Journal Article
. 2013 Jun; 4:68.
doi: 10.3389/fphar.2013.00068.

Is it time for a new paradigm for systemic cancer treatment? Lessons from a century of cancer chemotherapy

Sarah Crawford 1 
  • PMID: 23805101
  •     162 References
  •     30 citations


U.S. SEER (Surveillance Epidemiology and End Results) data for age-adjusted mortality rates for all cancers combined for all races show only a modest overall 13% decline over the past 35 years. Moreover, the greatest contributor to cancer mortality is treatment-resistant metastatic disease. The accepted therapeutic paradigm for the past half-century for the treatment of advanced cancers has involved the use of systemic chemotherapy drugs cytotoxic for cycling cells (both normal and malignant) during DNA synthesis and/or mitosis. The failure of this therapeutic modality to achieve high-level, consistent rates of disease-free survival for some of the most common cancers, including tumors of the lung, colon breast, brain, melanoma, and others is the focus of this paper. A retrospective assessment of critical milestones in cancer chemotherapy indicates that most successful therapeutic regimens use cytotoxic cell cycle inhibitors in combined, maximum tolerated, dose-dense acute treatment regimens originally developed to treat acute lymphoblastic leukemia and some lymphomas. Early clinical successes in this area led to their wholesale application to the treatment of solid tumor malignancies that, unfortunately, has not produced consistent, long-term high cure rates for many common cancers. Important differences in therapeutic sensitivity of leukemias/lymphomas versus solid tumors can be explained by key biological differences that define the treatment-resistant solid tumor phenotype. A review of these clinical outcome data in the context of recent developments in our understanding of drug resistance mechanisms characteristic of solid tumors suggests the need for a new paradigm for the treatment of chemotherapy-resistant cancers. In contrast to reductionist approaches, the systemic approach targets both microenvironmental and systemic factors that drive and sustain tumor progression. These systemic factors include dysregulated inflammatory and oxidation pathways shown to be directly implicated in the development and maintenance of the cancer phenotype. The paradigm stresses the importance of a combined preventive/therapeutic approach involving adjuvant chemotherapies that incorporate anti-inflammatory and anti-oxidant therapeutics.

Keywords: adjuvant; anti-inflammatory; anti-oxidant; chemotherapy; drug resistance; neoplasm; tumor microenvironment.

Predicting the course of Gompertzian growth.
L Norton, R Simon, H D Brereton, A E Bogden.
Nature, 1976 Dec 09; 264(5586). PMID: 1004590
Highly Cited.
Penetration of anticancer drugs through solid tissue: a factor that limits the effectiveness of chemotherapy for solid tumors.
J K Tunggal, D S Cowan, H Shaikh, I F Tannock.
Clin Cancer Res, 1999 Jul 02; 5(6). PMID: 10389947
Determinants of paclitaxel penetration and accumulation in human solid tumor.
H J Kuh, S H Jang, +2 authors, J L Au.
J Pharmacol Exp Ther, 1999 Jul 20; 290(2). PMID: 10411604
Doxorubicin gradients in human breast cancer.
J Lankelma, H Dekker, +5 authors, H M Pinedo.
Clin Cancer Res, 1999 Aug 03; 5(7). PMID: 10430072
Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25.
B Fisher, S Anderson, +18 authors, N Wolmark.
J Clin Oncol, 1999 Nov 05; 17(11). PMID: 10550131
Mechanisms of anti-cancer agents: emphasis on oxidative stress and electron transfer.
P Kovacic, J A Osuna.
Curr Pharm Des, 2000 Jan 19; 6(3). PMID: 10637380
Non-steroidal anti-inflammatory drugs and bladder cancer prevention.
J E Castelao, J M Yuan, +2 authors, R K Ross.
Br J Cancer, 2001 Feb 07; 82(7). PMID: 10755416    Free PMC article.
Nested case-control study of the effects of non-steroidal anti-inflammatory drugs on breast cancer risk and stage.
C R Sharpe, J P Collet, +3 authors, J A Hanley.
Br J Cancer, 2000 Jul 07; 83(1). PMID: 10883678    Free PMC article.
Concepts for systemic treatment of micrometastases.
F M Schabel.
Cancer, 1975 Jan 11; 35(1). PMID: 1109768
Prostaglandin E2 increases growth and motility of colorectal carcinoma cells.
H Sheng, J Shao, M K Washington, R N DuBois.
J Biol Chem, 2001 Mar 30; 276(21). PMID: 11278548
Highly Cited.
Electron transfer and oxidative stress as key factors in the design of drugs selectively active in hypoxia.
P Wardman.
Curr Med Chem, 2001 May 29; 8(7). PMID: 11375747
Anticancer therapy by overexpression of superoxide dismutase.
L W Oberley.
Antioxid Redox Signal, 2001 Aug 09; 3(3). PMID: 11491657
Clinical aspects of drug delivery to tumors.
Jessie L-S Au, Seong H Jang, M Guill Wientjes.
J Control Release, 2002 Jan 05; 78(1-3). PMID: 11772451
Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues.
Michael J Thun, S Jane Henley, Carlo Patrono.
J Natl Cancer Inst, 2002 Feb 21; 94(4). PMID: 11854387
Highly Cited. Review.
Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy.
Rama Pai, Brian Soreghan, +3 authors, Andrzej S Tarnawski.
Nat Med, 2002 Mar 05; 8(3). PMID: 11875501
Highly Cited.
Limited penetration of anticancer drugs through tumor tissue: a potential cause of resistance of solid tumors to chemotherapy.
Ian F Tannock, Carol M Lee, +2 authors, Merrill J Egorin.
Clin Cancer Res, 2002 Mar 16; 8(3). PMID: 11895922
Highly Cited.
Helicobacter pylori and gastrointestinal tract adenocarcinomas.
Richard M Peek, Martin J Blaser.
Nat Rev Cancer, 2002 Mar 21; 2(1). PMID: 11902583
Highly Cited. Review.
Origins of cancer therapy.
R J Papac.
Yale J Biol Med, 2002 Apr 02; 74(6). PMID: 11922186    Free PMC article.
The role of cyclooxygenase inhibitors in cancer prevention.
William F Anderson, Asad Umar, Jaye L Viner, Ernest T Hawk.
Curr Pharm Des, 2002 Apr 12; 8(12). PMID: 11945150
Inflammation and the development of pancreatic cancer.
Buckminster Farrow, B Mark Evers.
Surg Oncol, 2002 May 22; 10(4). PMID: 12020670
Highly Cited. Review.
The dominance of the microenvironment in breast and ovarian cancer.
Calvin D Roskelley, Mina J Bissell.
Semin Cancer Biol, 2002 May 25; 12(2). PMID: 12027581    Free PMC article.
Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941.
Charles Huggins, Clarence V Hodges.
J Urol, 2002 Jun 07; 168(1). PMID: 12050481
Highly Cited.
Vascular architecture, hypoxia, and proliferation in first-generation xenografts of human head-and-neck squamous cell carcinomas.
Anna S E Ljungkvist, Johan Bussink, +3 authors, Juliana Denekamp.
Int J Radiat Oncol Biol Phys, 2002 Aug 17; 54(1). PMID: 12182995
Combination chemotherapy as an adjuvant treatment in operable breast cancer.
G Bonadonna, E Brusamolino, +8 authors, U Veronesi.
N Engl J Med, 1976 Feb 19; 294(8). PMID: 1246307
Highly Cited.
Inflammation and cancer.
Lisa M Coussens, Zena Werb.
Nature, 2002 Dec 20; 420(6917). PMID: 12490959    Free PMC article.
Highly Cited. Review.
Tumor hypoxia at the micro-regional level: clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers.
Johan Bussink, Johannes H A M Kaanders, Albert J van der Kogel.
Radiother Oncol, 2003 May 22; 67(1). PMID: 12758235
Antagonists of nucleic acid derivatives. VIII. Synergism in combinations of biochemically related antimetabolites.
J Biol Chem, 1954 Jun 01; 208(2). PMID: 13174557
Highly Cited.
On the origin of cancer cells.
Science, 1956 Feb 24; 123(3191). PMID: 13298683
Highly Cited.
Fluorinated pyrimidines, a new class of tumour-inhibitory compounds.
Nature, 1957 Mar 30; 179(4561). PMID: 13418758
Highly Cited.
Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists.
N Engl J Med, 1958 Jul 10; 259(2). PMID: 13566422
Actinomycin D in childhood cancer; a preliminary report.
Pediatrics, 1959 Feb 01; 23(2). PMID: 13633349
Effects of combined drug therapy on metastatic cancer of the testis.
JAMA, 1960 Nov 05; 174. PMID: 13761819
Highly Cited.
The initial clinical trial of nitrogen mustard.
Am J Surg, 1963 May 01; 105. PMID: 13947966
Highly Cited.
Response of advanced breast carcinoma to the combination of the antimetabolite, Methotrexate, and the alkylating agent, thio-TEPA.
J Mt Sinai Hosp N Y, 1963 May 01; 30. PMID: 13950199
Primary chemotherapy of nonmetastatic trophoblastic disease in women.
Am J Obstet Gynecol, 1963 Jul 15; 86. PMID: 13954160
Cancer Res, 1963 Sep 01; 23. PMID: 14070392
Highly Cited. Review.
Adv Chemother, 1964 Jan 01; 13. PMID: 14195198
Blood, 1964 Nov 01; 24. PMID: 14236724
Cancer Chemother Rep, 1965 Apr 01; 45. PMID: 14321918
The chemistry and biochemistry of purine analogs.
Ann N Y Acad Sci, 1954 Dec 06; 60(2). PMID: 14350523
MnSOD up-regulates maspin tumor suppressor gene expression in human breast and prostate cancer cells.
Hong Duan, Hannah J Zhang, +3 authors, Frederick E Domann.
Antioxid Redox Signal, 2003 Oct 29; 5(5). PMID: 14580325
Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression.
Sung-Hee Chang, Catherine H Liu, +5 authors, Timothy Hla.
Proc Natl Acad Sci U S A, 2003 Dec 23; 101(2). PMID: 14688410    Free PMC article.
Highly Cited.
Inflammation and Cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy.
Mairi Macarthur, Georgina L Hold, Emad M El-Omar.
Am J Physiol Gastrointest Liver Physiol, 2004 Mar 11; 286(4). PMID: 15010360
Highly Cited. Review.
Cytostatic and cytotoxic effects of topotecan decoded by a novel mathematical simulation approach.
Monica Lupi, Giada Matera, +2 authors, Paolo Ubezio.
Cancer Res, 2004 Apr 17; 64(8). PMID: 15087399
Mitochondrial superoxide dismutase: a promising target for new anticancer therapies.
Giovambattista Pani, Renata Colavitti, +4 authors, Tommaso Galeotti.
Curr Med Chem, 2004 May 12; 11(10). PMID: 15134521
Exploiting tumour hypoxia in cancer treatment.
J Martin Brown, William R Wilson.
Nat Rev Cancer, 2004 Jun 02; 4(6). PMID: 15170446
Highly Cited. Review.
Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation.
Steven H Itzkowitz, Xianyang Yio.
Am J Physiol Gastrointest Liver Physiol, 2004 Jun 15; 287(1). PMID: 15194558
Highly Cited. Review.
Tumor microenvironmental physiology and its implications for radiation oncology.
Peter Vaupel.
Semin Radiat Oncol, 2004 Jul 16; 14(3). PMID: 15254862
Highly Cited. Review.
Inflammation as a tumor promoter in cancer induction.
Mary Philip, Donald A Rowley, Hans Schreiber.
Semin Cancer Biol, 2004 Oct 19; 14(6). PMID: 15489136
Highly Cited. Review.
Antioxidants and cancer therapy: furthering the debate.
Keith I Block.
Integr Cancer Ther, 2004 Nov 04; 3(4). PMID: 15523105
The role of inflammation in the pathogenesis of prostate cancer.
William G Nelson, Angelo M De Marzo, Theodore L DeWeese, William B Isaacs.
J Urol, 2004 Nov 13; 172(5 Pt 2). PMID: 15535435
Manganese superoxide dismutase overexpression inhibits the growth of androgen-independent prostate cancer cells.
Sujatha Venkataraman, Xiaohong Jiang, +6 authors, Garry R Buettner.
Oncogene, 2004 Nov 16; 24(1). PMID: 15543233
Aneuploidy and cancer.
Harith Rajagopalan, Christoph Lengauer.
Nature, 2004 Nov 19; 432(7015). PMID: 15549096
Highly Cited. Review.
Mechanism of the tumor suppressive effect of MnSOD overexpression.
Larry W Oberley.
Biomed Pharmacother, 2005 May 03; 59(4). PMID: 15862707
Modulation of skin tumorigenesis by SOD.
Daret St Clair, Yunfeng Zhao, Luksana Chaiswing, Terry Oberley.
Biomed Pharmacother, 2005 May 03; 59(4). PMID: 15862717
SOD2: a new type of tumor-suppressor gene?
A Bravard, L Sabatier, +3 authors, B Dutrillaux.
Int J Cancer, 1992 May 28; 51(3). PMID: 1592538
Repopulation of cancer cells during therapy: an important cause of treatment failure.
John J Kim, Ian F Tannock.
Nat Rev Cancer, 2005 Jun 21; 5(7). PMID: 15965493
Highly Cited. Review.
Drug resistance in cancer: principles of emergence and prevention.
Natalia L Komarova, Dominik Wodarz.
Proc Natl Acad Sci U S A, 2005 Jun 28; 102(27). PMID: 15980154    Free PMC article.
Highly Cited.
Dynamics of chronic myeloid leukaemia.
Franziska Michor, Timothy P Hughes, +4 authors, Martin A Nowak.
Nature, 2005 Jul 01; 435(7046). PMID: 15988530
Highly Cited.
Non-steroidal anti-inflammatory drugs for the prevention and treatment of cancer.
D Pereg, M Lishner.
J Intern Med, 2005 Jul 16; 258(2). PMID: 16018788
Manganese superoxide dismutase induces p53-dependent senescence in colorectal cancer cells.
Lars Behrend, Andrea Mohr, Tatjana Dick, Ralf M Zwacka.
Mol Cell Biol, 2005 Aug 19; 25(17). PMID: 16107721    Free PMC article.
Use of antioxidants during chemotherapy and radiotherapy should be avoided.
Gabriella M D'Andrea.
CA Cancer J Clin, 2005 Sep 17; 55(5). PMID: 16166076
Combination versus single agent chemotherapy: a review of the basis for selection of drug treatment of cancer.
V T DeVita, R C Young, G P Canellos.
Cancer, 1975 Jan 01; 35(1). PMID: 162854
Highly Cited. Review.
Mechanistic mathematical modelling of mercaptopurine effects on cell cycle of human acute lymphoblastic leukaemia cells.
J C Panetta, W E Evans, M H Cheok.
Br J Cancer, 2005 Dec 08; 94(1). PMID: 16333308    Free PMC article.
Changes in gene expression contribute to cancer prevention by COX inhibitors.
Seung Joon Baek, Thomas E Eling.
Prog Lipid Res, 2005 Dec 13; 45(1). PMID: 16337272
Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial.
Michael I Koukourakis, Søren M Bentzen, +6 authors, Adrian L Harris.
J Clin Oncol, 2006 Jan 19; 24(5). PMID: 16418497
The penetration of anticancer drugs through tumor tissue as a function of cellular adhesion and packing density of tumor cells.
Rama Grantab, Shankar Sivananthan, Ian F Tannock.
Cancer Res, 2006 Jan 21; 66(2). PMID: 16424039
Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics.
Cornelia M Ulrich, Jeannette Bigler, John D Potter.
Nat Rev Cancer, 2006 Feb 24; 6(2). PMID: 16491072
Highly Cited. Review.
A four-dimensional computer simulation model of the in vivo response to radiotherapy of glioblastoma multiforme: studies on the effect of clonogenic cell density.
G S Stamatakos, V P Antipas, N K Uzunoglu, R G Dale.
Br J Radiol, 2006 Apr 25; 79(941). PMID: 16632619
Hypoxia signalling in cancer and approaches to enforce tumour regression.
Jacques Pouysségur, Frédéric Dayan, Nathalie M Mazure.
Nature, 2006 May 26; 441(7092). PMID: 16724055
Highly Cited. Review.
Drug penetration in solid tumours.
Andrew I Minchinton, Ian F Tannock.
Nat Rev Cancer, 2006 Jul 25; 6(8). PMID: 16862189
Highly Cited. Review.
DNA repair pathways in clinical practice: lessons from pediatric cancer susceptibility syndromes.
Richard D Kennedy, Alan D D'Andrea.
J Clin Oncol, 2006 Aug 10; 24(23). PMID: 16896009
Mathematical models of targeted cancer therapy.
L H Abbott, F Michor.
Br J Cancer, 2006 Oct 13; 95(9). PMID: 17031409    Free PMC article.
NSAID activated gene (NAG-1), a modulator of tumorigenesis.
Thomas E Eling, Seung Joon Baek, Minsub Shim, Chang Ho Lee.
J Biochem Mol Biol, 2006 Nov 30; 39(6). PMID: 17129398
Drug distribution in tumors: mechanisms, role in drug resistance, and methods for modification.
Antonello Di Paolo, Guido Bocci.
Curr Oncol Rep, 2007 Feb 10; 9(2). PMID: 17288875
Chronic obstructive pulmonary disease is associated with lung cancer mortality in a prospective study of never smokers.
Michelle C Turner, Yue Chen, +2 authors, Michael J Thun.
Am J Respir Crit Care Med, 2007 May 05; 176(3). PMID: 17478615
A microenvironment based model of antimitotic therapy of Gompertzian tumor growth.
Frank Kozusko, Michele Bourdeau, Zeljko Bajzer, David Dingli.
Bull Math Biol, 2007 Jun 20; 69(5). PMID: 17577604
Some observations on the effect of folic acid antagonists on acute leukemia and other forms of incurable cancer.
Blood, 1949 Feb 01; 4(2). PMID: 18107667
Observations on the effect of a folic-acid antagonist on transplantable lymphoid leukemias in mice.
J Natl Cancer Inst, 1949 Aug 01; 10(1). PMID: 18143260
Weekly paclitaxel in the adjuvant treatment of breast cancer.
Joseph A Sparano, Molin Wang, +7 authors, Nancy E Davidson.
N Engl J Med, 2008 Apr 19; 358(16). PMID: 18420499    Free PMC article.
Highly Cited.
Stromal gene expression predicts clinical outcome in breast cancer.
Greg Finak, Nicholas Bertos, +9 authors, Morag Park.
Nat Med, 2008 Apr 29; 14(5). PMID: 18438415
Highly Cited.
Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy.
Isabelle Mercier, Mathew C Casimiro, +15 authors, Michael P Lisanti.
Cancer Biol Ther, 2008 May 07; 7(8). PMID: 18458534    Free PMC article.
Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid.
N Engl J Med, 1948 Jun 03; 238(23). PMID: 18860765
Highly Cited.
Growth curve of an experimental solid tumor following radiotherapy.
L Norton, R Simon.
J Natl Cancer Inst, 1977 Jun 01; 58(6). PMID: 194044
An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers.
Agnieszka K Witkiewicz, Abhijit Dasgupta, +6 authors, Michael P Lisanti.
Am J Pathol, 2009 May 05; 174(6). PMID: 19411448    Free PMC article.
Highly Cited.
Stromal cell expression of caveolin-1 predicts outcome in breast cancer.
Erica K Sloan, Daniel R Ciocca, +7 authors, Robin L Anderson.
Am J Pathol, 2009 May 05; 174(6). PMID: 19411449    Free PMC article.
Highly Cited.
Stromal caveolin-1 levels predict early DCIS progression to invasive breast cancer.
Agnieszka K Witkiewicz, Abhijit Dasgupta, +7 authors, Michael P Lisanti.
Cancer Biol Ther, 2009 Jun 09; 8(11). PMID: 19502809
An absence of stromal caveolin-1 is associated with advanced prostate cancer, metastatic disease and epithelial Akt activation.
Dolores Di Vizio, Matteo Morello, +3 authors, Michael P Lisanti.
Cell Cycle, 2009 Jun 27; 8(15). PMID: 19556867    Free PMC article.
Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial.
Noriyuki Katsumata, Makoto Yasuda, +10 authors, Japanese Gynecologic Oncology Group.
Lancet, 2009 Sep 22; 374(9698). PMID: 19767092
Highly Cited.
Dose-dense chemotherapy in advanced ovarian cancer.
Michael A Bookman.
Lancet, 2009 Sep 22; 374(9698). PMID: 19767094
The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma.
Stephanos Pavlides, Diana Whitaker-Menezes, +11 authors, Michael P Lisanti.
Cell Cycle, 2009 Nov 20; 8(23). PMID: 19923890
Highly Cited.
Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers.
Agnieszka K Witkiewicz, Abhijit Dasgupta, +7 authors, Michael P Lisanti.
Cancer Biol Ther, 2010 May 01; 10(2). PMID: 20431349    Free PMC article.
Transcriptional evidence for the "Reverse Warburg Effect" in human breast cancer tumor stroma and metastasis: similarities with oxidative stress, inflammation, Alzheimer's disease, and "Neuron-Glia Metabolic Coupling".
Stephanos Pavlides, Aristotelis Tsirigos, +9 authors, Michael P Lisanti.
Aging (Albany NY), 2010 May 06; 2(4). PMID: 20442453    Free PMC article.
The reverse Warburg effect: glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts.
Gloria Bonuccelli, Diana Whitaker-Menezes, +13 authors, Michael P Lisanti.
Cell Cycle, 2010 May 25; 9(10). PMID: 20495363
Highly Cited.
Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the "reverse Warburg effect": a transcriptional informatics analysis with validation.
Stephanos Pavlides, Aristotelis Tsirigos, +10 authors, Michael P Lisanti.
Cell Cycle, 2010 Jun 04; 9(11). PMID: 20519932
Highly Cited.
Oxidative stress promotes myofibroblast differentiation and tumour spreading.
Aurore Toullec, Damien Gerald, +14 authors, Fatima Mechta-Grigoriou.
EMBO Mol Med, 2010 Jun 11; 2(6). PMID: 20535745    Free PMC article.
Highly Cited.
Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: implications for breast cancer and DCIS therapy with autophagy inhibitors.
Ubaldo E Martinez-Outschoorn, Stephanos Pavlides, +11 authors, Federica Sotgia.
Cell Cycle, 2010 Jun 22; 9(12). PMID: 20562526
Highly Cited.
Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells.
Ubaldo E Martinez-Outschoorn, Renee M Balliet, +13 authors, Michael P Lisanti.
Cell Cycle, 2010 Sep 04; 9(16). PMID: 20814239    Free PMC article.
Highly Cited.
Ketones and lactate "fuel" tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism.
Gloria Bonuccelli, Aristotelis Tsirigos, +9 authors, Michael P Lisanti.
Cell Cycle, 2010 Sep 08; 9(17). PMID: 20818174    Free PMC article.
Highly Cited.
Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment.
Ubaldo E Martinez-Outschoorn, Casey Trimmer, +14 authors, Federica Sotgia.
Cell Cycle, 2010 Sep 22; 9(17). PMID: 20855962    Free PMC article.
Highly Cited.
Understanding the "lethal" drivers of tumor-stroma co-evolution: emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment.
Michael P Lisanti, Ubaldo E Martinez-Outschoorn, +8 authors, Federica Sotgia.
Cancer Biol Ther, 2010 Sep 24; 10(6). PMID: 20861671    Free PMC article.
The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism.
Stephanos Pavlides, Aristotelis Tsirigos, +11 authors, Michael P Lisanti.
Cell Cycle, 2010 Sep 24; 9(17). PMID: 20861672    Free PMC article.
Highly Cited.
Therapeutic applications of chemical warfare agents.
Fed Proc, 1946 Jun 01; 5. PMID: 20990888
Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders.
J Am Med Assoc, 1946 Sep 21; 132. PMID: 20997191
Highly Cited.
Small molecule inhibitors of NF-kB and JAK/STAT signal transduction pathways as promising anti-inflammatory therapeutics.
Y A Ivanenkov, K V Balakin, Y Lavrovsky.
Mini Rev Med Chem, 2010 Nov 03; 11(1). PMID: 21034406
Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo.
B A Teicher, T S Herman, +4 authors, E Frei.
Science, 1990 Mar 23; 247(4949 Pt 1). PMID: 2108497
Highly Cited.
Dose-dense chemotherapy in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials.
Luisa Bonilla, Irit Ben-Aharon, +3 authors, Salomon M Stemmer.
J Natl Cancer Inst, 2010 Nov 26; 102(24). PMID: 21098761    Free PMC article.
Systematic Review.
Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment: a new genetically tractable model for human cancer associated fibroblasts.
Casey Trimmer, Federica Sotgia, +10 authors, Michael P Lisanti.
Cancer Biol Ther, 2010 Dec 15; 11(4). PMID: 21150282    Free PMC article.
Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), C Davies, +11 authors, R Peto.
Lancet, 2011 Aug 02; 378(9793). PMID: 21802721    Free PMC article.
Highly Cited.
Drug-induced senescence generates chemoresistant stemlike cells with low reactive oxygen species.
Santhi Achuthan, Thankayyan R Santhoshkumar, +2 authors, M Radhakrishna Pillai.
J Biol Chem, 2011 Sep 01; 286(43). PMID: 21878644    Free PMC article.
Aspirin and colorectal cancer prevention in Lynch syndrome.
Andrew T Chan, Scott M Lippman.
Lancet, 2011 Nov 01; 378(9809). PMID: 22036018
Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.
John Burn, Anne-Marie Gerdes, +31 authors, CAPP2 Investigators.
Lancet, 2011 Nov 01; 378(9809). PMID: 22036019    Free PMC article.
Highly Cited.
Molecular mechanisms of cancer development in obesity.
Melin J Khandekar, Paul Cohen, Bruce M Spiegelman.
Nat Rev Cancer, 2011 Nov 25; 11(12). PMID: 22113164
Highly Cited. Review.
Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer.
Manfred Kaufmann, Gunter von Minckwitz, +16 authors, Lajos Pusztai.
Ann Surg Oncol, 2011 Dec 24; 19(5). PMID: 22193884
Highly Cited.
Causes and consequences of damage to mitochondria : morphological aspects.
J Miquel, C Bertoni-Freddari.
Methods Mol Med, 2000 Jan 01; 38. PMID: 22351278
Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials.
Annemijn M Algra, Peter M Rothwell.
Lancet Oncol, 2012 Mar 24; 13(5). PMID: 22440112
Highly Cited. Systematic Review.
Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials.
Peter M Rothwell, Michelle Wilson, +3 authors, Ziyah Mehta.
Lancet, 2012 Mar 24; 379(9826). PMID: 22440947
Highly Cited.
S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites.
Jiehui Deng, Yong Liu, +14 authors, Hua Yu.
Cancer Cell, 2012 May 26; 21(5). PMID: 22624714    Free PMC article.
Highly Cited.
Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy.
Y Boucher, L T Baxter, R K Jain.
Cancer Res, 1990 Aug 01; 50(15). PMID: 2369726
Highly Cited.
Chemosensitivity testing in V79 spheroids: drug delivery and cellular microenvironment.
R E Durand.
J Natl Cancer Inst, 1986 Jul 01; 77(1). PMID: 2425117
Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases.
A W Linnane, S Marzuki, T Ozawa, M Tanaka.
Lancet, 1989 Mar 25; 1(8639). PMID: 2564461
Highly Cited.
Deciphering death: a commentary on Gompertz (1825) 'On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies'.
Thomas B L Kirkwood.
Philos Trans R Soc Lond B Biol Sci, 2015 Mar 10; 370(1666). PMID: 25750242    Free PMC article.
Highly Cited. Review.
Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review.
P Vaupel, F Kallinowski, P Okunieff.
Cancer Res, 1989 Dec 01; 49(23). PMID: 2684393
Highly Cited. Review.
On the Treatment of Inoperable Cases of Carcinoma of the Mamma: Suggestions for a New Method of Treatment, with Illustrative Cases.
George T Beatson.
Trans Med Chir Soc Edinb, 1896 Jan 01; 15. PMID: 29584099    Free PMC article.
Highly Cited.
Multiple nuclear factors interact with the immunoglobulin enhancer sequences.
R Sen, D Baltimore.
Cell, 1986 Aug 29; 46(5). PMID: 3091258
Highly Cited.
Hypoxic cells as specific drug targets for chemotherapy.
K A Kennedy.
Anticancer Drug Des, 1987 Oct 01; 2(2). PMID: 3130070
A Gompertzian model of human breast cancer growth.
L Norton.
Cancer Res, 1988 Dec 15; 48(24 Pt 1). PMID: 3191483
Highly Cited.
Gene amplification in cultured cells.
R T Schimke.
J Biol Chem, 1988 May 05; 263(13). PMID: 3283115
Highly Cited. Review.
Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study.
G A Kune, S Kune, L F Watson.
Cancer Res, 1988 Aug 01; 48(15). PMID: 3390835
Highly Cited.
Cell kinetics and chemotherapy: a critical review.
I Tannock.
Cancer Treat Rep, 1978 Aug 01; 62(8). PMID: 356975
Implications of kinetic heterogeneity in clinical oncology.
L Norton.
Semin Oncol, 1985 Sep 01; 12(3). PMID: 3901264
Tumour cell proliferation in relation to the vasculature.
D G Hirst, J Denekamp.
Cell Tissue Kinet, 1979 Jan 01; 12(1). PMID: 421240
The use of drugs in combination for the treatment of cancer: rationale and results.
V T DeVita, P S Schein.
N Engl J Med, 1973 May 10; 288(19). PMID: 4348752
A decade of combination chemotherapy of advanced Hodgkin's disease.
V T DeVita, G P Canellos, J H Moxley.
Cancer, 1972 Dec 01; 30(6). PMID: 4565815
Cyclical combination chemotherapy for advanced breast carcinoma.
G P Canellos, V T Devita, +3 authors, R C Young.
Br Med J, 1974 Feb 09; 1(5901). PMID: 4818162    Free PMC article.
Kinetics of normal and leukemic leukocyte populations and relevance to chemotherapy.
H E Skipper, S Perry.
Cancer Res, 1970 Jun 01; 30(6). PMID: 4917694
Intensive combination chemotherapy and X-irradiation in Hodgkin's disease.
J H Moxley, V T De Vita, K Brace, E Frei.
Cancer Res, 1967 Jul 01; 27(7). PMID: 4952914
Drug dosage and remission duration in childhood lymphocytic leukemia.
D Pinkel, K Hernandez, +4 authors, C Pratt.
Cancer, 1971 Feb 01; 27(2). PMID: 5100389
Highly Cited.
A study of "total therapy" of acute lymphocytic leukemia in children.
P George, K Hernandez, +3 authors, D Pinkel.
J Pediatr, 1968 Mar 01; 72(3). PMID: 5237796
Resistance to adriamycin in multicellular spheroids.
R M Sutherland, H A Eddy, +2 authors, D Vanantwerp.
Int J Radiat Oncol Biol Phys, 1979 Aug 01; 5(8). PMID: 528267
Highly Cited.
The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia.
E Frei, M Karon, +17 authors, J H Moon.
Blood, 1965 Nov 01; 26(5). PMID: 5321112
Highly Cited.
Treatment of the leukemias.
J H Burchenal.
Semin Hematol, 1966 Apr 01; 3(2). PMID: 5326054
Combination chemotherapy in the treatment of advanced Hodgkin's disease.
V T Devita, A A Serpick, P P Carbone.
Ann Intern Med, 1970 Dec 01; 73(6). PMID: 5525541
Highly Cited.
Tumor size, sensitivity to therapy, and design of treatment schedules.
L Norton, R Simon.
Cancer Treat Rep, 1977 Oct 01; 61(7). PMID: 589597
Highly Cited.
Testicular cancer as a model for a curable neoplasm: The Richard and Hinda Rosenthal Foundation Award Lecture.
L H Einhorn.
Cancer Res, 1981 Sep 01; 41(9 Pt 1). PMID: 6167346
Penetration and binding of vinblastine and 5-fluorouracil in cellular spheroids.
T Nederman, J Carlsson.
Cancer Chemother Pharmacol, 1984 Jan 01; 13(2). PMID: 6467498
Prostaglandin in human breast cancer: Evidence suggesting that an elevated prostaglandin production is a marker of high metastatic potential for neoplastic cells.
P H Rolland, P M Martin, +2 authors, M Toga.
J Natl Cancer Inst, 1980 May 01; 64(5). PMID: 6767871
Highly Cited.
Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer.
L H Einhorn, J Donohue.
Ann Intern Med, 1977 Sep 01; 87(3). PMID: 71004
Highly Cited.
Limited penetration of methotrexate into human osteosarcoma spheroids as a proposed model for solid tumor resistance to adjuvant chemotherapy.
G W West, R Weichselbaum, J B Little.
Cancer Res, 1980 Oct 01; 40(10). PMID: 7438049
Resistance to vincristine of human cells grown as multicellular spheroids.
E Wibe.
Br J Cancer, 1980 Dec 01; 42(6). PMID: 7459228    Free PMC article.
Purification and characterization of hypoxia-inducible factor 1.
G L Wang, G L Semenza.
J Biol Chem, 1995 Jan 20; 270(3). PMID: 7836384
Highly Cited.
Drug and radiation resistance in spheroids: cell contact and kinetics.
P L Olive, R E Durand.
Cancer Metastasis Rev, 1994 Jun 01; 13(2). PMID: 7923546
Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice.
M T Huang, Y R Lou, +3 authors, A H Conney.
Cancer Res, 1994 Nov 15; 54(22). PMID: 7954412
Highly Cited.
Examination by laser scanning confocal fluorescence imaging microscopy of the subcellular localisation of anthracyclines in parent and multidrug resistant cell lines.
H M Coley, W B Amos, P R Twentyman, P Workman.
Br J Cancer, 1993 Jun 01; 67(6). PMID: 8099807    Free PMC article.
Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer.
F S Leach, N C Nicolaides, +7 authors, M Nyström-Lahti.
Cell, 1993 Dec 17; 75(6). PMID: 8261515
Highly Cited.
Manganese-containing superoxide dismutase overexpression causes phenotypic reversion in SV40-transformed human lung fibroblasts.
T Yan, L W Oberley, W Zhong, D K St Clair.
Cancer Res, 1996 Jun 15; 56(12). PMID: 8665527
Combination chemotherapy in disseminated testicular cancer: the Indiana University experience.
L H Einhorn, J P Donohue.
Semin Oncol, 1979 Mar 01; 6(1). PMID: 88074
Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.
M Jang, L Cai, +9 authors, J M Pezzuto.
Science, 1997 Jan 10; 275(5297). PMID: 8985016
Highly Cited.
Suppression of the malignant phenotype of human glioma cells by overexpression of manganese superoxide dismutase.
W Zhong, L W Oberley, T D Oberley, D K St Clair.
Oncogene, 1997 Jan 30; 14(4). PMID: 9053845
Induction and reversal of cell adhesion-dependent multicellular drug resistance in solid breast tumors.
R S Kerbel, B St Croix, V A Florenes, J Rak.
Hum Cell, 1996 Dec 01; 9(4). PMID: 9183656
Landscaping the cancer terrain.
K W Kinzler, B Vogelstein.
Science, 1998 Jun 06; 280(5366). PMID: 9616081
Highly Cited.
Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B.
D R Budman, D A Berry, +8 authors, E Frei.
J Natl Cancer Inst, 1998 Aug 27; 90(16). PMID: 9719081
Highly Cited.
High cofilin-1 levels correlate with cisplatin resistance in lung adenocarcinomas.
Matheus Becker, Marco Antônio De Bastiani, +3 authors, Fábio Klamt.
Tumour Biol, 2013 Sep 11; 35(2). PMID: 24018823
Anti-inflammatory/antioxidant use in long-term maintenance cancer therapy: a new therapeutic approach to disease progression and recurrence.
Sarah Crawford.
Ther Adv Med Oncol, 2014 Mar 04; 6(2). PMID: 24587831    Free PMC article.
Metronomic cyclophosphamide schedule-dependence of innate immune cell recruitment and tumor regression in an implanted glioma model.
Junjie Wu, David J Waxman.
Cancer Lett, 2014 Jul 30; 353(2). PMID: 25069038    Free PMC article.
The Repurposing Drugs in Oncology (ReDO) Project.
Pan Pantziarka, Gauthier Bouche, +3 authors, P Vikas.
Ecancermedicalscience, 2014 Jul 31; 8. PMID: 25075216    Free PMC article.
Highly Cited.
A metal-containing nucleoside that possesses both therapeutic and diagnostic activity against cancer.
Jung-Suk Choi, Ayan Maity, Thomas Gray, Anthony J Berdis.
J Biol Chem, 2015 Feb 26; 290(15). PMID: 25713072    Free PMC article.
Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting.
Curtis D Hodge, Ross A Edwards, +7 authors, J N Mark Glover.
ACS Chem Biol, 2015 Apr 25; 10(7). PMID: 25909880    Free PMC article.
Cancer microenvironment, inflammation and cancer stem cells: A hypothesis for a paradigm change and new targets in cancer control.
Russell L Blaylock.
Surg Neurol Int, 2015 Jun 23; 6. PMID: 26097771    Free PMC article.
Cancer Metabolism and Drug Resistance.
Mahbuba Rahman, Mohammad Rubayet Hasan.
Metabolites, 2015 Oct 06; 5(4). PMID: 26437434    Free PMC article.
Bacteria in Cancer Therapy: Renaissance of an Old Concept.
Sebastian Felgner, Dino Kocijancic, Michael Frahm, Siegfried Weiss.
Int J Microbiol, 2016 Apr 07; 2016. PMID: 27051423    Free PMC article.
[Bone metastases : New aspects of pathogenesis and systemic therapy].
T D Rachner, F Jakob, L C Hofbauer.
Internist (Berl), 2016 Jun 09; 57(7). PMID: 27270907
Regulation of MAPKs Signaling Contributes to the Growth Inhibition of 1,7-Dihydroxy-3,4-dimethoxyxanthone on Multidrug Resistance A549/Taxol Cells.
Jian Zuo, Hui Jiang, +3 authors, Jia-Jie Luan.
Evid Based Complement Alternat Med, 2016 Jul 13; 2016. PMID: 27403196    Free PMC article.
Ubc13: the Lys63 ubiquitin chain building machine.
Curtis D Hodge, Leo Spyracopoulos, J N Mark Glover.
Oncotarget, 2016 Aug 04; 7(39). PMID: 27486774    Free PMC article.
Gold nanoparticles for cancer radiotherapy: a review.
Kaspar Haume, Soraia Rosa, +6 authors, Nigel J Mason.
Cancer Nanotechnol, 2016 Nov 22; 7(1). PMID: 27867425    Free PMC article.
Nanoparticle-Based Celecoxib and Plumbagin for the Synergistic Treatment of Melanoma.
Raghavendra Gowda, Gregory Kardos, +2 authors, Gavin P Robertson.
Mol Cancer Ther, 2016 Dec 23; 16(3). PMID: 28003325    Free PMC article.
Aggregation Effects and Population-Based Dynamics as a Source of Therapy Resistance in Cancer.
Joel S Brown, Jessica J Cunningham, Robert A Gatenby.
IEEE Trans Biomed Eng, 2017 Jan 24; 64(3). PMID: 28113286    Free PMC article.
Tumour-targeting bacteria-based cancer therapies for increased specificity and improved outcome.
Sebastian Felgner, Vinay Pawar, +2 authors, Siegfried Weiss.
Microb Biotechnol, 2017 Aug 05; 10(5). PMID: 28771926    Free PMC article.
Preclinical Evaluation and Monitoring of the Therapeutic Response of a Dual Targeted Hyaluronic Acid Nanodrug.
Minglong Chen, Wenqi Zhang, +6 authors, Shi Gao.
Contrast Media Mol Imaging, 2017 Nov 04; 2017. PMID: 29097925    Free PMC article.
Spatial Heterogeneity and Evolutionary Dynamics Modulate Time to Recurrence in Continuous and Adaptive Cancer Therapies.
Jill A Gallaher, Pedro M Enriquez-Navas, +2 authors, Alexander R A Anderson.
Cancer Res, 2018 Feb 01; 78(8). PMID: 29382708    Free PMC article.
Highly Cited.
A bibenzyl from Dendrobium ellipsophyllum induces apoptosis in human lung cancer cells.
Anirut Hlosrichok, Somruethai Sumkhemthong, +2 authors, Chatchai Chaotham.
J Nat Med, 2018 Mar 01; 72(3). PMID: 29488156
Preservation of muscle mass as a strategy to reduce the toxic effects of cancer chemotherapy on body composition.
Fabrizio Pin, Marion E Couch, Andrea Bonetto.
Curr Opin Support Palliat Care, 2018 Aug 21; 12(4). PMID: 30124526    Free PMC article.
Dihydropyrimidine Dehydrogenase Levels in Colorectal Cancer Cells Treated with a Combination of Heat Shock Protein 90 Inhibitor and Oxaliplatin or Capecitabine.
Mahshid Mohammadian, Shima Zeynali-Moghaddam, +3 authors, Fatemeh Kheradmand.
Adv Pharm Bull, 2019 Oct 09; 9(3). PMID: 31592113    Free PMC article.
BZD9L1 sirtuin inhibitor as a potential adjuvant for sensitization of colorectal cancer cells to 5-fluorouracil.
Yi Jer Tan, Yeuan Ting Lee, +5 authors, Chern Ein Oon.
Ther Adv Med Oncol, 2019 Oct 22; 11. PMID: 31632470    Free PMC article.
Molecular Mechanisms of Action of Genistein in Cancer: Recent Advances.
Hardeep Singh Tuli, Muobarak Jaber Tuorkey, +7 authors, Anupam Bishayee.
Front Pharmacol, 2019 Dec 24; 10. PMID: 31866857    Free PMC article.
Genome-wide CRISPR knockout screens identify NCAPG as an essential oncogene for hepatocellular carcinoma tumor growth.
Yu Wang, Bin Gao, +10 authors, Kam Man Hui.
FASEB J, 2019 Apr 26; 33(8). PMID: 31022357    Free PMC article.
Prevalence, Safety and Long-Term Retention Rates of Biologics in Hong Kong from 2001 to 2015.
Mengqin Ge, Kenneth K Man, +3 authors, Xue Li.
Drug Saf, 2019 Jun 07; 42(9). PMID: 31168709
Diethyldithiocarbamate-copper nanocomplex reinforces disulfiram chemotherapeutic efficacy through light-triggered nuclear targeting.
Liting Ren, Wenya Feng, +5 authors, Sijin Liu.
Theranostics, 2020 Jun 03; 10(14). PMID: 32483459    Free PMC article.
Effect of Compound Kushen Injection, a Natural Compound Mixture, and Its Identified Chemical Components on Migration and Invasion of Colon, Brain, and Breast Cancer Cell Lines.
Saeed Nourmohammadi, Thazin Nwe Aung, +6 authors, Andrea J Yool.
Front Oncol, 2019 May 21; 9. PMID: 31106149    Free PMC article.
Highly Cited.
Advances in Gold Nanoparticle-Based Combined Cancer Therapy.
Kyle Bromma, Devika B Chithrani.
Nanomaterials (Basel), 2020 Aug 30; 10(9). PMID: 32858957    Free PMC article.
Three-Dimensional Tumor Spheroids as a Tool for Reliable Investigation of Combined Gold Nanoparticle and Docetaxel Treatment.
Kyle Bromma, Abdulaziz Alhussan, +3 authors, Devika B Chithrani.
Cancers (Basel), 2021 Apr 04; 13(6). PMID: 33806801    Free PMC article.
Chinese Herbal Medicine for Chemotherapy-Induced Leukopenia: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials.
Qing Wang, Hui Ye, +4 authors, Gui-Hua Xu.
Front Pharmacol, 2021 May 22; 12. PMID: 34017246    Free PMC article.