Podstawy chemioterapii nowotworów złośliwych презентация

Bari was an air attack by German was an air attack by German bombers was an air attack by German bombers on Allied was an air attack by German bombers on Allied forces and shipping in Bari was an air attack by German bombers on Allied forces and shipping in Bari, Italy, on 2 December 1943 during World War II was an air attack by German bombers on Allied forces and shipping in Bari, Italy, on 2 December 1943 during World War II. In the attack, 105 German Junkers Ju 88 bombers of Luftflotte 2 2, achieving complete surprise, bombed shipping and personnel operating in support of the Allied Italian campaign 2, achieving complete surprise, bombed shipping and personnel operating in support of the Allied Italian campaign, sinking 27 cargo and transport ships and a schooner in Bari harbour.
The attack, which lasted a little more than one hour, put the port out of action until February 1944 and was called the "Little Pearl HarborThe attack, which lasted a little more than one hour, put the port out of action until February 1944 and was called the "Little Pearl Harbor". The release of mustard gas from one of the wrecked cargo ships added to the loss of life. The British and US governments covered up the presence of mustard gas and its effects on victims of the raid.

John Harvey—had been carrying a secret cargo of 2000 M47A1—had been carrying a secret cargo of 2000 M47A1 mustard gas—had been carrying a secret cargo of 2000 M47A1 mustard gas bombs, each holding 60–70 lb (27–32 kg) of the agent. According to Royal Navy historian Stephen Roskill, this cargo had been sent to Europe for retaliatory use if Germany carried out its threatened use of chemical warfare in Italy.[26] The destruction of John Harvey caused liquid sulfur mustard from the bombs to spill into waters already contaminated by oil from the other damaged vessels. The many sailors who had abandoned their ships into the water became covered with this oily mixture which provided an ideal solvent for the sulfur mustard. Some mustard evaporated and mingled with the clouds of smoke and flame.[4] The wounded were pulled from the water and sent to medical facilities which were unaware of the mustard gas. Medical staff focused on personnel with blast or fire injuries and little attention was given to those merely covered with oil.[27] Many injuries caused by prolonged exposure to low concentrations of mustard might have been reduced by bathing or a change of clothes.[28]
Within a day, the first symptoms of mustard poisoning had appeared in 628 patients and medical staff, with symptoms including blindness and chemical burns. This puzzling development was further complicated by the arrival of hundreds of Italian civilians also seeking treatment, who had been poisoned by a cloud of sulfur mustard vapor that had blown over the city when some of the John Harvey's cargo exploded. As the medical crisis worsened, little information was available about what was causing these symptoms, as the U.S. military command wanted to keep the presence of chemical munitions secret from the Germans.[29] Nearly all crewmen of the John Harvey had been killed, and were unavailable to explain the cause of the "garlic-like" odor noted by rescue personnel.[27]
Informed about the mysterious symptoms, Deputy Surgeon General Fred Blesse sent for Lieutenant Colonel Stewart Francis Alexander, an expert in chemical warfare. Carefully tallying the locations of the victims at the time of the attack, Alexander traced the epicenter to the John Harvey, and confirmed mustard gas as the responsible agent when he located a fragment of the casing of a U.S. M47A1 bomb.[3]
By the end of the month, 83 of the 628 hospitalized military victims had died. The number of civilian casualties, thought to have been even greater, could not be accurately gauged since most had left the city to seek shelter with relatives.[3]
The U.S. destroyer escortThe U.S. destroyer escort (DE)—USS Bistera—though lightly damaged—picked up survivors from the water during the raid and put out to sea; during the night members of the crew went blind and developed chemical burns. The Bistera had to return, with great difficulty, to Taranto harbour.[30][30][31]
Cover-up
A member of Allied Supreme Commander General Dwight D. EisenhowerA member of Allied Supreme Commander General Dwight D. Eisenhower's medical staff, Dr. Stewart F. Alexander, was dispatched to Bari following the raid. Alexander had trained at the Army's Edgewood Arsenal in Maryland, and was familiar with some of the effects of mustard gas. Although he was not informed of the cargo carried by the SS John Harvey, and most victims suffered atypical symptoms caused by exposure to mustard diluted in water and oil (as opposed to airborne), Alexander rapidly concluded that mustard gas was present. Although he could not get any acknowledgment from the chain of command, Alexander convinced medical staffs to treat patients for mustard gas exposure and saved many lives as a result. He also preserved many tissue samples from autopsied victims at Bari. After WWII, these samples would result in the development of an early form of chemotherapy, and most victims suffered atypical symptoms caused by exposure to mustard diluted in water and oil (as opposed to airborne), Alexander rapidly concluded that mustard gas was present. Although he could not get any acknowledgment from the chain of command, Alexander convinced medical staffs to treat patients for mustard gas exposure and saved many lives as a result. He also preserved many tissue samples from autopsied victims at Bari. After WWII, these samples would result in the development of an early form of chemotherapy based on mustard, Mustine.[32]
From the start, Allied High Command tried to conceal the disaster, in case the Germans believed that the Allies were preparing to use chemical weapons, which might provoke them into preemptive use, but there were too many witnesses to keep the secret, and in February 1944, the U.S. Chiefs of Staff issued a statement admitting to the accident and emphasizing that the U.S. had no intention of using chemical weapons except in the case of retaliation.[31]
General Dwight D. Eisenhower approved Dr. Alexander's report. Winston Churchill, however, ordered all British documents to be purged, listing mustard gas deaths as "burns due to enemy action".[3]
U.S. records of the attack were declassified in 1959, but the episode remained obscure until 1967 when author Glenn B. Infield published the book Disaster at Bari.[32] In 1986 the British government finally admitted to survivors of the Bari raid that they had been exposed to poison gas and amended their pension payments accordingly.[33]
In his autobiographical work Destroyer Captain published in 1975 by William Kimber & Co, Lieutenant Commander Roger Hill describes refuelling HMS Grenville in Bari shortly after the attack. He describes the damage done and details how a shipload of mustard gas came to be in the harbour because of intelligence reports which he viewed as "incredible".
In 1988, through the efforts of Nick T. SparkIn 1988, through the efforts of Nick T. Spark, U.S. Senator Dennis DeConciniIn 1988, through the efforts of Nick T. Spark, U.S. Senator Dennis DeConcini and U.S. Senator Bill BradleyIn 1988, through the efforts of Nick T. Spark, U.S. Senator Dennis DeConcini and U.S. Senator Bill Bradley, Alexander received recognition from the Surgeon General of the United States Army for his actions in the aftermath of the Bari disaster.[34]
Aftermath
A subsequent inquiry exonerated Coningham but found that the absence of previous air attacks had led to complacency.[6]

apparently blind to the dressing station

chemotherapy agents similar to mustard gas. Although their common use is medicinal,[1][1][2] in principle these compounds can also be deployed as chemical warfare agents.[3][3][4] Nitrogen mustards are nonspecific DNA alkylating agents Nitrogen mustards are nonspecific DNA alkylating agents. Nitrogen mustard gas Nitrogen mustards are nonspecific DNA alkylating agents. Nitrogen mustard gas was stockpiled by several nations during the Second World War, but it was never used in combat.[5][5][6] As with all types of mustard gas, nitrogen mustards are powerful and persistent blister agents As with all types of mustard gas, nitrogen mustards are powerful and persistent blister agents and the main examples (HN1, HN2, HN3, see below) are therefore classified as Schedule 1 substances As with all types of mustard gas, nitrogen mustards are powerful and persistent blister agents and the main examples (HN1, HN2, HN3, see below) are therefore classified as Schedule 1 substances within the Chemical Weapons Convention.[7] Production and use is therefore strongly restricted.[8]
During WWII nitrogen mustards were studied at the Yale School of MedicineDuring WWII nitrogen mustards were studied at the Yale School of Medicine by Alfred GilmanDuring WWII nitrogen mustards were studied at the Yale School of Medicine by Alfred Gilman and Louis Goodman, and classified human clinical trials of nitrogen mustards for the treatment of lymphoma started in December 1942.[9] Also during WWII, an incident during the air raid on Bari, Italy, led to the release of mustard gas that affected several hundred soldiers and civilians.[10] Medical examination of the survivors showed a decreased number of lymphocytes.[11] After WWII was over, the Bari incident and the Yale group's studies eventually converged prompting a search for other similar compounds. Due to its use in previous studies, the nitrogen mustard known as "HN2" became the first chemotherapy known as "HN2" became the first chemotherapy drug mustine.
Nitrogen mustards are not related to the mustard plantNitrogen mustards are not related to the mustard plant or its pungent essence, allyl isothiocyanate: the name comes from the pungent smell of chemical weapons preparations.

the USAN, however) also known as mustine and HN2 and in former USSR known as Embichin is a nitrogen mustard sold under the brand name Mustargen. It is the prototype of alkylating agents. It is the prototype of alkylating agents, a group of anticancer. It is the prototype of alkylating agents, a group of anticancer chemotherapeutic drugs. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA base guanine. It is the prototype of alkylating agents, a group of anticancer chemotherapeutic drugs. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA base guanine. As the chemical is a blister agent. It is the prototype of alkylating agents, a group of anticancer chemotherapeutic drugs. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA base guanine. As the chemical is a blister agent, its use is strongly restricted within the Chemical Weapons Convention. It is the prototype of alkylating agents, a group of anticancer chemotherapeutic drugs. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA base guanine. As the chemical is a blister agent, its use is strongly restricted within the Chemical Weapons Convention where it is classified as a Schedule 1 substance.
Successful clinical use of chlormethine (mechlorethamine) resulted in development of the field of anticancer chemotherapy, led by Cornelius P. RhoadsSuccessful clinical use of chlormethine (mechlorethamine) resulted in development of the field of anticancer chemotherapy, led by Cornelius P. Rhoads at Memorial Sloan-KetteringSuccessful clinical use of chlormethine (mechlorethamine) resulted in development of the field of anticancer chemotherapy, led by Cornelius P. Rhoads at Memorial Sloan-Kettering. The drug is a nitrogen-based analogue of mustard gasSuccessful clinical use of chlormethine (mechlorethamine) resulted in development of the field of anticancer chemotherapy, led by Cornelius P. Rhoads at Memorial Sloan-Kettering. The drug is a nitrogen-based analogue of mustard gas (which is sulfur-based) and was derived from chemical warfareSuccessful clinical use of chlormethine (mechlorethamine) resulted in development of the field of anticancer chemotherapy, led by Cornelius P. Rhoads at Memorial Sloan-Kettering. The drug is a nitrogen-based analogue of mustard gas (which is sulfur-based) and was derived from chemical warfare research. Secret clinical trials of the agent for Hodgkin's diseaseSuccessful clinical use of chlormethine (mechlorethamine) resulted in development of the field of anticancer chemotherapy, led by Cornelius P. Rhoads at Memorial Sloan-Kettering. The drug is a nitrogen-based analogue of mustard gas (which is sulfur-based) and was derived from chemical warfare research. Secret clinical trials of the agent for Hodgkin's disease and several other lymphomasSuccessful clinical use of chlormethine (mechlorethamine) resulted in development of the field of anticancer chemotherapy, led by Cornelius P. Rhoads at Memorial Sloan-Kettering. The drug is a nitrogen-based analogue of mustard gas (which is sulfur-based) and was derived from chemical warfare research. Secret clinical trials of the agent for Hodgkin's disease and several other lymphomas and leukemias in humans began in December 1942. Because of wartime secrecy restrictions, it was not until 1946 that the results of these trials were published openly.[14]

Chu E Cancer Res 2008;68:8643-8653

©2008 by American Association for Cancer Research

Chu E Cancer Res 2008;68:8643-8653

©2008 by American Association for Cancer Research

three groups of cancers, in the first of which we can achieve a high complete response rate and a high cure rate
This first group includes diseases such as Hodgkin’s disease, childhood leukaemia and testicular cancer (less than 5% of the global cancer burden)

with a low complete response and low cure rate, such as pancreatic cancer, HCC, lung and stomach cancers.

high complete response but a low cure rate.

many patients, and when deciding on priorities, we have to assess how much we are willing to pay for a month of reasonable quality of life.

DNA/RNA or protein synthesis and function.

sam odsetek komórek populacji nowotworowej (wg zasad kinetyki pierwszego rzędu, w postępie logarytmicznym).

2. Chemioterapeutyki wywierają efekt cytotoksyczny niemal wyłącznie w stosunku do komórek dzielących się (frakcja komórek proliferujących).

masy guza
Choroba w zaawansowanym stadium Duża ilość komórek nowotworowych mało komórek proliferujących dużo komórek w fazie spoczynkowej G0 długi czas podwajania masy guza

angiogeneza

Opisuje wzrost nowotworów litych, w funkcji czasu i ilości komórek nowotworowych

leczenie

Choroba w zaawansowanym stadium Duża częstość mutacji Dużo komórek opornych na leczenie

przeciwnowotworowe

w dawkach podzielonych jest skuteczniejsze niż podanie tej samej dawki jednorazowo.

Ich działanie jest tym skuteczniejsze im więcej komórek proliferujących znajduje się w populacji.

Fazoniezależne

Wynik ich działania jest
Wprost proporcjonalny do
wielkości dawki jednorazowej.

Działają w tych nowotworach, w których odsetek komórek proliferujących jest niewielki

ujemnym łądunku (np. kwasy nukleinowe)
Alkilacja powoduje rozluźnienie wiązania zasady azotowej z resztą cukrową, depurynację, rozpad łańcucha głównego DNA.

CYKLIFOSFAMID
IFOSFAMID
MELFALAN
BUSULFAN
STREPTOZOCYNA
DAKARBAZYNA (G2)
CISPLATYNA
KARBOPLATYNA
OKSALIPLATYNA

be given orally and intravenously
Require increased fluid intake, emptying bladder several times daily
Dose reduction in the setting of renal dysfuncion
Toxicity: myelotoxicity, hemorrhagic cystitis, nausea, vomiting, alopecia, amenorrea, sterility, cardiotoxicity (high dose), secondary maignancies (AML, bladder cancer), immunosupression, SIADH, hypersensitivity reactions (rhinitis, pharyngitis)

require hydration, uroprotection with mesna, monitoring of urine
Dose reduction in the setting of renal dysfuncion
Toxicity: myelotoxicity, hemorrhagic cystitis, nausea, vomiting, neurotoxicity, alopecia, amenorrea, infertility, SIADH, teratogenic

; formation of DNA adducts results in inhibition of DNA synthesis and function
Dose must be reduced in the setting of renal dysfunction, vigorous hydration obligatory, potent emetogenic agent, contraindicated in patients with pre-existing hearing deficit
Toxicity: nephrotoxicity, nausea, vomiting, neurotoxicity, myelosupression, ototoxicity, hypersensitivity reactions, ocular toxicity, vascular events, including myocardial infarction, infertility, alopecia, SIADH

kwasów nukeinowych i śmierć komórki
Leczenie opiera się na różnicy kinetyki rozrostu między tkanką nowotworową, a prawidłową (szybko rosnąca tkanka pochłania większą ilość antymetabolitu)

ANTAGONIŚCI KWASU FOLIOWEGO
METOTREKSAT
EDATREKSAT
ANTAGONIŚCI PIRYMIDYN
5’-FLUOROURACYL
KAPECYTABINA
CYTARABINA
GEMCYTABINA
ANTAGONIŚCI PURYN
MERKAPTOPURYNA
AZATIPRYNA
INHIBITORY DEAMINAZY ADENOZYNOWEJ
PENTOSTATYNA
INNE ANTYMETABOLITY
FLUDARABINA
KLADRYBINA

enzyme thymidylate synthase (TS); incorporation of the 5-FU metabolite into RNA or DNA resulting in RNA or DNA processing, synthesis and function
Leucovorin enhances the toxicity and antitumor activity of 5-FU
Deficiency in dihydropirymidine dehydrogenase may lead to unexpected severe toxicity
Toxicity: myelosupression, diarrhoea, mucositis, hand-foot syndrome, neurotoxicity, cardiotoxicity, blepharitis, conjunctivitis, dry skin, photosensitivity, vein inflammation

i DNA, powodując zachowanie przecięcia spirali i zahamowanie fizjologicznej funkcji DNA.

KAPTOTECYNA
TOPOTEKAN
IRINOTEKAN

the Camptotheca acuminata tree
Converted enzymatically to active metabolite SN-38 in the liver
Toxicity: myelosupression, diarrhoea, cholinergic syndrome, nausea, vomiting, alopecia, asthenia, fever

wolnych rodników tlenowych
Uszkadzają funkcję błony komórkowej

Antracykliny I generacji
DOKSORUBICYNA
DAUNORUBICYNA
Antracykliny II generacji
AKLARUBICYNA
EPIRUBICYNA
IDARUBICYNA
MITOKSANTRON
Inne antybiotyki cytostatyczne
DAKTYNOMYCYNA
BLEOMYCYNA (G1)

DNA – inhibition of DNA synthesis and function
Inhibits transcription through inhibition of DNA-dependent RNA polymerase
Inhibition of topoisomerase II leading to DNA breaks
Formation of cytotoxic oxygen free radicals leading to DNA breaks
Special considerations:
monitor cardiac function, strong vesicant, dose reduction in the setting of liver dysfunction, cumulative doses of >450mg/m2 are associated with increased risk of cardiotoxicity
Toxicity: myelosupression, nausea, vomiting, cardiotoxicity, mucositis, diarrhoea, alopecia

jego destabilizację.
Zahamowanie podziału komórki w stadium metafazy
Chaotyczne rozmieszczenie chromosomów i śmierć komórki

WINKRYSTYNA

WINBLASTYNA

WINDEZYNA

WINORELBINA

polymeryzation, disrupting formation of microtubule assembly during mitosis
Dose reduction in the setting of liver dysfunction,
Toxicity: neurotoxicity, constipation, ileus, alopecia, skin rash, fever, myelosupression, SIADH, hypersensitivity reactions, infertility

mikrotubuli
Powstają nieprawidłowe konfiguracje polimeru uniemożliwiające prawidłowe ukształtowanie się wrzeciona kariokinetycznego.

PAKLITAKSEL

DOCETAKSEL

tree
High-affinity binding to microtubules enhances tubulin polymerization; normal dynamic process of microtubule network is inhibited, leading to inhibition of mitosis and cell division
Special considerations: Steroid premedication
Toxicity: Hypersensitivity reactions, myelosupression, fluid retention syndrome, skin rash, discoloration of fingernails, mucositis, diarrhoea, peripheral neuropathy, fatigue, arthralgias, myalgias

do fazy M
Hamują aktywność topoizomerazy II
Hamują syntezę kwasów nukleinowych
Generują wolne rodniki tlenowe

ETOPOZYD

TENIPOZYD

considerations: Dose reduction in the setting of renal dysfunction or liver dysfunction, risk for hypotension, monitor for anaphylactic reactions
Toxicity: myelosupression, nausea, vomiting, anorexia, alopecia, mucositis, diarrhoea, hypersensitivity reactions, increased risk of secondary malignancies, especially AML

polega na stosowaniu cytostatyków przed planowanym leczeniem radykalnym (radioterapia, chirurgia). Ma ona na celu zniszczenie istniejących mikroprzerzutów.
Adiuwantowa - polega na stosowaniu cytostatyków po leczeniu radykalnym (radioterapia, chirurgia). Postępowanie to również ma na celu zniszczenie istniejących mikroprzerzutów.

Paliatywna - stosowana jest u chorych, u których uzyskanie wyleczenia jest niemożliwe. W tym przypadku stosowanie cytostatyków ma na celu wydłużenie życia chorego i/lub poprawę jakości życia chorego.

dojamowa (do jamy opłucnej, osierdzia, otrzewnej)
Chemioterapia lokoregionalna (dotętnicza, miejscowa, implantacja polimerów z aktywnym cytostatykiem)

po ustaleniu rozpoznania. Wiarygodne i precyzyjne rozpoznanie histopatologiczne jest niezbędne dla wdrożenia leczenia cytostatycznego.

2. Należy stosować największe tolerowane dawki leków z pewnymi przerwami, koniecznymi do odnowy prawidłowych tkanek organizmu.
3. Należy dążyć do maksymalnie wybiórczego zniszczenia tkanki nowotworowej z minimalnym i odwracalnym uszkodzeniem prawidłowych tkanek.

cykl komórkowy, histopatologii nowotworu, charakterystyki jego wzrostu i stopnia zaawansowania choroby.

5. Regułą jest stosowanie terapii wielolekowej (polichemioterapii), przy uwzględnieniu następujących zasad:
a.  każdy z preparatów powinien być skuteczny w monoterapii,
b. należy łączyć leki o różnym mechanizmie działania i punkcie uchwytu w cyklu komórkowym,

zastosowane w kombinacji powinny mieć różne lub występujące w różnym czasie działania niepożądane, ich natężenie powinno pozostać w zakresie subtoksycznym.
e. możliwe jest zastosowanie dawek preparatów mniejszych od stosowanych w monoterapii, dzięki temu toksyczność leczenia jest mniejsza,

f. polichemioterapia pozwala na zmniejszenie prawdopodobieństwa selekcji klonów komórek nowotworowych opornych na leczenie.

przy zastosowaniu zasad „mobilizacji” i „synchronizacji”.

Mobilizacja Przyspieszenie przejścia komórek z fazy spoczynku G0 do cyklu komórkowego. Synchronizacja Polega na zahamowaniu jak największej liczby komórek w jednej fazie cyklu i podaniu dużej dawki leku, swoistego dla kolejnej fazy cyklu podziałowego, w celu zniszczenia jak największej ilości komórek nowotworowych.

prowadzona od początku do końca choroby, obejmująca m. in.: zwalczanie zakażeń, leczenie przeciwbólowe, wyrównywanie zaburzeń wodno-elektrolitowych, profilaktykę i leczenie powikłań terapii cytostatycznej.

Fluorouracyl – w dawce 500 mg / m2 w 1 dniu terapii   Doksorubicyna – w dawce 50 mg / m2 w 1 dniu terapii   Cyklofosfamid – w dawce 500 mg / m2 w 1 dniu terapii

FAC w terapii adiuwantowej raka piersi

Cykl leczenia powtarza się co 3 tygodnie licząc od 1 dnia (co 21 dni).

lub WHO
(Markery nowotworowe)

biochemicznych nowotworu, potwierdzone przez 2 obserwacje w odstępie co najmniej 4 tygodni.

PR (Częściowa odpowiedź) Zmniejszenie się o co najmniej 30% sumy największych wymiarów zmian, potwierdzone przez 2 obserwacje w odstępie co najmniej 4 tygodni. Równocześnie nie stwierdza się pojawienia nowych zmian, ani powiększenia żadnej z istniejących zmian.

SD (Stabilizacja choroby) Zmniejszenie się o mniej niż 50% wszystkich zmian lub ich powiększenie o nie więcej niż 25% (przy uwzględnieniu w/w kryteriów).


PD (Progresja choroby) Powiększenie się sumy największych wymiarów zmian o więcej niż 20% lub pojawienie się nowych zmian.

w grupie chorych, którzy po leczeniu przeżyli 10 – 20 lat, bez objawów choroby nowotworowej, odsetek zgonów ze wszystkich powodów jest taki sam, jak w zdrowej populacji ludzi tej samej płci i wieku.”