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Journal of Cancer Research and Molecular Medicine

Review Article

Natural and Synthetic Molecular Medicine in Cancer Research: A Review

Hardesh K Maurya*

Medicinal Chemistry Department, CSIR-Central Institute of Aromatic and Medicinal Plants, Picnic Spot road, Lucknow-226015, India


Corresponding author: Hardesh K Maurya, Medicinal Chemistry Department, CSIR-Central Institute of Aromatic andMedicinal Plants, Picnic Spot road, Lucknow-226015, India; Telephone No.: +919451407702, E-Mail: hardesh11@yahoo


Citation: Maurya HK. Natural and Synthetic Molecular Medicine in Cancer Research: A Review. J Cancer Res Molecul Med. 2014;1(1): 101.


Copyright © Hardesh K Maurya 2014. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Journal of Cancer Research and Molecular Medicine | Volume: 1, Issue: 1


Submission: Submission: 21/10/2014; Accepted: 08/12/2014; Published: 10/12/2014


Abstract


This review presents the stimulating area of natural and synthetic anticancer drugs which are presently used for the cure of various type of cancer. In this review, twenty one naturally, semisynthetic naturally occurring and 109 synthetic anticancer drugs are reported. The emphasis of this review has described related structure, mechanism of action and major disadvantage of these drugs with the aims of providing an overview of anticancer drugs. This review will be provide current status of cancer drug and helpful to make strategy in the search of novel anticancer molecular medicine in future.


Keywords: Anticancer drugs; Chemotherapy; Cancer; Carcinoma; Tumor; Cancer medicine

Introduction


Cancer is a disease with abnormal cell growth of any part ofour body. It is also called malignancy. Cancer’s cells are divideduncontrollably and forms lumps. These lumps are called tumor and harms our body.


On the bases of part of our body more than hundred type carcinoma cells have been reported [1,2]. The most common cancer type are bladder cancer, lung cancer, breast cancer, melanoma (cancer of pigment making cells), colon and rectal cancer, non Hodgkin lymphoma (cancer of white blood cells), endometrial cancer (cancer of uterus), pancreatic cancer, kidney cancer, prostrate cancer, leukemia (cancer of blood forming tissue e.g. bone marrow), thyroid cancer etc [3].


For the treatment of these cancers, various methods were applied such as surgery (a method to remove tumors from body), radiation therapy (a method to destroy or damage carcinoma cell though applies the high wave radiation), targeted therapy (other substances or useing drugs to more accurately discover and attack carcinoma cells), immunotherapy (increase immune system to fight cancer cells), hyperthermia (using heat to treat cancer), Stem cell transplant (stem cells were transplant to treat cancer cells), photodynamic therapy (photosensitizing agents are a special drugs and used along with light to kill cancer cells), lasers in cancer treatment, blood product donation and transfusion, and most important tools chemotherapy (use of medicine to treat cancer) [2]. Cancer therapies are not secured to cure cancer completely. Some cases, it secure to cure cancer completely but it is much costly and maximum population cannot efforts such treatment. Thus maximum patients were died without proper treatment in world. In 2014, 1.66 million new case and 0.556 million deaths have been reported in USA [4], while 14.1 million new case and 8.2 million deaths were estimated in 2012. Cancer is second most common disease (0.806 million) [5] in world as well as in India [6]. These results showing that various therapy are not sufficient to cure this deadly disease.


The future of chemotherapy is only a way to control this disease. More than hundreds molecular medicines are available in market. Current review is a compilation of structures, type of cancer therapy, mechanism of action and major disadvantage of these drugs with the aims of providing an overview of anticancer drugs for further modification in the search of potent anticancer molecular medicine.


Molecular Medicines


However, various molecular medicines are containing nitrogen atoms; therefore, I have classified these medicines on the basis of nitrogen atoms present in drugs.


Natural and semi synthetic medicines


a) One nitrogen containing natural and semi synthetic medicines (Tables 1-4)


Daunorubicin (daunomycin) is an anthracycline antibiotic which was isolated from Streptomyces peucetius [7-9]. It is used to treat acute lymphocytic and myelocytic leukemia since 1960 with the side effects such as hair loss, low white blood cells, vomiting, nausea, decrease platelet counts etc..


Table 1: One nitrogen containing natural and semi synthetic medicines.


Table 2: One nitrogen containing natural and semi synthetic medicines.


Table 3: One nitrogen containing natural and semi synthetic medicines.


Doxorubicin (adriamycin) [10,11]is a semi synthetic medicine of daunorubicin. It is used to treat various type of cancer such as Hodgkin’s lymphoma (a white blood cells’ cancer), acute leukemia, multiple myeloma, Ewing sarcoma, Kaposi sarcoma, breast, ovary, lung, endometrium, adrenal cortex and other cancers with side effect cardiomyopathy (heart muscles disease) with heart failure, hair loss, low white blood cells, vomiting, nausea, decrease platelet counts etc.


Epirubicin [12] (an anthracycline analog) was synthesized from 13-dihydrodaunorubicine (13-daunorubicinol). It is used to treatment of breast cancer with the combination of other drugs and it has low side effects as comparison with doxorubicin.


Daunorubicin, doxorubicin and epirubicin acts as DNA cleavage of carcinoma cells by topoisomerase II inhibitor.


Paclitaxel (Taxol) [13] was isolated from the inner bark of Taxus brevifolia (Pacific yew tree) in 1967. It is used to treatment of long, breast, ovarian, neck, head, Kaposi (a tumor caused by herpes virus) carcinoma with the side effects such as hair loss, low white and red blood cells, vomiting, nausea, decrease platelet counts, diarrhea, numbness, pain in joint etc.


Docetaxel is a semi-synthetic medicine, synthesized from paclitaxel and used to treatment of breast [14], lung, prostate, stomach, head and neck cancers with the side effects such as fever, low white blood cell count, hair loss, diarrhea, nausea, tiredness, anemia, menstrual cycle abnormality in women, skin rash etc.


Cabazitaxel is also a semi-synthetic derivative of taxol and approved to cure prostate cancer [15] since 2010 with similar side effects as indocetaxel.


Paclitaxel, Docetaxel and Cabazitaxel are grouped as taxane and act as microtubule inhibitors (stop the formation of microtubule during the cancer’s cell division).


Temsirolimus [16] is a semi synthetic medicine of sirolimus (also called rapamycin). Sirolimus was isolated from the soil bacteria Streptomyces hygroscopicus. Temsirolimus was approved to cure of renal cell carcinoma (kidney cancer) in 2007 with the side effects of skin rash, tiredness, mouth sores, nausea, swelling in hand, loss of appetite, anaemia, low white blood cell count, high blood sugar, high blood cholesterol etc.


Everolimus [17] is also a semi synthetic medicine of sirolimus and approved to cure renal cell carcinoma in 2009 with similar side effects as temsirolimus.


Temsirolimus and everolimus acts as mTOR inhibitors (mechanistic target of rapamycin). In which these drugs are interface the synthesis of proteins that control the proliferation, growth and survival of cancer cells.


5-Aminolevulinic acid [18] is a natural product intermediate in the formation of porphyrin and also found in insects, fungi, some bacteria, protozoans etc. Due to fluorescent characteristic, it is used detection of cancer and also as photodynamic therapy for various type cancers.


Eribulin [19] is a synthetic analogue of natural product halichondrin B, which was isolated from the marine sponge Halichondria okadai. Eribulin was approved to treatment of metastatic breast cancer (4th state breast cancer) in 2010 with the side effects low white blood and red cell count, numbness, hair loss, tiredness, weakness, nausea, joint and muscle pain, weight loss, loss of appetite, constipation, fever etc. Eribulin acts as microtubule inhibitors of cancer cells.


Omacetaxine [20,21] is a semi synthetic derivative of the alkaloid cephalotaxine which was isolated from Cephalotaxus harringtonia. It is approved to treatment of chronic myelogenous (chronic granulocytic), leukemia (a white blood cell cancer) in 2012 with following side effects anemia, low blood platelet count, low white blood cell count, diarrhea, nausea, pain, tiredness, fever, weakness etc and it works as tyrosine kinase inhibitors.


b) Two nitrogen containing natural and semi synthetic medicines (Table 4)


Ixabepilone (azaepothilone B) is isolated by Sorangium cellulosum (a soil-dwelling gram-negative bacterium). Ixabepilone [22] had shown very high potential at very low concentration as microtubule inhibitors and approved to treatment of metastatic breast cancer in 2007 with side effects hair loss, diarrhea, mouth sores, vomiting, nausea, join and muscle pain, tiredness, numbness, low white blood cell count etc.


Table 4: One and two nitrogen containing natural and semi synthetic medicines.




c) Four nitrogen containing natural and semi synthetic medicines (Table 5,Table 6)


Vincristine ( leurocristine) was isolated from the Catharanthus roseus (a vinca alkaloid) [23]. Vincristine is used to treatment of leukemias, hodgkin’s lymphomas and childhood cancers with side effects constipation, tiredness, hair loss, pain etc. Vinblastine was also obtained from Catharanthus roseus (vinca rosea, a madagascar periwinkle) and used to treatment of Hodking’s lymphomas, breast, lung, testicular (a man reproductive system) head and neck cancers with side effects such as mouth sores, tiredness, low blood platelet count, low white blood cell count etc. Vinorelbine is a semi-synthetic vinca alkaloid and approved for the treatment of non small cell lung and breast cancer in 1989 with side effects constipation, tiredness, weakness, vomiting, nausea, anemia, low white blood cell count etc. Vincristine, vinblastine and vinorelbine are worked as mitotic inhibitors (as antimicrotubule) and inhibit the formation mitosis of carcinoma cells.


Table 5: Four nitrogen containing natural and semi synthetic medicines.






Table 6: Four nitrogen containing natural and semi synthetic medicines.


Irinoteca is a semi-synthetic medicine of the natural alkaloid camptothecin [24] and approved to treatment of colon and rectal cancer which worked as topoisomerase I inhibitors with the side effects such as diarrhea, hair loss, appetite loss, nausea, vomiting, abdominal pain, weakness, low white blood cell count etc.


Mitomycins C [25] are a member of mitomycins natural products family, isolated from Streptomyces caespitosus or Streptomyces lavendulae and Mitomycins C is an antibiotics and worked as alkylating agents for the treatment of stomach, colon, rectal, pancreatic as well as breast, cervical, lung, head and neck cancers with the side effects such as hair loss, tiredness, low white blood cell count, low platelet count etc.




Romidepsin [26] (a depsipeptide) is a natural product obtained from the bacteria Chromobacterium violaceum. It is approved for the treatment for cutaneous T-cell lymphoma (a skin cancer), peripheral T-cell lymphoma in 2005 as histone deacetylase inhibitor with various side effects such as constipation, diarrhea, rashes on skin, other infection, increase blood sugar, anemia, low platelet count, low white blood cell count, appetite loss, tiredness, poor food taste, change in blood mineral level etc.




d) Five and more nitrogen containing natural and semi synthetic medicines (Table 7)


Carfilzomib (a tetrapeptide epoxyketones) is semisynthetic drug of a natural product epoxomicin. Carfilzomib [27] was approved for the treatment of multiple myeloma (cancer of plasma cell) in 2012 and acts as proteasome inhibitors (block the action of proteasomes) with the side effects such as fatigue, anemia, low platelet count, nausea, vomiting, shortness in breathing, fever, diarrhea, cold, cough, headache, diarrhea, swelling, back pain, constipation, low white blood cell count, increase of blood creatinine level etc.


Table 7: Five or more nitrogen containing natural and semi synthetic medicines.


Dactinomycin [28] (actinomycin D) is a polypeptide antibiotics which was isolated from soil bacteria of the genus Streptomyces. Dactinomycin was approved to treatment of Wilms tumors (a type of children’s kidney tumors), Ewings tumors of bone or soft tissues, testicular cancer, sarcomas (in cartilage, fat, muscle or bone) in 1964 and acts as transcription inhibitors (stop cancer cells growing) with the side effects such as radiation effects, hair loss, diarrhea, rash, skin darking, mouth sores, appetite loss, low platelet count, vomiting, nausea, low white blood cell count.




Bleomycin (a glycopeptide) is an antibiotic which was isolated from the bacterium Streptomyces verticillus. Bleomycin [29,30] is used to treatment of Hodgkin’s sarcoma, lymphoma, squamous cell cancer of the head, neck, cervix, testicular cancer etc and acting as DNA breaking of cancer cells with side effects such as fever, chill, nausea, vomiting, appetite loss, hair loss, mouth sores, darkened skin etc.


Synthetic molecular medicines


a) One nitrogen containing synthetic medicines (Table 8,Table 9)


Chlorambucil [31] is a nitrogen mustard alkylating agents (act as binding DNA) approved before 1984 for the treatment of Hodgkin and non-Hodgkin lymphoma, chronic lymphocytic leukemia, trophoblastic neoplasms, waldenström macroglobulinemia (a white blood cell carcinoma), polycythemia vera (formation of more red blood cell) and ovarian carcinoma with side effects low white blood cells count, low platelet count, menstrual period stop, sperm reduction, hair loss etc.


Table 8: One nitrogen containing synthetic medicines.


Table 9: One nitrogen containing synthetic medicines.


Chlormethine (mechlorethamine, mustine) is also nitrogen mustard alkylating agents and used to treatment of prostate cancer since 1946[32] with side effects such as low white blood cell count, low platelet count, anemia, nausea, vomiting, tasteless, low appetite, hair loss, longterm infertility etc.


Abiraterone was approved to treatment of advanced prostate cancer in 2011 however [33] and works as 17 α-hydroxylase/C17, 20 lyase (CYP17A1) inhibitor with side effects such as joint pain, swelling, tiredness, muscle aches, low blood levels of potassium or phosphate, high cholesterol, anemia, low white blood cell count, abnormal blood test results, high blood sugar etc.




Tamoxifen is an essential medicine with very less side effects as comparison with other anticancer drugs and it is used to treatment of breast cancer [34]. It is a special type hormone prodrug, used as estrogen receptor and known as selective estrogen receptor modifier (SERM).


Toremifene [35] was approved for the treatment of breast cancer in 1997 and also used for the treatment of prostate cancer and acts as selective estrogen receptor modifier (SERM) similar to tamoxifen.


Raloxifene [36] is also a selective estrogen receptor modifier (SERM) and approved to treatment of breast cancer in 2007. Tamoxifen, toremifen and raloxifene were showing common side effects such as hot flashes, tiredness and leg cramps.




b) Two nitrogen containing synthetic medicines (Tables 10-12)


Fluorouracil (5-FU) [37] is an important essential drug of varies cancer treatment such as breast, anal, stomach, colorectal, pancreatic, skin and oesophageal. It acts as thymidylate synthase inhibitors with side effects such as nausea, headache, vomiting, hair loss, photosensitivity low white blood cell count, low platelet count, sores in mouth, brittle nails, dry skin etc.


Table 10: Two nitrogen containing synthetic medicines.


Table 11: Two nitrogen containing synthetic medicines.


Table 12: Two nitrogen containing synthetic medicines.


Palonosetron [38] is an anti-nausea 5HT3 antagonist medicine which is used to prevent vomiting and nausea after chemotherapy.


Bicalutamide [39] is a hormone antagonist (block androgen male hormone) and approved to treatment of prostate cancer in 1995 with side effects swelling, hot flashes, pain in breast etc.




Vismodegib [40] was approved to treatment of basal cell carcinoma (a skin cancer) in 2012. It acts as hedgehog signaling pathway antagonist with side effects hair loss, weight loss, nausea, muscle spam, tiredness, change in taste, diarrhea etc.


Cyclophosphamide [41] is nitrogen alkylating agent which used for the treatment of lymphoma, multiple myeloma, leukemia, neuroblastoma, mycosis fungoides, retinoblastoma etc with side effects hair loss, diarrhea, nausea, low white blood cell count, mouth sores, appetite loss, bleeding from bladder, vomiting etc.


Ifosfamide [42] is a nitrogen mustard alkylating agents and used for the treatment of breast cancer, lung cancer, cervical cancer, testicular cancer, ovarian cancer, lymphoma, bone cancer with side effects hair loss, diarrhea, nausea, low white blood cell count, mouth sores, appetite loss, bleeding from bladder, vomiting etc.


Cisplatin [43] (cis-diamminedichloroplatinum(II), cisplatinum) is a platinum containing anticancer drug which acts as cross linking of DNA (alkylating agents) of carcinoma cells and approved to treatment of ovarian, testicular, bladder, lung cancer with side effect kidney damage, decreased potassium, magnesium and calcium level in blood, vomiting, nausea, low white blood count, low platelet count, anemia, change in taste, numbness, swelling etc.


Oxaliplatin [44] is also a platinum containing drug which was approved to cure colorectal cancer in 2012 and acts cross linking of DNA (alkylating agents) of carcinoma cells with side effects such as vomiting, numbness, nauea, abdominal pain, mouth sores, tiredness, diarrhea etc.


Carboplatin [45] (a platinum containing drug) was approved to treatment of ovarian, lung, head, neck etc carcinoma in 1989. It acts as cross linking of DNA (alkylating agents) of carcinoma cells with side effects such as low white blood cell count, low platelet count, anemia, brittle hair, abnormal kidney function etc.


Thalidomide [46] was approved to treatment of multiple myeloma (bone marrow cancer) in 2006. It is an immunomodulating agents with various side effects tiredness, rash, low white blood cell counts sleepiness, dizzy feeling etc.


Vorinostat [47] was approved to treatment of cutaneous T-cell lymphoma (a skin cancer) in 2006 and acts as histone deacetylase inhibitors with side effect tiredness, diarrhea, vomiting, nausea, appetite loss, weight loss, low blood platelet count, high blood sugar, muscle arches, food taste change.




c) Three nitrogen containing synthetic medicines (Tables 13-15)


Table 13: Three nitrogen containing synthetic medicines.


Table 14: Three nitrogen containing synthetic medicines.


Table 15: Three nitrogen containing synthetic medicines.


Cytarabine is a most essential drug which is used to cure acute myeloid leukemia (a white blood cell cancer) and non-hodgkin lymphoma. Itacts as DNA synthesis inhibitors of carcinoma cell with a side effects such as nausea, vomiting, low blood cell count, low platelet count, stomach pain, tiredness, mouth sore etc [48].


Gemcitabine is used to treatment of various type cancers such as pancreatic, lung [49], ovarian, breast cancers. It also acts as DNA synthesis inhibitors of carcinoma cells with side effects such as fever, low white blood cell count, low platelet count, anemia, nausea, vomiting, tiredness, rash on skin, appetite loss etc.


Procarbazine is an alkylating agent and approved to treatment of Hodgkin’s lymphoma and glioblastoma (brain cancer) in 1969 with side effects low white blood cell count, low platelet count, depression, nausea, vomiting, felling nervousness, appetite loss, sleeping problems etc. It is used with combination of other anticancer medicines [50].


Bendamustine [51] was approved to treatment of chronic lymphocytic leukemia and non Hodgkin lymphoma in 2008. It is a nitrogen mustard and acts as alkylating agents with side effects low white blood cell count, low platelet count, anemia, fever, nausea, vomiting, diarrhea, appetite loss, tiredness etc.




Cabozantinib [52] was recently approved (2012) for the treatment of modularly thyroid cancer. It acts as targeted tyrosine kinase inhibitors with side effects weight loss, diarrhea, mouth sores, nausea, appetite loss, weakness, abdomen pain, vomiting, high blood pressure, change in voice etc.


Capecitabine [53] was used to treatment of numerous type cancers such as breast cancer, colon, rectal etc. It acts as anti metabolized with side effects such as fever hair loss, diarrhea, headache, nausea, appetite loss, weakness, abdomen pain, vomiting, eye irritations.


Erlotinib [54] was approved to treatment of pancreatic and non small lung cancer in 2004. It acts as epidermal growth factor receptor (EGFR, a tyrosine kinase inhibitor) with side effects such as skin rash, nausea, diarrhea, tiredness, appetite loss.




Vemurafenib [55] was approved to treatment of melanoma (a skin cancer) in 2011. It acts as B-raf enzymes inhibitors with side effects such as hair loss, pain in joint, rash, warts, tiredness, headache, sunlight sensitivity, diarrhea, nausea etc.


Topotecan [56] was approved for the treatment of ovarian, cervical and lung cancers in 1996. It acts as topoisomerase I inhibitors with side effects such as nausea, vomiting, hair loss, low white blood cell count, low blood platelet count, anemia etc.


Lomustine [57] was used to treatment of brain cancer due to high lipid solubility. It acts as alkylating agents with side effect such as vomiting, nausea, fatal disorder during pregnancy, low white blood cell count, low blood platelet count etc.




Lenalidomide [58] was approved to treatment of multiple myeloma in 2005 with side effects such as tiredness, rash, itching, diarrhea, low white blood cell count, low blood platelet count etc.




Pomalidomide [59] was approved to treatment of multiple myloma in 2013. Possible, it acts as angiogenesis inhibitors with side effects such as tiredness, back pain, anemia, diarrhea, nausea, chest pain, appetite loss, pneumonia, breathing problem, rash, low white blood cell count, low blood platelet count etc.


d) Four nitrogen containing synthetic medicines (Tables 16-19)


Mercaptopurine (azathioprine) [60] is used for the treatment of leukemia (a cancer of bone marrow). It acts as anti-metabolite with side effects such as low white blood cell count, low blood platelet count and anemia etc.


Table 16: Four nitrogen containing synthetic medicines.


Table 17: Four nitrogen containing synthetic medicines.


Table 18: Four nitrogen containing synthetic medicines.


Table 19: Four nitrogen containing synthetic medicines.


Imiquimod [61] was approved in 1997 and it is used as cream for the treatment of skin cancers with the change of immune response and side effects such as skin redness, sunburns, drying skin etc.


Azacitidine [62] was first approved in 2004. It is used for the treatment of myelodysplastic syndromes and chronic myelomonocytic leukemia which act as anti-metabolite with side effects such as anemia, low platelet count, vomiting, fever, nausea and tiredness etc.


Decitabine [63] was approved in 2006 for the treatment of myelodysplastic syndromes and acts as hypomethylating agents with side effects such as anemia, low platelet count, low white blood cell count, vomiting, diarrhea, fever, nausea, pain in legs and tiredness etc.




Gefitinib [64] was approved in 2003. It used to treatment of breast and lung cancer. It acts as epidermal growth factor receptor (EGFR) for a tyrosine kinase protein with side effects such as skin rash and diarrhea etc.


Lapatinib [65] was approved to treatment of breast cancer. It acts as tyrosine kinase inhibitor with side effects diarrhea, rashes, swelling, numbness and pain in hand and foot.


Vandetanib [66] was approved in 2011 for the treatment of thyroid cancers. It acts as kinase inhibitor with side effects diarrhea, nausea, tiredness, appetite loss, abdomen pain, headache, high blood pressures, rashes etc.




Axitinib [67] was approved in 2012 for the treatment of renal cell carcinoma. It acts as vascular epidermal growth factor receptor (VEGFR) for a tyrosine kinase protein with side effects such as skin rashes, diarrhea, nausea, low blood cell counts, tiredness, appetite loss, weight loss, swelling, numbness and pain in hand and high blood pressures etc.


Sorafenib [68] was approved in 2005 for the treatment of renal and hepatocelluar carcinoma. It also acts as oral receptor tyrosine kinase inhibitor with side effects tiredness, diarrhea, itching, rashes, swellings in hand and feet etc.


Regorafenib [69] was approved in 2012 for the treatment of metastatic colorectal and advanced gastrointestinal stromal tumors. It acts as oral receptor tyrosine kinase inhibitor with side effects fever, appetite loss, tiredness, weakness, diarrhea, infection, weight loss, moth’s sores, rashes, high blood pressure, change in voice, bleeding etc.


Sunitinib [70] was approved in 2006 for the treatment of renal cell carcinoma and gastrointestinal carcinoma. It acts as tyrosine kinase receptor with side effects such as low white blood cell count, nausea, vomiting, diarrhea, mouth sore, appetite loss, taste of food change, tiredness, weakness, and change in hair and skin color, high blood pressure, hair loss etc.




Aprepitant [71] was approved in 2003 for the treatment of nausea caused by various anticancer drugs with side effects such as diarrhea, itching, appetite loss etc.


Eltrombopag [72] was approved in 2008 for the treatment of low plate count (thrombocytopenia) caused by various anticancer drugs.


Bortezomib [73] was approved in 2003 for the treatment of blood and bone marrow (multiple myloma and mantle cell lymphoma) cancer.


It acts as proteasome inhibitor with side effects such as weakness, nausea, vomiting, tiredness, diarrhea, constipation etc.


Dexrazoxane [74] was approved in 1995 to protect heart damage caused by anti-cancer drug doxorubicin with side effect low white blood cell count and low blood platelet counts.


Enzalutamide [75] was approved in 2012 for the treatment of prostate cancer. It acts an androgen receptor antagonist (blocking the male hormones androgens) with side effects such as tiredness, weakness, diarrhoea, joint pain, hot flashes, swelling in head etc.




e) Five nitrogen containing synthetic medicines (Tables 20-23)


Anastrazole [76] was approved in 1995 for the treatment of breast cancer. It acts as aromatase inhibitors (block aromatase which is necessary for the formation of estrogen) with side effects such as pain in joint and bones, hot flashes etc.


Table 20: Five nitrogen containing synthetic medicines.


Table 21: Five nitrogen containing synthetic medicines.


Table 22: Five nitrogen containing synthetic medicines.


Table 23: Five nitrogen containing synthetic medicines.


Letrozole [77] was approved in 1997 for the treatment of breast cancer. It also acts as aromatase inhibitors with side effects such as weakness, pain in joint and bones, hot flashes etc.


Pemetrexed [78] was approved in 2004 and used for the treatment of malignant pleural mesothelioma (the lining of the chest cavity around the lungs cancer) and non small cell lung cancer. It acts as anti-metabolites with side effects such as breathing difficulty, tiredness, rashes, appetite loss, mouth sores, constipation, nausea, vomiting, low platelet count, low white blood cell count, anemia etc.




Nelarabine [79] was approved in 2005 and used for the treatment of T-cell acute lymphoblastic leukemia (a white blood cell cancer). It also acts as anti-metabolites (block the formation of DNA and RNA of carcinoma cells) with side effects such as headache, tiredness, low platelet count, low white blood cell count, anemia etc.


Fludarabine [80] was approved in 1991 and used for the treatment of cancers of blood cells lymphomas and leukemias (hematological malignancies). It also acts as anti-metabolites with side effects such as tiredness, low platelet count, low white blood cell count, anemia, vomiting, nausea, infections, fever etc.


Clofarabine [81] was approved in 2004 and used for the treatment of acute lymphoblastic leukemia, acute myeloid leukaemia and juvenile myelomonocytic leukaemia. It acts a anti-metabolites with side effects such as tiredness, low platelet count, low white blood cell count, anemia, vomiting, nausea, infections, fever etc.




Afatinib (Gilotrif) [82] was approved in 2013 and used for the treatment of non small cell lung carcinoma. It acts as tyrosine kinases inhibitors with side effects scratchy and dry skin, appetite loss, infections in around nails skin, sores in mouth, rashes in skin, diarrhea etc.


Bosutinib [83] was approved in 2012 and used for the treatment of chronic myelogenous leukemia (a white blood cell carcinoma). It also acts as tyrosine kinases inhibitors with side effects headache, cough, anemia, low white blood cell count, tiredness, fever, vomiting, nausea, diarrhea, rashes in skin, abdomen pain etc.


Dabrafenib [84] was approved in 2013 and used for the treatment of melanoma caused by changing in BRAF gene (a gene responsible for the formation of B-Raf protein). It acts as kinase inhibitors (inhibit associated enzyme B-Ref) with side effects high blood sugar, fever, pain in joint, warts, hair loss, headache, skin thickness, etc.




Ceritinib [85] was approved in 2014 and used for the treatment of non small cell lung carcinoma. It acts as anaplastic lymphoma kinase (ALK) inhibitor with side effects anemia, low white blood cell count, constipation, tiredness, appetite loss, abdomen pain, diarrhea, nausea, vomiting etc.


Trametinib [86] was approved in 2013 and used for the treatment of melanoma caused by changing in BRAF gene. It acts as kinase inhibitors with side effects anemia, low blood albumin level, rashes in skin, diarrhea, swelling etc.


Crizotinib [87] was approved in 2011 and used for the treatment of non small lung cancer. It acts as anaplastic lymphoma kinase (ALK) inhibitor with side effects rashes in diarrhea, nausea, vomiting, vision disorder, constipation, appetite loss, breathing problem, cold, swelling, nerves disorders etc.




f) Six nitrogen containing synthetic medicines (Table 24)


Ibrutinib [88] was approved in 2013 and used for the treatment of chronic lymphocytic leukemia and mantle cell lymphoma (a non-Hodgkin’s lymphomas). It acts as tyrosine kinase inhibitor with side effects nausea, vomiting, diarrhea, tiredness, pain in bone and muscles, cold, swelling, breath disorder, rashes in skin, constipation, abdominal pain, appetite loss, anemia, low platelet count etc.


Table 24: Six nitrogen containing synthetic medicines.


Ponatinib [89] was approved in 2012 and used for the treatment of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). It acts tyrosine kinase inhibitor with side effects high blood pressure, heart attack disorder, dry skin, rashes in skin, abdomen pain, tiredness, weakness, headache, constipation, pain in joint and muscle, fever, nausea, low platelet count, low white blood cell count etc.


Ruxolitinib [90] was approved in 2011 and used for the treatment of myelofibrosis (a bone marrow carcinoma) and pancreatic carcinoma. It acts as Janus kinase inhibitor (JKI) with side effects low blood platelet counts, fatigue, anemia, diarrhea, breath disorder, headache, nausea, dizziness etc.


Dacarbazine [91] is an alkylating agents used for the treatment of Hodgkin lymphoma, malignant melanoma, islet cell carcinoma of the pancreas and sarcoma with side effects low white blood cell count, low platelet count, vomiting, nausea, hair loss, appetite loss, tiredness, headache, fever etc.


Temozolomide [92] was approved in 1999 and used for the treatment of glioblastoma multiforme (brain tumor) and melanoma (skin cancer). It acts as alkylating agents with side effects low white blood cell count, low platelet count, weakness, vomiting, nausea, hair loss, appetite loss, constipation, tiredness, headache, pain, itching etc.




g) Seven nitrogen containing synthetic medicines (Table 25)


Dasatinib [93] was approved in 2006 and used for the treatment of chronic myelogenous leukemia, acute lymphocytic leukemia and prostrate carcinoma. It acts a tyrosine kinase inhibitor with side effects low white blood cell count, low blood platelet count, breath disorder, rashes in skin, pain in bone and muscle, headache, fever, tiredness, nausea, diarrhea, swelling etc.


Table 25: Seven nitrogen containing synthetic medicines.


Pazopanib [94] was approved in 2009 and used for the treatment of renal cell carcinoma (kidney cancer) and soft tissue sarcoma (a connective tissue carcinoma). It acts as tyrosine kinase inhibitor with side effects slow heart beat, weight loss, pain in joint and muscles, abdomen pain, change in taste, appetite loss, tiredness, high blood pressure, headache, vomiting, diarrhea, nausea etc.


Imatinib [95] was approved in 2001 and used for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. It acts as tyrosine kinase inhibitor with similar side effects of pazopanib.


Nilotinib [96] was approved in 2007 and used for the treatment of chronic myelogenous leukemia. It acts as tyrosine kinase inhibitor with side effects low white blood cell count, low blood platelet count, tiredness, headache, fever, diarrhea, constipation, nausea, vomiting, rashes in skin, itching etc.


Leucovorin [97] is used as combinatorial chemotherapy drug with 5-fluorouracil for the better treatment of colorectal, head and neck carcinoma.


Pralatrexate [98] was approved in 2009 and used for the treatment of peripheral T-cell lymphoma (a non-Hodgkin lymphoma). It acts as anti-metabolites with side effects mouth sore, nausea, vomiting, diarrhea, anemia, low white blood cell count, low platelet count, tiredness, constipation, fever, cough, swelling, nose bleeding etc.




h) Eight nitrogen containing synthetic medicines (Table 26)


Methotrexate [99] is used for the treatment of head and neck, breast, lymphoma, leukemia, osteosarcoma, lung, bladder and trophoblastic neoplasms carcinoma. It acts as anti-metabolites with side effects mouth sores, diarrhea, vomiting, nausea, appetite loss, sunburn of skin, fever etc.


Table 26: Eight nitrogen containing synthetic medicines.


Plerixafor [100] was approved in 2008 for the treatment of non-Hodgkin lymphoma and multiple myeloma. It acts as immunostimulant for mobilize hematopoietic stem cells in cancer patients with side effects diarrhea, nausea, headache, pain in muscles, dizziness etc.




i) Multiple nitrogen containing synthetic medicines (Table 27)


Goserelin [101] was approved in 1989 and used for the treatment of prostate and breast cancers. It is a decapeptide hormone also called luteinizing hormone releasing hormone (LHRH). It acts gonadotropin releasing hormone super agonist (block the formation of testosterone and estrogen) with side effects swelling, decease in breast size, skin disorder, depression, vaginal dryness, hot flashes, stooping menstrual period etc.


Table 27: Multiple nitrogen containing synthetic medicines.


Leuprolide [102] was approved in 1985 and used for the treatment of prostate cancer. It is also decapeptide hormone (a luteinizing hormone releasing hormone). It also acts similar to goserelin as well as similar side effects.




Degarelix [103] was approved in 2008 and used for the treatment of prostate cancer. It is also a decapeptide hormone. It acts gonadotropin releasing hormone super agonist with side effects sleeping disorder, hot flashes, breast enlargement, pain in breast, back pain, headache, constipation, tiredness, increase urination etc.


Ibritumomab tiuxetan [104] was approved in 2002 and used for the treatment of follicular B‑cell non‑Hodgkin’s lymphoma. It is a monoclonal antibody drugs. It acts as CD20 antigen inhibitor with side effects nausea, tiredness, fever, low white blood cell count, low platelet count, low red blood cell count.




Trastuzumab Emtansine [105] was approved in 2013 and used for the treatment of breast cancer. It contains monoclonal antibody part trastuzumab and second part is emtansine. Transtuzumab inhibit to grow cancer cell binding from HER2/neu receptor and emtansine bind with tubulin. It has found side effect nausea, tiredness, pain in joint, bone and muscles, diarrhea, constipation, headache, low blood platelet count, nose bleeding, numbness etc.


Brentuximab vedotin [106,107] was approved in 2011 and used for the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma (a non-Hodgkin lymphoma). It is also consist of two parts, first part is a monoclonal antibody which inhibit CD30 antigen of carcinoma cell and second part is monomethyl auristatin E (MMAE) which bind with microtubule of carcinoma cells. It has shown side effects tiredness, rashes, cough, fever, nausea, vomiting, diarrhea, numbness in hands, abdomen pain etc.




Without nitrogen containing synthetic medicines (Table 28)


Table 28: Without nitrogen containing synthetic medicines.


Etoposide [108] was approved in 1983 and used for the treatment of small cell lung and testicular cancer. It acts as topoisomerase II enzyme inhibitors with side effects hair loss, appetite loss, vomiting, nausea, low white blood cell count, low blood platelet count etc.


Bexarotene [109] was approved in 1999 and used for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma and also for lung and breast cancer. It is aretenoid and acts as retinoic acid receptors with side effects diarrhea, headache, rashes, itching, low cholesterol disorder, high lipid levels, pain etc.


Busulfan [110] was approved in 1999 and used for the treatment of chronic myelogenous leukemia (a white blood cell carcinoma). It acts as alkylating agents with side effects low platelet count, low white blood cell count, anemia, hair loss, infertility disorder etc.


Mesna [111] was approved in 1988 and used for the risk reduction of bladder damage during chemotherapy drugs treatment of patients.




Steroidal medicines without nitrogen (Table 29)


Prednisone and dexamethasone [112] is used for the treatment of leukemias and lymphomas as well as treatment of allergic reactions, treatment of nausea and vomiting, increase of appetite caused by various carcinoma drugs. It are a glucocorticosteroid hormones and have shown side effects sleeping disorder, stomach problem, weight gain, high blood glucose level etc.


Table 29: Steroidal medicine without nitrogen.


Megestrol [113] is used for the treatment of breast and endometrial carcinoma. It acts as hormone antagonists with side effects such as weight gain, increase in appetite, swelling in hands, legs and feet etc.




Exemestane [114] was approved in 1999 and used for the treatment of breast cancer. It acts as aromatase inhibitors (block the formation of estrogen by inhibit aromatose) with a side effects such as pain in join and bone, hot flashes, tiredness, headache etc.


Fulvestrant [115] was approved in 2002 and used for the treatment of metastatic breast cancer. It acts as estrogen receptor antagonist with side effects nausea, weight gain, tiredness, vomiting etc.




Other Protein, antibody and amino acids as anticancer medicines (Table 30)


Interleukin 2 (Aldesleukin) [116] was approved in 1992 and used for the treatment of skin melanomas and kidney carcinoma. It is an interleukin (a cytokine signaling molecule in the immune system). It belongs to cytokines protein group and acts as enhancement of immune system for the fight of cancers with side effects fever, headache, pain in joint and muscles, low blood pressure, rashes, weakness, breath problem, confusion, itching in skin, nausea, vomiting, diarrhea etc.


Table 30: Other Protein, antibody and amino acids as anticancer medicines.


Alemtuzumab [117] was approved in 1992 and used for the treatment of chronic lymphocytic leukemia, cutaneous T-cell lymphoma, T-cell lymphoma, multiple sclerosis as lemtrada, regimens for bone marrow, kidney and islet cell transplantation. It is a monoclonal antibody and bind with CD52 protein of carcinoma cells. It has shown side effects vomiting, fever, nausea, anemia, low white blood cell and platelet count, allergic reactions etc.


Ofatumumab [118] was approved in 2009 and used for the treatment of chronic lymphocytic leukemia. It is a fully human monoclonal antibody and bind with CD20 protein of carcinoma cells to inhibit early-stage B lymphocyte activation with side effects fever, low white blood cell count, lung infection, allergies, tiredness etc.


Bevacizumab [119] was approved in 2004 and used for the treatment of colon, cervical, kidney, breast, brain, non small cell lung cancer. It is also a human monoclonal antibody and acts as angiogenesis inhibitor which inhibit vascular endothelial growth factor (VEGF) protein of carcinoma cells with side effects headache, mouth sores, diarrhea, tiredness, weaknes, back pain, skin dryness, appetite loss, nose bleeding, high blood pressure, bleeding form rectum, red and scaly skin etc.


Cetuximab [120] was approved in 2004 and used for the treatment of head and neck cancer, metastatic colorectal cancer and metastatic non-small cell lung cancer. It is also a human monoclonal antibody and acts as angiogenesis inhibitor which inhibit vascular endothelial growth factor (VEGF) protein of carcinoma cells with side effects itching, mouth sores, tiredness, weakness, rashes, fever etc.


Ramucirumab [121] was approved in 2014 and used for the treatment of stomach cancer. It is also a human monoclonal antibody and acts as angiogenesis inhibitor which inhibits vascular endothelial growth factor (VEGF) protein of carcinoma cells.


Denileukin diftitox [122] was approved in 1999 and used for the treatment of non-Hodgkin lymphoma (cutaneous T-cell lymphoma). It is a combined 2 fusion protein of diphtheria toxin and interleukin-2 and acts CD25 (IL 2 receptor protein) inhibiter and diphtheria toxin inhibit the formation of new carcinoma cell with side effects chills, fever, rashes, weakness, appetite loss, vomiting, nausea, low blood pressure etc.


Denosumab [123] was approved in 2010 and used for the treatment of multiple myeloma in bones. It is also a human monoclonal antibody and acts as osteoclasts inhibitor with side effects diarrhea, nausea, weakness, tiredness, breathe disorder etc.


Liposomal cytarabine [124] was approved in 1999 and used for the treatment of lymphoma which spread from brain or spinal card. It is a form of cytarabine contained liposomes. It acts as anti-metabolites with side effects fever, nausea, vomiting, diarrhea, headache, back pain, sleepiness, weakness etc.


Rasburicase [125] was approved in 1999 and used for the treatment of tumor lysis syndrome (a metabolic complication after treatment of cancer drugs). It is a tetrameric protein and acts as urate oxidase (metabolizes uric acid to allantoin) with side effects fever, mouth sores, diarrhea, headache etc.


Filgrastim [126] was approved in 1999 and used for the treatment of neutropenia (increase white blood cell) in cancer patients. It is a protein called granulocyte colony-stimulating factor (G-CSF).


Obinutuzumab [127] was approved in 1999 and used for the treatment of chronic lymphocytic leukemia. It is a humanized monoclonal antibody and bind with CD20 protein of carcinoma cells and inhibits B-cell (B lymphocytes) with side effects low white blood cell count, fever etc.


Gemtuzumab ozogamicin [128] was approved for 2000-2010 and used for the treatment of acute myelogenous leukemia. It is a monoclonal antibody and bind with CD33 protein of carcinoma cells.


Glucarpidase [129] was approved in 2012 and used for the treatment of toxic plasma methotrexate in cancer patients.


Romiplostim [130] was approved in 2003 and used for the treatment of blood platelet regulation. It is a fusion protein hormone analog of thromboprotein.


Peginterferon alfa-2b [131] was approved in 2011 and used for the treatment of melanoma with side effects such as abdominal pain, chills, fever, cough, depression, nausea, vomiting, etc.


Rituximab [132] was approved in 1997 and used for the treatment of chronic lymphocytic leukemia. It is a chimeric (fusion of human and mouse antibody) monoclonal antibody and bind with CD20 protein of carcinoma cells with side effect headache, fever, nausea, etc.


Siltuximab [133,134] was approved in 2014 and used for the treatment of prostrate cancer, renal cancer and Castleman disease. It is a chimeric (fusion of more than one gene of separated proteins) monoclonal antibody and bind with interleukin-6 protein of carcinoma cells with side effect rashes, weight gain, infections in respiratory system, etc.


Panitumumab [134] was approved in 2006 and used for the treatment of colorectal cancer. It is a fully human monoclonal antibody and bind with epidermal growth factor receptor (EGFR) protein of carcinoma cells with side effect diarrhea, tiredness, abdomen pain, constipation, etc.


Ziv-Aflibercept [135] was approved in 2012 and used for the treatment of colorectal cancer. It is a recombinant fusion protein and bind with epidermal growth factor receptor (EGFR) protein of carcinoma cells with side effects weight loss, diarrhea, mouth sores, low white blood cell count, appetite loss, tiredness, weakness, low blood platelet count etc.


Ipilimumab [136] was approved in 2011 and used for the treatment of melanoma. It is a is a monoclonal antibody and block CTLA-4 protein of carcinoma cells and increase immune efficacy with side effects tiredness, itching, rashes, diarrhea etc.


Palifermin [137] was approved in 2004 and used for the treatment of mouth sores of cancer patients. It is produced in Escherichia coli and acts as keratinocyte growth factor (KGF) for enhancement damaged epithelial cells of mouth and throat of cancer patient.


Sipuleucel-T [138] was approved in 2010 and used for the treatment of prostate cancer. It is a protein subunit and increase immune system of patient with side effects fever, chill, nausea, weakness, back pain etc.


Enzymes and Vaccine medicines (Table 31)


Recombinant Human Papillomavirus [139] was approved in 2006 and used for prevent from cervical, anal, vaginal, vulvar (external genital organs of female) cancers. It is a virus-like particle which is not produce in human body.


Table 31: Enzymes and Vaccine medicines.


Asparaginase Erwinia chrysanthemi [140] was approved in 2011 and used for the treatment of acute lymphoblastic leukemia.


Asparaginase (colaspase) is an enzyme that catalyzes the hydrolysis of asparagines (aspartic acid). Asparaginases are naturally occurringenzymes and produced by microorganisms Erwinia chrysanthemi.


Pegaspargase [141] was approved in 2006 and used for the treatment of acute lymphoblastic leukemia. It is a pegylated E. coli L-asparagine amidohydrolase.


Inorganic medicines (Table 32)


Arsenic Trioxide (As2O3) [142] was approved in 2000 and used for the treatment of leukemia with side effects vomiting, nausea, appetite loss, abdomen pain, headache, tiredness, cough, fever, rashes etc.


Table 32: Inorganic medicines.


Radium223dichloride [143] was approved in 2013 and used for the treatment of prostrate cancer. It is a radio pharma drug and its radiation damaged DNA of cancer cell in body with side effects such as nausea, diarrhea, anemia, low white blood cell and platelet count etc.


Combined drugs (Table 33)


Due to several side effects of a single drug, resistant of drug, unavailability of drugs for advanced carcinona and for a better chemotherapy result combined drugs course are used for the treatment ofcancer. The combined drugs are ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine; used in Hodgkin lymphoma), ABVE (Adriamycin, Bleomycin, Vinblastine, Etopside, used in Hodgkin lymphoma of children), ABVE-PC (ABVE-Prednisone, Cyclophosphamide; used in Hodgkin lymphoma of children), AC (Adriamycin, Cyclophosphamide; used in breast cancer) AC-T(AC-Taxol; used in breast cancer), ADE (Cytarabine, Daunorubicin, Etopside; used for acute myeloid leukemia in children), BEACOPP(Bleomycin, Etopside, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone; used in Hodgkin lymphoma), BEP (Bleomycin, Etopside, Cisplatin, used in malignant tumor of ovaries and testis), CAF (Cyclophosphamide, Adriamycin, Fluorouracil; used in breast cancer), CAPOX (Capecitabine, Oxaliplatin; used in Colorectal cancer), CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone; used in non Hodgkin lymphoma), CMF (Cyclophosphamide, Methotrexate, Fluorouracil; used in breast cancer), COPP (Cyclophosphamide, Vincristine, Procarbazine, Prednisone; used in non Hodgkin lymphoma and Hodgkinlymphoma) COPP-ABV (COPP- Adriamycin, Bleomycin, Vinblastine; used in Hodgkin lymphoma), CVP (Cyclophosphamide, Vincristine, Prednisone; used in non Hodgkin lymphoma and Chronic lymphocytic leukemia), EPOCH (Etopside, Prednisone, Vincristine, Cyclophosphamide, Hydroxydaunomycin; used in non Hodgkin lymphoma), FEC (Fluorouracil, Epirubicin,Cyclophosphamide; used in breast cancer), FOLFIRI (Leucovorin, Fluorouracil, Irinotecan; used in colorectal cancer, FOLFOX (Leucovorin, Fluorouracil, Oxaliplatin; used in colorectal cancer), FU-LU (Fluorouracil, Leucovorin; used in colorectal cancer), ICE (Ifosfamide, Carboplatin, Etopside; used in non Hodgkin lymphoma and Hodgkin lymphoma), MOPP (Mechlorethamine, Vincristine, Procarbazine, Prednisone; used in Hodgkin lymphoma), OEPA (Vincristine, Etopside, Prednisone, Adriamycin; used in Hodgkin lymphoma), OFF (Oxaliplatin, Fluorouracil, Leucovorin; used in pancreatic cancer), OPPA (Vincristine, Procarbazine, Prednisone, Adriamycin, Dexamethasone; used in multiple myloma), R-CHOP(Rituximab-CHOP; used in non Hodgkin lymphoma), R-CVP (Rituximab-CVP; used in non Hodgkin lymphoma), STANFORD V (Mechlorethamine, Doxorubicin, Vinblastine, Bleomycin, Etopside, Prednisone; used in Hodgkin lymphoma), TAC (Docetaxel, Adriamycin, Cyclophosphamide; used in breast cancer), TPF(Docetaxel, Cisplatin, Florouracil; used in gastric and squamous cell carcinoma of the head and neck), VAMP (Vincristine, Adriamycin, Methotrexate, Prednisone; used in Hodgkin lymphoma), XELOX (Capecitabine, Oxaliplatin; used in colorectal cancer).


Table 33: Combined drugs.


Conclusion


This review have been covered anticancer drugs classified on the bases of present of nitrogen in the anticancer drugs with their structure, actions on cancer cell and side effects, the results are showing that these medicine are effecting cancer patient with a serious side effects. These side effects are itself a disease and several times these side effects became a main reason for a patient death. Thus, it needs new efforts with new thoughts to develop an anticancer medicine without side effects as well as cost effective medicine. Classification shown that four and three nitrogen containing anticancer are available in greater number as comparison of others.


Acknowledgement


This review is dedicated to my maternal grandfather (Let. Sohan Lal), his elder brother, my favorite teacher and an aunt. They weredied after suffering from deadly side effects of cancer drugs for morethan six month treatment. I am also acknowledged DST, New Delhi, India for the awarded of DST fast track young scientist fellowship.


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