Cosmetology: A Hands-On Training in Skin & Hair Care
byDrAmruthaSajeevan
 
Urinary tract infection- sample collection , transport and processing
byBilalMaheen
 
NATURAL HISTORY OF DISEASE : Definitions , key terms & Example
byZoha Sajjad Hussain
 
Presentation HTN pregnancy (ANAESTHESIA IN HYPERTENSIVE DISORDERS OF PREGNANCY)
bybezupasana3
 
spirometry workshop, physiology department, GMC surat.pdf
bydralpnamathur
 
Physiotherapy Case Presentation of Left-Sided Subdural Hematoma (SDH)
byFarseen Mohammed P
 
Vaccine Preventable Diseases and immunization.pptx
byBilaspaBashyal
 
MCQ of 10th NHPC Masters of Optometry.pdf
byBipin Koirala
 
intracanal medicaments and in endodontics
byvarunrajarn
 
Imaging approach to Intraventricular tumors
byDr. Aryan (Anish Dhakal)
 
Tourniquet, Types and it's application in a clinical setting.pptx
byNandhakumar S
 
Hip Joint -Prof.Dr.N.Mugunthan. KMMC Medical College.pdf
byKanyakumari Medical Mission Research Center, Muttom
 
lec3.Triangles of the neck...... (1).pdf
byeimili1234err
 
Safe Water, Sanitation, and Hygiene (WASH).pptx
byDr.Bharti Koria
 
Anatomy of respiratory system in Pediatrics View.pptx
bydoshiharsh814
 
A BRIEF STUDY ON MENINGITIS WITH HOMOEOPATHIC APPROACH
bysadanandarya1
 
Journey of HFPEF diagnosis to treatment.pptx
byGauravVerma555753
 
WCPCCS 2025 Intelligent Digital Agents Final.pptx
byJAI NAHAR, MD MBA
 
Spirituality and Mental Health - therapy perspectives and formulation pptx
bySaju Pj
 
Public Health Status of Nepal: Data, Facts, and Resources
byPublic Health Concern Nepal
 
Ayurvedic Cosmetology: A Hands-On Training in Skin & Hair Care
byDrAmruthaSajeevan
 

Chapter 20 alkylating agent extra

  • 1.
  • 4.
  • 5.
    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.
  • 6.
    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.
  • 7.
    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.
  • 8.
     A bis(chloroethyl)amineforms 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.
  • 9.
    RESISTANCE • Increased capabilityto 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
  • 10.
    ADVERSE EFFECTS • NAUSEAAND 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.
  • 11.
    ADVERSE EFFECTS • INTERSTITIALPNEUMONITIS 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
  • 12.
    IMPORTANT CLINICALLY USEFUL ALKYLATINGAGENTS CISPLATIN TRADE NAME :- CIS-DIAMMINEDICHLOROPLATINUM, CDDP, PLATINOL
  • 13.
    ABSORPTION: • Not absorbedorally. • 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.
  • 14.
    DOSAGE RANGE: • OVARIANCANCER— 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)
  • 15.
    SPECIAL CONSIDERATIONS: • Contraindicatedin 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
  • 16.
  • 17.
    ABSORPTION: Not absorbed bythe 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.
  • 18.
    DOSAGE RANGE: • Usuallycalculated 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.
  • 19.
    SPECIAL CONSIDERATIONS: • Contraindicatedin 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.
  • 20.
    OXALIPLATIN • TRADE NAME:-ELOXATIN, DIAMINOCYCLOHEXANE PLATINUM
  • 21.
    ABSORPTION • Not orallybioavailable. 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.
  • 22.
    DOSAGE RANGE: • Recommendeddose 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.
  • 23.
    SPECIAL CONSIDERATIONS • Calcium/magnesiuminfusions (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.
  • 25.
  • 26.
    ABSORPTION • Well-absorbed bythe GI tract with a bioavailability of nearly 90% INDICATIONS 1. BREAST CANCER. 2. NON-HODGKIN’S LYMPHOMA. 3. CHRONIC LYMPHOCYTIC LEUKEMIA. 4. OVARIAN CANCER. 5. BONE AND SOFT TISSUE SARCOMA. 6. RHABDOMYOSARCOMA. 7. NEUROBLASTOMA 8. WILMS’ TUMOR.
  • 27.
    DOSAGE RANGE: • BREASTCANCER— 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.
  • 28.
    SPECIAL CONSIDERATIONS: • Usewith 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. • Pregnancy category D. Breastfeeding should be avoided. • Myelosuppression is dose-limiting.
  • 29.
    CARMUSTINE • TRADE NAME:-BCNU, BISCHLOROETHYLNITROSOUREA
  • 30.
    ABSORPTION • Not absorbedvia the oral route. INDICATIONS 1. BRAIN TUMORS— Glioblastoma Multiforme, Brain Stem Glioma, Medulloblastoma,astrocytoma, And Ependymoma. 2. HODGKIN’S LYMPHOMA. 3. NON-HODGKIN’S LYMPHOMA. 4. MULTIPLE MYELOMA. 5. GLIOBLASTOMA MULTIFORME— Implantable BCNU - impregnated wafer (GLIADEL). 6. CUTANEOUS T-CELL LYMPHOMA
  • 31.
    DOSAGE RANGE: • Usualdose 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)
  • 33.
    SPECIAL CONSIDERATIONS: • PFTsshould 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. • Pregnancy category D. Breastfeeding should be avoided.
  • 34.
  • 35.
    MECHANISM OFACTION • Methylatesguanine 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.
  • 36.
    ABSORPTION • Rapidly andcompletely 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.
  • 37.
    DOSAGE RANGE: • Temozolomideis 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.
  • 38.
    SPECIAL CONSIDERATIONS • Monitoredclosely 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.
  • 39.
  • 40.
  • 41.
  • 42.
  • 44.
    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)
  • 45.
    MECHANISM OF ACTION •PURINE ANTAGONISTS inhibit enzymes involved in de novo purine synthesis and purine interconversion reactions.
  • 46.
    RESISTANCE • Alteration inantifolate 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)
  • 47.
    ADVERSE EFFECTS • Dose-limitingmyelosuppression • Gastro-intestinal (GI) toxicity • Acute elevations in hepatic enzyme levels and hyperbilirubinemia (with high doses) • Mucositis, skin rash (hand-foot syndrome)
  • 48.
  • 49.
    ABSORPTION • Oral bioavailabilityis 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.
  • 50.
    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.
  • 51.
    DOSAGE RANGE • Lowdose: 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.
  • 52.
    SPECIAL CONSIDERATIONS • Methotrexateenhances 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.
  • 55.
    SPECIAL CONSIDERATIONS • Thymidine—thymidinerescues 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.
  • 56.
    SPECIAL CONSIDERATIONS • Withhigh-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.
  • 57.
    SPECIAL CONSIDERATIONS • Instructpatients 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. • Pregnancy category D. Breastfeeding should be avoided.
  • 58.
  • 59.
    ABSORPTION • Oral absorptionis 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.
  • 60.
    INDICATIONS: • Colorectal cancer—adjuvantsetting 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.
  • 61.
    DOSAGE RANGE • Bolusmonthly 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.
  • 63.
    SPECIAL CONSIDERATIONS • 5FUalone 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.
  • 64.
  • 65.
    ABSORPTION : • Capecitabineis 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.
  • 66.
    DOSAGE RANGE • Recommendeddose 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.
  • 67.
    SPECIAL CONSIDERATIONS • Capecitabineshould 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.
  • 68.
  • 69.
    ABSORPTION : • Administeredby 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.
  • 70.
    DOSAGE RANGE • Pancreaticcancer: 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
  • 71.
    SPECIAL CONSIDERATIONS • Gemcitabineis a potent radiosensitizer. • Monitor CBCS on a regular basis during therapy. • Myelosuppression is dose-limiting. • Pregnancy category D. Breastfeeding should be avoided.
  • 72.
  • 73.
  • 74.