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Patent Issued for Process for the Isolation of Organic Compounds Useful for the Treatment of Cancer

February 14, 2014



By a News Reporter-Staff News Editor at Drug Week -- According to news reporting originating from Alexandria, Virginia, by NewsRx journalists, a patent by the inventors Mandal, Chitra (Kolkatta, IN); Pal, Bikas Chandra (Kolkatta, IN); Bhattacharya, Kaushik (Kolkatta, IN); Samanta, Suman Kumar (Kolkatta, IN); Sarkar, Sayantani (Kolkatta, IN); Das, Ranjita (Kolkatta, IN), filed on March 9, 2012, was published online on January 28, 2014 (see also Council of Scientific and Industrial Research).

The assignee for this patent, patent number 8637679, is Council of Scientific and Industrial Research (New Delhi, IN).

Reporters obtained the following quote from the background information supplied by the inventors: "References may be made to Journal 'Biochem Pharmacol. 79:361-72', wherein apoptotic effects of mahanine on human leukemic cells mediated through crosstalk between Apo-1/Fas signaling and the Bid protein and via mitochondrial pathways has been reported. Mahanine is a very potent anti-leukemic compound in vivo and in vitro with minimal toxicity towards Balb/c and NIH (nu/nu) nude mice. In another orthotopic nu/nu mouse model, the compound showed strong anticancer activity against pancreatic cancer. Both these mouse model studies strongly support the in vivo efficacy of mahanine against cancer cells. Mahanine has minimum toxic effects in vivo indicating that mahanine is non-toxic towards nonspecific tissues of athymic nude mice model. Additionally, in vivo testing of mahanine did not show any adverse change in total body mass of normal Balb/c and athymic nude mice model. Additionally, an apoptotic pathway and a novel mechanism induced by mahanine on human leukemic cells are mediated through crosstalk between Apo-1/Fas signaling and the Bid protein and via mitochondrial pathways has established.

"References may be made to Journal 'J Agric Food Chem. 47: 444-47', wherein it is reported that the acetone extract of the fresh leaves of Murraya koenigii resulted in the isolation of three bioactive carbazole alkaloids, mahanimbine, murrayanol and mahanine. All three compounds were found to be mosquitocidal and antimicrobial, and exhibited topoisomerase I and II inhibitory activities.

"References may be made to Patent Publication No. and Journal 'WO/2008/051523 A2 and Biochem Biophys Res Commun. 362:212-17', wherein it was reported that mahanine is an activator of epigenetically suppressed tumor suppressor gene RASSF1A in a selected cancer cell lines [i.e., epidermoid (A431), lung (A549), pancreatic (ASPC-1), colon (HT-29), breast (MCF7), androgen-responsive (LNCaP) and androgen-negative (PC3) prostate and ovarian (SKOV-3) cells], where RASSF1A was not expressed.

"References may be made to Patent Publication No. WO2010019271, wherein a method for the treatment of cancer in a subject comprising administering a dansyl-carbazole compound has been provided. The compounds are useful for treating a cancer in a subject; suppressing the growth of a cell; rand educing DNA methyltransferase activity in a cell.

"References may be made to Journal 'J Med Chem 53:2376-82', wherein it is also reported that a fluorescent carbazole analogue of mahanine was designed and synthesized which can up-regulate RASSF1A in vitro, and thus potently inhibited human prostate cancer cell proliferation, and fluoresced at a visible wavelength, allowing for the observation of intracellular distribution and 10 mg/kg dose reduced human xenograft tumor volume by about 40%.

"References may be made to Patent Publication No. and Journal 'WO/2007/026203 and Prostate. 66:1257-65', wherein it was established that mahanine is an inhibitor of serine/threonine kinase Akt and inducer of apoptosis in prostate cancer cell line PC-3 and LNCaP.

"References may be made to Journals 'Phytomedicine 13:359-65, Biochem Pharmacol. 67:41-51 and Br J. Pharmacol. 145:145-55', wherein it is also reported that mahanine can induce apoptosis towards promyelocytic leukemic cells (HL60) and histiocytic leukemia (U937).

"References may be made to Journal 'Indian J Physiol Pharmacol. 48:348-52', wherein it was reported the hypoglycemic effect of the aqueous extract and the methanol extract of Murraya koenigii Spreng leaves. Daily oral administration of aqueous extract (600 mg/kg body wt.) and methanol extract (200 mg/kg body wt.) of Murraya koenigii Spreng leaves significantly elevated plasma insulin level in treated group than that of the control.

"References may be made to Journal 'Nat Prod Commun. 4:1089-92', wherein it is reported that three extracts (DCM, EtOAc and MeOH) of Murraya koenigii (L.) Spreng leaves (Rutaceae) exhibited pancreatic antilipase activity greater than 80%.

"References may be made to Journal 'J Agric Food Chem. 49:5589-94', wherein it is reported that the antioxidant activity of the leaf-extracts of Murraya koenigii using different solvents were evaluated based on the oil stability index (OSI) together with their radical scavenging ability against 1-1-diphenyl-2-picrylhydrazyl (DPPH).

"References may be made to Journal 'Fitoterapia, 81:1129-33', wherein it is also reported that Murraya koenigii (L.) Spreng leaf-extract has anti-obesity and lipid lowering effects and mahanimbine also significantly lowered the body weight on high fat diet induced obese rats.

"Glioma

"A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of glioma is the brain. The exact causes of glioma are not known. Hereditary genetic disorders such as neurofibromatoses (type 1 and type 2) and tuberous sclerosis complex are known to predispose to their development. Individuals who were obese during adolescence have a three to four times greater risk of developing glioma than do individuals of normal weight during adolescence. Being tall also increases the risk; each 10-centimeter increase in height increases the risk nearly 20 percent. The molecular factors are also involved in this disease; TP53, EGFR, PDGFR and PTEN mutation are most well known alteration in this disease. EGFRvIII is the most lethal and oncogenic mutation in glioma. Gliomas cannot be cured. The prognosis for patients with high-grade gliomas is generally poor, and is especially so for older patients. Of 10,000 Americans diagnosed each year with malignant gliomas, about half are alive for 1 year after diagnosis, and 25% after two years. Those with anaplastic astrocytoma survive about three years. Glioblastoma multiforme has a worse prognosis with less than a 12-month survival after diagnosis. Temozolomide is an orally active alkylating agent that is used for persons newly diagnosed with glioblastoma multiforme. The United States Food and Drug Administration (FDA) approved it in March 2005. Studies have shown that the drug was well tolerated and provided a survival benefit. Adjuvant and concomitant temozolomide with radiation was associated with significant improvements in median progression-free survival over radiation alone (6.9 vs 5 month), overall survival (14.6 vs 12.1 month), and the likelihood of being alive in 2 years (26% vs 10%). MGMT is a DNA repair enzyme that contributes to temozolomide resistance. Methylation of the MGMT promoter, found in approximately 45% of glioblastoma multiformes, results in an epigenetic silencing of the gene, decreasing the tumor cell's capacity for DNA repair and increasing susceptibility to temozolomide. When patients with and without MGMT promoter methylation were treated with temozolomide, the groups had median survivals of 21.7 versus 12.7 months, and 2-year survival rates of 46% versus 13.8%, respectively. O-6-benzylguanine, carmustine (BCNU) and cis-platinum (cisplatin) have been the primary chemotherapeutic agents used against malignant gliomas. A small proportion of glioblastomas responds to gefitinib or erlotinib (tyrosine kinase inhibitors). A major hindrance to the use of chemotherapeutic agents for brain tumors is the fact that the blood-brain barrier (BBB) effectively excludes many agents from the CNS. For this reason, novel methods of intracranial drug delivery are being developed to deliver higher concentrations of chemotherapeutic agents to the tumor cells while avoiding the adverse systemic effects of these medications.

"Cervical Cancer

"Cervical cancer is the second most common malignancy among women worldwide. Every year 529,409 new cases of cervical cancer are diagnosed globally and it is responsible for 274,883 deaths. Cervical cancer comprises 13% of all cancers in women. In India, cervical cancer ranks as the first most frequent cancer among women. The cancer mostly affects women between 15 and 44 years of age and especially those from the lower economic status who fail to carry out regular health check-ups due to financial inadequacy.

"Human papilloma virus infection with high risk type is main factor for the development of cervical cancer. There are 15 subtypes of high-risk type HPV strains, among which types 16 and 18 are mainly responsible for 70% of all cervical cancers and 76.7% in Indian women (Lowy D R, Schiller J T. (2006) Prophylactic human papillomavirus vaccines. J. Clin. Invest. 116 (5): 1167-73). High-risk HPV types encode two oncogenes, E6 and E7 that can immortalize cervical epithelial cells. E6 binds to and degrades the p53 regulatory protein, while E7 interacts with members of the retinoblastoma family. This abrogates apoptosis and cell cycle checkpoint function to enhance cell proliferation (Desaintes C, Goyat S, Garbay S, Yaniv M, Thierry F. (1999) Papillomavirus E2 induces p53-independent apoptosis in HeLa cells. Oncogene, 18, 4538-4545).

"According to U.S. Food and Drug Administration, the standards of treatment of cervical cancer include radiation therapy, chemotherapy and surgery. Chemotherapy uses either cisplatin alone or combination of two drugs, hycamtin (topotecan hydrochloride) and cisplatin depending on the stage of cancer. But this combinational therapy is associated with high risk of neutropenia, thrombocytopenia, and anemia. Less serious side effects include nausea and vomiting, rash, and liver toxicity. Although patient survival is favorable in early-stage cervical cancer, patients in advanced stages suffer greatly resulting in a 5-year survival rate of about 20-40%.

"For prevention of cervical cancer two HPV vaccines, Gardasil and Cervarix are currently used in the market. Gardasil can prevent infection against HPV types 6, 11, 16, 18 whereas; cervarix is a vaccine against HPV types 16 and 18. Both vaccines are given in three doses i.e. on 0, 1, 6 months. The costs of gardasil and cervarix are Rs.2800/dose and Rs.3200/dose respectively.

"Precautions for Using Vaccines are as Follows:

"i. Both are preventative vaccines and do not treat HPV infection or cervical cancer. The U.S. Food and Drug Administration (FDA) recommend vaccination before adolescence and potential sexual activity. ii. These vaccines are recommended for women who are 9 to 25 years old who have not been exposed to HPV. The vaccines have been shown to be effective for at least 4 to 6 years. iii. Side effects of Gardasil may include joint and muscle pain, fatigue, physical weakness, general malaise and dizziness. iv. Gardasil cannot be taken in an allergic reaction after getting a dose of Gardasil or a severe allergic reaction to yeast, amorphous aluminum hydroxyphosphate sulfate, polysorbate. v. Gardasil is not recommended for pregnant women, have immune problems, like HIV infection, cancer, or in fever over 100.degree. F. Pancreatic Cancer

"Pancreatic cancer is the fourth leading cause of death among both men and women, comprising 5% of all cancer-related deaths. The incidence of pancreatic cancer has risen slowly over the years. The disease is notoriously difficult to diagnose in its early stages. At the time of diagnosis, 52% of all patients have distant disease and 26% have regional spread. The relative 1-year survival is only 24% and the overall 5-year survival rate for this disease is less than 5%. Pancreatic cancers can arise from both the exocrine and endocrine portions of the pancreas. Of pancreatic tumors, 95% develop from the exocrine portion of the pancreas, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.

"Hsp90 and Cancer

"Hsp90, are the housekeeping proteins, mainly aid the folding of the nascent proteins. The chaperonic activity of Hsp90 promotes the function of several key signaling proteins by stabilizing themselves and endorses the abnormal proliferation of malignant cells locally, help them to migrate from restricted niche, to escape the effects of chemotherapeutic drugs, and to override their own intracellular abnormality (Whitesell L, Lindquist S L. Hsp90 and the chaperoning the cancer. Nat Rev Cancer. 2005 October; 5(10): 761-72). There is a review discussed these recent advances in the understanding of tumor Hsp90 for the treatment and diagnosis of cancer. Additionally, the role of Hsp90 in non-oncological diseases was discussed by Kamal et al., ((2004) Therapeutic and diagnostic implications of Hsp90 activation. Trends Mol. Med. 10:283-90). For another review discussing the discovery and development of novel heat shock protein 90 small-molecule inhibitors by targeting multiple signalling pathways, as well as the alternative approaches to inhibit HSP90 activity, see, for example, Powers M V and Workman P ((2006) Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. Endocr Relat Cancer. 13: S125-35).

"This chaperonic protein has flexible characteristics to attach with different co-chaperones depending upon the energy execution (Neckers L. Heat shock protein 90: the cancer chaperone. (2007) J Biosci. April; 32(3): 517-30). In cancer cells, Hsp90 serves an immense role for survival of the malignant cells and being constitutively expressed more or less about 10 fold higher than that of the normal cells signifying the crucial role of this protein in growth and survival of malignant cells (Isaacs J S, Xu W, Neckers L. Heat shock protein 90 as a molecular target for cancer therapeutics. (2003) Cancer Cell. March; 3(3):213-17). There is also a documentation which enclosed the Hsp90 is a novel anti-cancer target (Neckers L, Mimnaugh E, Schulte T W. (1999) Hsp90 as an anti-cancer target. Drug Resist Updat. 2:165-72). In a review authors have also discussed the mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should augment the treatment of multiple forms of cancer (Neckers L, Ivy S P. (2003) Heat shock protein 90. Curr Opin Oncol. 15: 419-24). There is also a review which summarizes recent literature implicating Hsp90 as a key facilitator for the maturation of proteins represented in all six hallmarks of cancer: i) growth signal self-sufficiency, ii) anti-growth signal insensitivity, iii) evasion of apoptosis, iv) unlimited replicative potential, v) metastasis and tissue invasion, and vi) sustained angiogenesis. This review also described the recent advances towards the development of novel Hsp90 inhibitors via structure-based drug design that have contributed to the number of compounds undergoing clinical development (Bishop S C, Burlison J A, Blagg B S. (2007) Hsp90: a novel target for the disruption of multiple signaling cascades. Curr Cancer Drug Targets 7:369-88).

"It is a great promise to identify, characterize or customize the new chemotherapeutic agents by targeting specific cellular protein(s) or event. The group of compounds like benzoquinone ansamycins (geldanamycin, 17-AAG) is proved to be potent Hsp90 inhibitor. 17-AAG shows inhibitory effects in colon, breast and prostate cancer xenograft models (Basso A D, Solit D B, Munster P N, Rosen N. Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2. Oncogene. 2002 Feb. 14; 21(8):1159-66; Kelland L R, Sharp S Y, Rogers P M, Myers T G, Workman P. DT-Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. J Natl Cancer Inst. 1999 Nov. 17; 91(22):1940-49; Solit D B, Zheng F F, Drobnjak M, Munster P N, Higgins B, Verbel D et al. 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res. 2002 May; 8(5): 986-93). Macrolide group (Radicicol and derivatives) also established as effective Hsp90 inhibitor (Neckers L. Development of small molecule Hsp90 inhibitors: utilizing both forward and reverse chemical genomics for drug identification. Curr Med. Chem. 2003 May; 10(9):733-9). The other chemical groups like pyrazoles, isoxazoles, sulfanyl analogues, resorcinol bearing compounds block the N-terminal ATP binding pocket of Hsp90. Novobiocin along with its derivatives and cisplatin can block the C-terminal ATP binding pocket (Janin Y L. Heat shock protein 90 inhibitors. A text book example of medicinal chemistry? J Med. Chem. 2005 Dec. 1; 48(24):7503-12; Taldone T, Sun W, Chiosis G. Discovery and development of heat shock protein 90 inhibitors. Bioorg Med. Chem. 2009 Mar. 15; 17(6):2225-35; Powers M V, Workman P. Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett. 2007 Jul. 31; 581(19):3758-69). References may be made to Journal 'Pearl L H. (2005) Hsp90 and Cdc37--a chaperone cancer conspiracy. Curr Opin Genet Dev. 15:55-61' wherein a review discussed on the emerging role of Cdc37 as a key component of the Hsp90 molecular chaperone system and described its particular responsibility for enabling protein kinase oncogenes to do their damage.

"References may be made to Journal 'Mol Cancer Ther. 7:162-70', wherein it was shown that celastrol disrupted Hsp90-Cdc37 interaction in the superchaperone complex to exhibit antitumor activity in vitro and in vivo.

"References may be made to Journal 'Cancer Res. 67:11942-50', wherein it was shown that Cdc37 is essential for maintaining prostate tumor cell growth and may represent a novel target in the search for multi-targeted therapies based on the HSP90 chaperone system.

"References may be made to Journal 'J Med. Chem. 49:7721-30', wherein a nonpeptidic small molecule, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), was identified as a structurally novel inhibitor of Hsp90. The compound is selected to bind the Hsp90 N-terminal domain.

"References may be made to journal 'J. Agric. Food Chem., 2001, 49 (11), pp 5589-5594', wherein antioxidative properties of the leaves extracts of Murraya koenigii using different solvents were evaluated based on the oil stability index (OSI) together with their radical scavenging ability against 1-1-diphenyl-2-picrylhydrazyl (DPPH). Five carbazole alkaloids were isolated from the CH.sub.2Cl.sub.2 extract and their structures were identified to be euchrestine B (1), bismurrayafoline E (2), mahanine (3), mahanimbicine (4), and mahanimbine (5) based on .sup.1H and .sup.13C NMR and mass (MS) spectral data. In this process, initial extraction was done by Acetone. Seven different fractionations were separated by vacuum liquid chromatography (VLC). Selection of bioactive fractions was done from seven different fractions. Bioactive fractions were further separated by Medium pressure liquid chromatography (MPLC) to isolate five more fractions. Selection of bioactive fractions was done from these five different fraction. The bioactive fraction was finally purified by preparative thin layer chromatography (PTLC). Yield of pure compounds is 4.26 mg per gm of acetone extract. However, in the present invention, initial extraction was done by MeOH. Total alkaloids were isolated by chloroform, precipitated with acid-base and dissolved in ethyl acetate. Pure compounds were purified by silica gel column chromatography. Yield of pure compounds is .about.41 mg from 1.0 gm of MeOH extract.

"In summary, the major drawbacks of the hitherto known processes described herein above for the extraction of mahanine and mahanimbine are: 1) Leads to many more steps for actual identification of active alkaloids. 2) Several costly chromatography processes (VLC, MPLC, PTLC). 3) Consumes lots of solvents. 4) Many fractions (more than 12) are needed for in vitro testing for its biological activity. 5) The total extract may content polar, non-polar, waxy material like lipid, steroid, flavonoid etc. 6) The process is expensive and time consuming. 7) Yield is also lower than present invention."

In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "Accordingly, present invention provides a process for the isolation of compound of general formula 1:

"##STR00001## wherein R.sub.1.dbd.H mahanimbine (1a) or R.sub.1.dbd.OH mahanine (1b); from the extract of Murraya koeniigii wherein the said process comprising the steps of: i. extracting leaves of Murraya koeniigii with methanol followed by concentrating to obtain residue; ii. dissolving the residue as obtained in step (i) in solvent followed by adding 8 to 10% acid (e.g., or 5% to 20% acid, such as 5% to 10%, 5% to 15%, 8% to 15%, and 8% to 20%); iii. separating the acid soluble part from the mixture as obtained in step (ii) and making the solution alkaline to obtain a precipitate; iv. dissolving the precipitate as obtained in step (iii) in ethyl acetate followed by evaporating to obtain an alkaloid; and v. subjecting the alkaloid as obtained in step (iv) to repeated (e.g., more than once, twice, three times, or more) chromatography on silica gel using petrol-chloroform solvent as eluent followed by crystallization on petrol to obtain the compound of general formula 1.

"In an embodiment of the present invention, acid used is selected from the group consisting of HCl, H.sub.2SO.sub.4, CH.sub.3COOH or HNO.sub.3.

"In another embodiment of the present invention, yield of the compound is in the range of 10 to 40% of methanolic extract.

"In yet another embodiment of the present invention, solvent used is selected from the group consisting of chloroform, diethylether or ethylacetate.

"In yet another embodiment of the present invention, the invention features a pharmaceutical composition including an effective amount of at least one compound of general formula 1 optionally along with pharmaceutically acceptable additives:

"##STR00002## wherein R.sub.1.dbd.H mahanimbine (1a) or R.sub.1.dbd.OH mahanine (1b).

"In yet another embodiment of the present invention, an effective amount of the compound of general formula 1 is in the range of 50-150 mg/kg body weight for 1 to 9 days.

"In yet another embodiment of the present invention, compound 1a exhibits in vitro anticancer activity against human cancer cell lines selected from the group consisting of lymphoid cell lines, myeloid cell lines, glioma cell lines (U373MG, U87MG, LN229, T98G, A172), cervical cell lines (HeLa), pancreatic cell lines (Panc10.05, Panc1, AsPC1, MIAPaCa-2), colon cell lines and lung cancer cell lines (A549).

"In yet another embodiment of the present invention, compound 1b exhibits in vitro anticancer activity against human cancer cell lines selected from glioma cancer cell line (U373MG, U87MG, LN229, T98G, A172) and cervical cancer cell line (HeLa).

"In yet another embodiment of the present invention, compounds 1a and 1b inhibit cell proliferation in glioma and cervical cancer cells at IC.sub.50 in the range of 10-20 .mu.M and 30-50 .mu.M respectively.

"In yet another embodiment of the present invention, compound 1b hinders the Hsp90's chaperonic activity without hampering ATP binding site.

"In an embodiment of the present invention, mahanine was derivatized to an epoxide form into the C20-C21 double bond. Mahanine was incubated with meta-chloro perbenzoic acid (MCPB) at room temp. for 48 hr and C20-C21 epoxy mahanine was generated. This epoxy mahanine was little less active than mahanine and IC.sub.50 was identified in REH cell line was 18.4.+-.1.1 .mu.M after 48 hr treatment.

"Yet another embodiment of the present invention provides a method for the treatment of cancer comprising administering to a patient suffering therefrom an effective dose of compound of general formula 1 or salt thereof, optionally along with pharmaceutically acceptable excipients.

"Yet another embodiment of the present invention provides that the compound of general formula 1 is administrated by intra-peritoneal, oral, intra-muscular and sub-cutaneous routes.

"Yet another embodiment of the present invention provides that the dosage of compound of general formula 1 for the treatment of cancer ranges between 50-150 mg/kg body weight for a period of 0 to 9 days.

"Yet another embodiment of the present invention provides that the compound 1a is useful for the treatment of cancers selected from lymphoid leukemia, myeloid leukemia, gliomas, cervical carcinoma, pancreatic cancer, colon cancer and lung cancer.

"Yet another embodiment of the present invention provides that the compound 1b is useful for the treatment of cancers selected from gliomas and cervical carcinoma.

"Yet another embodiment of the present invention provides that the compound 1b hinders the Hsp90's chaperonic activity without hampering ATP binding site.

"Yet another embodiment of the present invention provides that the compound of general formula 1 for use in treatment of cancers is obtained by chemical route or by herbal route.

"For any of recited values herein, .+-.10% of that value are also included in any recited range."

For more information, see this patent: Mandal, Chitra; Pal, Bikas Chandra; Bhattacharya, Kaushik; Samanta, Suman Kumar; Sarkar, Sayantani; Das, Ranjita. Process for the Isolation of Organic Compounds Useful for the Treatment of Cancer. U.S. Patent Number 8637679, filed March 9, 2012, and published online on January 28, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=60&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=2989&f=G&l=50&co1=AND&d=PTXT&s1=20140128.PD.&OS=ISD/20140128&RS=ISD/20140128

Keywords for this news article include: Antineoplastics, Drugs, Kinase, Acetone, Therapy, Alcohols, Genetics, Methanol, Oncology, Peptides, Proteins, Chemicals, Chemistry, Treatment, Viral DNA, Chloroform, Silica Gel, Amino Acids, Legal Issues, Temozolomide, Ketone Bodies, Women's Health, Cervical Cancer, Trihalomethanes, Alkylating Agents, Risk and Prevention.

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