Anticancer Drug; The latest classification of anti cancer drug

Anticancer Drug
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Anticancer or antineoplastic drugs are used to treat malignancies, or cancerous growths&control the growth of cancerous cells. Cancer is commonly defined as the uncontrolled growth of cells, with loss of differentiation and commonly, with metastasis, the spread of cancer to other tissues and organs. Cancers are malignant growths. In contrast, benign growths remain encapsulated and grow within a well-defined area. Drug therapy may be used alone, or in combination with other treatments such as surgery or radiation therapy.

The top 10 best-selling (in terms of revenue) cancer drugs list

No. Global Sales INN Trade names Marketing authorization holder Indications
1 $7.78 billion Rituximab Rituxan, MabThera Roche, Pharmstandard non-Hodgkin’s lymphoma, CLL
2 $6.75 billion Bevacizumab Avastin Roche Colorectal, lung, ovarian and brain cancer
3 $6.56 billion Trastuzumab Herceptin Roche Breast, esophagus and stomach cancer
4 $4.69 billion Imatinib Gleevec Novartis Leukemia, GI cancer
5 $1.09 billion Lenalidomide Revlimid Celgene, Pharmstandard Multiple myeloma, mantle cell lymphoma
6 $2.7 billion Pemetrexed Alimta Eli Lilly Lung cancer
7 $2.6 billion Bortezomib Velcade Johnson & Johnson, Takeda, Pharmstandard Multiple myeloma
8 $1.87 billion Cetuximab Erbitux Merck KGaA, Bristol-Myers Squibb Colon and head and neck cancer
9 $1.73 billion Leuprorelin Lupron, Eligard AbbVie and Takeda; Sanofi and Astellas Pharma Prostate and ovarian cancer
10 $1.7 billion Abiraterone Zytiga Johnson & Johnson Prostate cancer

1.    Polyfunctional alkylating agents

  • Nitrosourea
  •  Mustards (Nitrogen Mustards)
  • Methanesulphonates (Busulphan)
  • Ethylenimines

2.    Other Alkylating Drugs

  • Procarbazine (Matulane)
  • Dacarbazine (DTIC)
  • Altretamine (Hexalen)
  • Cisplatin (Platinol)

3.    Antimetabolites

  •  Antifolic acid compounds (Methotrexate)
  • Amino acid Antagonists (Azaserine)

4.    Purine antagonists

  • Mercaptopurine (6-MP)
  • Thioguanine (6-TG)
  • Fludarabine Phosphate
  • Cladribine (Leustatin)
  • Pentostatin (Nipent)

5.    Pyrimidine antagonists

  • Mucositis
  • Fluorouracil (5-FU)
  • Cytarabine (ARA-C)
  • Azacitidine

6.    Plant alkaloids

  • Vinblastine (Velban)
  • Vincristine (Oncovin)
  • Etoposide (VP-16,VePe-sid)
  • Teniposide (Vumon)
  • Topotecan (Hycamtin)
  • Irinotecan (Camptosar)
  • Paclitaxel (Taxol)
  • Docetaxel (Taxotere)

7.    Antibiotics

  • Anthracyclines
  • Doxorubicin (Adriamycin, Rubex, Doxil)
  • Daunorubicin (DaunoXome)
  • Dactinomycin (Cosmegen)
  • Idarubincin (Idamycin)
  • Plicamycin (Mithramycin)
  • Mitomycin (Mutamycin)
  • Bleomycin (Blenoxane)

8.    Monoclonal Antibodies

9.    Hormonal agents

  • Tamoxifen (Nolvadex)
  • Flutamide (Eulexin)
  • Gonadotropin-Releasing Hormone Agonists
  • (Leuprolide and Goserelin (Zoladex))
  • Aromatase Inhibitors
  • Aminoglutethimide
  • Anastrozole (Arimidex)

10.    Miscellaneous anticancer drugs

  • Amsacrine
  • Hydroxyurea (Hydrea)
  • Asparaginase (El-spar)
  • Mitoxantrone (Novantrone)
  • Mitotane
  • Retinoic Acid Derivatives
  • Bone Marrow Growth Factors
  • Amifostine

Newer and experimental approaches

Hematopoietic stem cell transplant approaches

Stem cell harvesting and autologous or allogeneic stem cell transplant have been used to allow for higher doses of chemotherapeutic agents where dosages are primarily limited by hematopoietic damage. Years of research in treating solid tumors, particularly breast cancer, with hematopoeitic stem cell transplants, has yielded little proof of efficacy. Hematological malignancies such as myeloma, lymphoma, and leukemia remain the main indications for stem cell transplants.

Isolated infusion approaches

Isolated limb perfusion (often used in melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumors. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage. These approaches can help control solitary or limited metastases, but they are by definition not systemic, and, therefore, do not treat distributed metastases or micrometastases.

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Targeted delivery mechanisms

Specially-targeted delivery vehicles aim to increase effective levels of chemotherapy for tumor cells while reducing effective levels for other cells. This should result in an increased tumor kill and/or reduced toxicity.
Specially-targeted delivery vehicles have a differentially higher affinity for tumor cells by interacting with tumor-specific or tumour-associated antigens.
In addition to their targeting component, they also carry a payload – whether this is a traditional chemotherapeutic agent, or a radioisotope or an immune stimulating factor. Specially-targeted delivery vehicles vary in their stability, selectivity, and choice of target, but, in essence, they all aim to increase the maximum effective dose that can be delivered to the tumor cells. Reduced systemic toxicity means that they can also be used in sicker patients, and that they can carry new chemotherapeutic agents that would have been far too toxic to deliver via traditional systemic approaches.

Nanoparticles
Nanoparticles have emerged as a useful vehicle for poorly-soluble agents such as paclitaxel. Protein-bound paclitaxel (e.g., Abraxane) or nab-paclitaxel was approved by the U.S. Food and Drug Administration (FDA) in January 2005 for the treatment of refractory breast cancer and allows reduced use of the Cremophor vehicle usually found in paclitaxel. Nanoparticles made of magnetic material can also be used to concentrate agents at tumor sites using an externally applied magnetic field.

Polyfunctional alkylating agents of Anticancer Drug

•    Common Structural Features:
o    bis(chloroethyl)amine
o    ethylenimine
o    nitrosoureas
•    Not cell-cycle specific: Cells most susceptible in late G1 and S phase– Blocks in G2
Most useful agents:
•    Cyclophosphamide (Cytoxan)
o    fosfamide
•    Mechlorethamine
•    Melphalan (Alkeran)
•    Chlorambucil (Leukeran)     Secondary agents
•    Thiopeta (Thioplex)
o    Ovarian cancer
•    Busulfan (Myleran)
o    Chronic myeloid leukemia

Major nitrosoureas:
•    Carmustine (BCNU)
•    Lomustine (CCNU)
•    Semustine (methyl CCNU)

Polyfunctional Alkylating Drugs:
Mechanism of Action:
•    Alkyl group transfer
o    Major interaction: Alkylation of DNA
Primary DNA alkylation site: N7 position of guanine (other sites as well)
interaction may involve single strands or both strands (cross linking, due to bifunctional  characteristics)
o    Other interactions: these drugs react with carboxyl, sulfhydryl, amino, hydroxyl, and phosphate groups of other cellular constituents
o    These drugs usually form a reactive intermediate — ethyleneimonium ion

Polyfunctional Alkylating Drug Resistance
•    Increased ability to repair DNA defects
•    Decreased cellular permeability to the drug
•    Increased glutathione synthesis
o    inactivates alkylating agents through conjugation reactions (catalyzed by glutathione S-transferase)

Polyfunctional Alkylating Drugs:
S.A.R.
Genotoxic carcinogens, able to damage DNA by alkylation reactions, represent a very diverse class of agents which are capable of producing a wide range of DNA modifications. The mechanisms leading to genetic changes as a result of exposure to alkylating agents (AAs) have been studied in male germ cells of Drosophila using a structure-activity relationship approach (SAR). The analytical tools available concern both genetic and molecular assays. The genetic tests enable to quantify excision repair and clastogenic potency of the AA after treatment of post-meiotic male germ cells and to determine the degree of germ-cell specificity, i.e., the mutagenic effectiveness in post- versus premeiotic cell stages. For a selected group of alkylating agents the molecular spectra have been studied in post-meiotic cell stages. On the basis of these descriptors clear SAR’s between genotoxic activity in germ cells and physico-chemical parameters (s-values and O6/N7-alkylguanine adducts) and carcinogenic potency in rodents became apparent, resulting in five distinct classes of alkylating agents so far. These classes are: 1) SN2-type monofunctional AAs, 2) SN1-type monofunctional AAs, 3) polyfunctional AAs, 4) agents able to form etheno-DNA adducts, and 5) aflatoxin B1 (AFB1) a bulky-adduct forming agent. The recent finding that the molecular data obtained with Drosophila and data of the specific locus tests in male mice show remarkable similarities for most genotoxic agents supports the view that Drosophila is a useful model system for the study of transgenerational damage.

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Pharmacological Effects: Polyfunctional Alkylating Drugs
•     Injection site damage (vesicant effects) and systemic toxicity.
•    Toxicity:
o    dose related
o    primarily affecting rapidly dividing cells
bone marrow
GI tract
nausea and vomiting within less than an hour– with mechlorethamine, carmustine (BCNU) or cyclophosphamide
Emetic effects: CNS
reduced by pre-treatment with phenothiazines or cannabinoids.
gonads

o    Cyclophosphamide cytotoxicity depends on activation by microsomal enzyme system.
Hepatic microsomal P450 mixed-function oxidase catalyzes conversion of cyclophosphamide to the active forms:
4-hydroxycyclophosphamide
aldophosphamide

o     Major Toxicity: bone marrow suppression
dose-related suppression of myelopoiesis: primary effects on
megakaryocytes
platelets
granulocytes
Bone marrow suppression is worse when alkylating agents are combined with other myelosuppressive drugs and/or radiation (dose
reduction required)
If bone marrow suppression is severe, treatment may have to be suspended and then re–initiated upon hematopoietic recovery.
Long-term consequences of alkylating agent treatment include:
ovarian failure (common)
testicular failure (common)
acute leukemia (rare)
•    Oral Route of Administration:
Cyclophosphamide (Cytoxan), melphalan (Alkeran), chlorambucil (Leukeran), busulfan (Myleran), lomustine (CCNU, CeeNU)
•    Cyclophosphamide (Cytoxan):   most useful alkylating agent at present.
•    Busulfan (Myleran): specificity for granulocytes — chronic myelogenous leukemia

•    Nitrosoureas:
o     Not cross reactive (with respect to tumor resistance) with other alkylating drugs.
o    Nonenzymatic by transformation required to activate compounds.
o    Highly lipid- soluble– crosses the blood-brain barrier (BBB)
useful in treating brain tumors
o    Act by cross-linking: DNA alkylation
o    More effective against cells in plateau phase than cells in exponential growth phase
o    Major route of elimination:urinary excretion
o    Steptozocin:
sugar-containing nitrosourea
minimal bone marrow suppression
effective in insulin-secreting islet cell pancreatic carcinoma and sometimes in non-Hodgkin’s lymphoma
SAR
A novel series of symmetrical ureas of [(7-amino(2-naphthyl))sulfonyl]phenylamines were designed, synthesized, and tested for their ability to increase glucose transport in mouse 3T3-L1 adipocytes, a surrogate readout for activation of the insulin receptor (IR) tyrosine kinase (IRTK). A structure-activity relationship was established that indicated glucose transport activity was dependent on the presence of two acidic functionalities, two sulfonamide linkages, and a central urea or 2-imidazolidinone core. Compound 30 was identified as a potent and selective IRTK activator. At low concentrations, 30 was able to increase the tyrosine phosphorylation of the IR stimulated by submaximal insulin. At higher concentrations, 30 was able to increase tyrosine the phosphorylation levels of the IR in the absence of insulin. When administered intraperitoneally (ip) and orally (po), 30 improved glucose tolerance in hypoinsulinemic, streptozotocin-treated rats. These data provide pharmacological validation that small molecule IRTK activators represent a potential new class of antidiabetic agents.

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Other Alkylating Drugs
•    Procarbazine (Matulane)
o    Methylhydrazine derivative
o    Active in Hodgkin’s disease (combination therapy)
o    Teratogenic, mutagenic, leukemogenic.

o     Side effects:
nausea, vomiting, myelosuppression
hemolytic anemia
pulmonary effects
•    Dacarbazine (DTIC)

o    Clinical use:
Melanoma
Hodgkin’s disease
soft tissue sarcoma
o    Synthetic drug; requires activation by liver microsomal system.
o    Parenteral administration
o     Side effects:
nausea, vomiting, myelosuppression
•    Altretamine (Hexalen)
o    Clinical use:
alkylating agent-resistant: ovarian carcinoma
o    Activated by biotransformation (demethylation)
o     Side effects:
nausea, vomiting, central and peripheral nervous system neuropathies.
relatively mild myelosuppressive effects.

•    Cisplatin (Platinol)

o    Clinical use:
Genitourinary cancers
testicular
ovarian
bladder
In combination with bleomycin and vinblastine: curative treatment for nonseminomatous testicular cancer
Carboplatin (less GI and renal toxicity; with myelosuppressive toxicity): alternative to cisplatin
o    Inhibits DNA synthesis; cross-linking; guanine N7 site
o    Platinum compounds: synergistic with other anticancer agents
o    Site effects:
major acute effect: nausea, vomiting
relatively little bone marrow effects
significant renal dysfunction (minimized by adequate hydration/diuretics)
acoustic nerve dysfunction

Alkylating Agent Toxicity: Summary
•    IV mechlorethamine, cyclophosphamide, carmustine: Nausea and Vomiting (common)
•    Oral cyclophosphamide: Nausea and Vomiting (less frequently)
•     Most Important Toxic Effect:Bone marrow suppression, leukopenia, thrombocytopenia
o    secondary to myelosuppression —
severe infection
septicemia
o    hemorrhage
•    Cyclophosphamide (Cytoxan):
Alopecia, hemorrhagic cystitis (may be avoided by adequate hydration)

References

Anticancer Drug

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