116:, who argued that every remaining cancer cell in the body must be eradicated in order to ensure the survival of the patient, shifted clinical practice towards more aggressive chemotherapy regimens. Importantly, Skipper also established that the use of multiple chemotherapy drugs at once provided synergistic benefits over single agents. However, the idea of combination chemotherapy was initially met with resistance by researchers concerned about the toxicity of multiple harmful drugs being used simultaneously.
69:. The first clinical trial of VAMP began in 1961. Because it was the first time that four chemotherapeutic agents were used at once, the trial was highly controversial at its time. Although new combination chemotherapy regimens have replaced the use of VAMP in the treatment of childhood leukemia, VAMP is considered an important precursor to modern treatments, confirming the effectiveness of combination chemotherapy and leading to the use of combination chemotherapy regimens to treat other types of cancer.
134:(NCI), took bold and decisive action, proposing a regimen of four chemotherapeutic agents, more drugs than had ever been previously attempted. The aggressiveness and potential lethal toxicity of this proposal was alarming to many fellow members of the NCI, who felt that Frei and Freireich were making a dangerous break with the systematic trial processes that characterized the leukemia group of the NCI. However, Frei and Freireich felt that the current pace of the NCI was too slow to make progress.
188:
218:
236:
137:
Initially, the leukemia group rejected the VAMP proposal, denying funding until many of their current trials had been completed. However, an arrangement was reached that involved the VAMP trial being run separately from the rest of the leukemia group at the NCI. The trial began in 1961 on children
141:
In the initial weeks, the children were pushed to the brink of death by VAMP's four chemotherapy agents, each cytotoxic on its own. After a few weeks, however, the children's marrow healed, remissions came, and leukemia was undetectable in many of the patients. These remissions astounded Frei and
165:
VAMP includes four drugs, vincristine, amethopterin, mercaptopurine, and prednisone, operating under independent pathways, which work in concert with one another as an anti-tumor therapy. Combining multiple chemotherapeutic drugs into one treatment helps overcome the problem of drug resistance.
666:; Link, M. P.; Kun, L; Billett, A. L.; Marcus, K. C.; Hurwitz, C. A.; Young, J. A.; Tarbell, N. J.; Weinstein, H. J. (July 2002). "VAMP and low-dose, involved-field radiation for children and adolescents with favorable, early-stage Hodgkin's disease: results of a prospective clinical trial".
232:, and inhibits cellular replication through multiple mechanisms. 6-MP halts purine synthesis, and also products of the metabolism of 6-MP become incorporated during DNA replication, leading to a mismatching of nucleotides that triggers apoptosis through the cell's DNA repair mechanisms.
119:
VAMP emerged amid a period of cautious and methodical testing of various combinations of chemotherapeutic agents. Due to the immense possibilities of combinations and the potential dangers of these aggressive regimens, this trial process was slow and, in the view of some, inefficient.
614:
Donaldson, Sarah S.; Link, Michael P.; Weinstein, Howard J.; Rai, Shesh N.; Brain, Sam; Billett, Amy L.; Hurwitz, Craig A.; Krasin, Matthew; Kun, Larry E.; Marcus, Karen C.; Tarbell, Nancy J.; Young, Jeffrey A.; Hudson, Melissa M. (2007).
153:
166:
Furthermore, combination chemotherapy allows multiple independently-acting drugs to be administered at their maximum dose, which increases the treatments toxicity to cancer cells without being deadly to the patient.
142:
Freirdrich's peers, and gained supporters even from those who formerly resisted the trial. The remission rate ultimately increased to 60%, and around half of those remissions lasted for several years.
149:, there was nothing stopping the leukemia from reemerging in the nervous system and invading the brain. These relapses proved deadly for all but five percent of the patients.
180:. However, it was soon found to be an effective anti-leukemia agent even at small doses. Vincristine functions by binding to and inhibiting microtubule production in the
88:. Now, other combinations and doses that are referred to as VAMP, including C-VAMP and a VAMP regimen that replaces the mercaptopurine of the original combination with
176:, first discovered by the Eli Lilly company in 1958 in a search process that involved testing thousands of plant extracts. It was initially planned to be an
905:
Tian, Henghe; Cronstein, Bruce N. (2007). "Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis".
57:, used today in the treatment of Hodgkin lymphoma. It was one of the earliest combination chemotherapy regimens, originally developed as a treatment for
254:
in the treatment of a variety of medical conditions. Generally, it reduces redness and swelling, but its use in cancer involves inducing apoptosis in
184:
necessary for the cellular replication, halting cell division in metaphase. With their chromosomes unable to separate, the cells ultimately die.
617:"Final Results of a Prospective Clinical Trial With VAMP and Low-Dose Involved-Field Radiation for Children With Low-Risk Hodgkin's Disease"
532:
Ribatti, Domenico (May 2012). "Sidney Farber and the treatment of childhood acute lymphoblastic leukemia with a chemotherapeutic agent".
583:
Raje, N.; Powles, R.; Hickish, T.; Gore, M.; Milan, S.; Mehta, J.; Singhal, S.; Viner, C.; Treleaven, J.; Cunningham, D. (1995).
1012:
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177:
146:
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However, the remissions were not permanent for most. Because none of the components of VAMP could cross the
92:. All these regimens take advantage of the synergistic effects of combining multiple chemotherapy agents.
585:"799 VAMP/C-VAMP infusional chemotherapy as induction treatment for previously untreated multiple myeloma"
54:
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More research remains to be done to determine the exact mechanism of prednisone-induced apoptosis.
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Drug
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Chabner, Bruce A.; Roberts, Thomas G. (January 2005). "Chemotherapy and the war on cancer".
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Moudi, Maryam; Go, Rusea; Yien, Christina Yong Seok; Nazre, Mohd. (November 2013).
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112:, each with their own individual history and development. Furthermore, the work of
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Morrison, W.B. (2010-11-01). "Cancer
Chemotherapy: An Annotated History".
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The VAMP regimen developed by
Freireich and Frei was a combination of
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1013:"Prednisone (Oral Route) Description and Brand Names - Mayo Clinic"
846:"Vincristine - FDA prescribing information, side effects and uses"
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By 1960, several chemotherapeutic agents had emerged, among these
61:
by a group of researchers at the
National Cancer Institute led by
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DeVita, Vincent T.; Rosenberg, Steven A. (2012-06-06).
477:"Understanding resistance to combination chemotherapy"
206:, a precursor to cellular DNA that is necessary for
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18:
1039:McKay, Lorraine I.; Cidlowski, John A. (2003).
907:Bulletin of the NYU Hospital for Joint Diseases
202:. It operates by inhibiting the production of
965:(Second ed.). Elsevier. pp. 515–516.
306:DeVita, Vincent T.; Chu, Edward (2008-11-01).
214:, methotrexate disrupts cellular replication.
1042:Corticosteroids in the Treatment of Neoplasms
8:
802:International Journal of Preventive Medicine
198:, or amethopterin, is a drug developed by
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941:"Methotrexate: Mechanism of Action"
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870:"Vincristine: Mechanism of Action"
308:"A History of Cancer Chemotherapy"
156:Molecular structure of Vincristine
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995:"Prednisone: Mechanism of Action"
662:Donaldson, S. S.; Hudson, M. M.;
534:Pediatric Hematology and Oncology
239:Molecular structure of Prednisone
891:. NY: Scribbler. pp. 28–29.
55:combination chemotherapy regimen
764:10.1111/j.1939-1676.2010.0590.x
707:New England Journal of Medicine
887:Mukherjee, Siddhartha (2011).
404:Mukherjee, Siddhartha (2011).
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621:Journal of Clinical Oncology
601:10.1016/0959-8049(95)96048-I
546:10.3109/08880018.2012.678969
172:is a drug isolated from the
889:The Emperor of All Maladies
406:The Emperor of All Maladies
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589:European Journal of Cancer
493:10.1016/j.drup.2012.10.003
228:, or 6-MP is an analog of
132:National Cancer Institute
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633:10.1200/JCO.2006.08.4772
961:Hande, Kenneth (2002).
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252:anti-inflammatory agent
212:dihydrofolate reductase
963:Encyclopedia of Cancer
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161:Mechanisms of Action
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59:childhood leukemia
808:(11): 1231–1235.
798:"Vinca Alkaloids"
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170:Vincristine
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262:References
244:Prednisone
204:folic acid
86:prednisone
919:1936-9719
850:Drugs.com
814:2008-7802
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