Antibióticos Antitumorais

Descrição Geral

Os antibióticos antitumorais, agentes isolados de estirpes de Streptomyces, são utilizados para o tratamento de cancro devido à sua capacidade de interferir com a síntese de ADN e/ou RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure, levando assim à morte de células cancerígenas. Os efeitos destes fármacos são demasiado tóxicos para serem usados em infeções bacterianas.

Os agentes nesta classe incluem:

• Específico para o ciclo celular: bleomicina
• Não específico para o ciclo celular:
  • Dactinomicina
  • Mitomicina
  • Antraciclinas

Bleomicina

Descrição

• Fármaco específico do ciclo celular que atua na fase G2 do ciclo celular
• Mecanismo de ação:
  • Contém um local de ligação de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure e um local de ligação de ferro → liga-se o DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure, formando um complexo (DNA-bleomicina Fe(II))
  • Efeito: Quebras no DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure de cadeia dupla e simples
• Farmacocinética:
  • IV, IM, SC, intrapleural
  • Metabolismo: inativado enzimaticamente pela bleomicina hidrolase (não encontrada em quantidades significativas na pele e nos pulmões)
  • Meia-vida: 2 horas (IV)
  • Excreção: renal
• Indicações (rotuladas):
  • Linfoma de Hodgkin
  • Cancro da cabeça e do pescoço
  • Cancro do testículo
  • Efusão pleural maligna (agente esclerosante)

Efeitos adversos

• Toxicidade pulmonar que se apresenta como pneumonite:
  • Toxicidade mais MAIS Androgen Insensitivity Syndrome grave
  • Pode levar a fibrose pulmonar
• Hepatotoxicidade
• Toxicidade renal
• Reação idiossincrática (↓ tensão arterial, pieira, febre, calafrios)
• Dermatológica:
  • Erupções cutâneas
  • Hiperpigmentação
  • Alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia

Contraindicações e interações medicamentosas

• Contraindicações:
  • Hipersensibilidade ao fármaco
  • Gravidez (1.º trimestre)
• Se houver alterações pulmonares, o tratamento deve ser retido e a relação com a bleomicina deve ser investigada.
• Ajuste da dose em função renal deficiente
• Interações medicamentosas (↑ toxicidade pulmonar da bleomicina):
  • Brentuximab
  • Gemcitabina
  • Fatores estimulantes de colónias de granulócitos
  • Oxigénio

Dactinomicina

Descrição

• Dactinomicina (actinomicina D)
• Cromopéptido de Streptomyces
• Mecanismo de ação:
  • Forma uma ligação com o DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure, intercalando-se entre pares de bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance (citosina e guanina)
  • Evita a atividade da RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure polimerase, bloqueando a transcrição de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
  • Também produz quebras no DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure de cadeia simples
• Farmacocinética:
  • IV
  • Não atravessa a barreira hematoencefálica
  • Metabolismo residual
  • Meia-vida: 36 horas
  • Excreção: urina e fezes, 30%
• Indicações (rotuladas):
  • Tumores sólidos
  • Tumor Tumor Inflammation de Wilms
  • Sarcoma de Ewing
  • Neoplasia trofoblástica gestacional
  • Rabdomiossarcoma

Efeitos adversos

• Mielossupressão
• Toxicidade mucocutânea (como a síndrome de Stevens-Johnson, necrólise epidérmica tóxica)
• Hepatotoxicidade ( tal TAL Renal Sodium and Water Regulation como ↑ bilirrubina, enzimas hepáticas)
• Nefrotoxicidade
• Toxicidade GI: náuseas, vómitos, diarreia
• Extravasamento (causa danos locais nos tecidos)
• Malignidade secundária (como a leucemia)

Contraindicações e interações medicamentosas

• Evitar vacinas vivas antes e durante o tratamento com dactinomicina.
• Dactinomicina:
  • ↑ Toxicidade quando combinada com radioterapia
  • ↓ Efeitos das vacinas inativadas e vivas
  • ↑ Efeitos tóxicos das vacinas vivas

Mitomicina

Descrição

• Mitomicina: isolada de Streptomyces caespitosus
• A mitomicina é ativada em mitoseno.
• Mecanismo de ação:
  • O mitoseno alquila o DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure → cria ligações cruzadas no DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
  • Previne a síntese de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure e de RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure
• Farmacocinética:
  • Metabolismo: fígado
  • Meia-vida: < 1 hora
  • Excreção: principalmente nas fezes (alguma parte através de excreção renal)
• Indicações:
  • Cancro do estômago
  • Cancro do pâncreas
  • “Off-label”: cancro anal, cancro da bexiga, cancro do esófago, cancro do colo do útero, cancro da vulva Vulva The vulva is the external genitalia of the female and includes the mons pubis, labia majora, labia minora, clitoris, vestibule, vestibular bulb, and greater vestibular glands. Vagina, Vulva, and Pelvic Floor: Anatomy

Efeitos adversos

• Mielossupressão
• Toxicidade miocárdica (insuficiência cardíaca)
• Síndrome hemolítica urémica e insuficiência renal
• Fibrose da bexiga (com administração intravesical)
• Toxicidade pulmonar
• Toxicidade GI: náuseas, vómitos, mucosite
• Extravasamento

Contraindicações e interações medicamentosas

• Contraindicações:
  • Hipersensibilidade
  • Tendência para hemorragia
  • Interromper a medicação com toxicidade significativa nos órgãos
• Interações medicamentosas:
  • O tratamento concomitante com alcaloides da vinca pode causar broncoespasmo.
  • ↓ Efeitos das vacinas inativadas e vivas
  • ↑ Efeitos tóxicos das vacinas vivas

Antraciclinas

Descrição

• As antraciclinas ou antibióticos de antraciclina são derivados de Streptomyces peucetius var. caesius.
• Agentes quimioterápicos frequentemente usados para diferentes tipos de cancros (cancros hematológicos e tumores sólidos)
• Mecanismos de ação:
  • Inibem a topoisomerase II Topoisomerase II DNA topoisomerases that catalyze ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands. These enzymes bring about relaxation of the supercoiled DNA and resolution of a knotted circular DNA duplex. Fluoroquinolones e impedem a reparação do DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
  • Formam radicais livres de oxigénio, que se ligam ao DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure de cadeia simples e dupla → causam danos
  • Intercalam com o DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure para bloquear a transcrição e a replicação
  • Ligam-se a membranas celulares e alteram o transporte de iões
• Farmacocinética:
  • IV
  • Metabolismo: fígado por hidrólise do anel de antraciclina
  • Eliminação: principalmente nas fezes através de excreção biliar
• Indicações:
  • Doxorrubicina:
    • Cancro da mama
    • Cancro do ovário
    • Leucemia linfoblástica aguda (LLA), leucemia mieloide aguda (LMA)
    • Linfoma de Hodgkin, linfoma não Hodgkin
    • Cancro da bexiga
    • Sarcoma ósseo, sarcoma dos tecidos moles Moles Primary Skin Lesions
    • Carcinoma broncogénico
    • Cancro do estômago
    • Neuroblastoma Neuroblastoma Neuroblastoma is a malignancy that arises from the neural crest cell derivatives along the sympathetic chain (neuroblasts) and is most commonly located in the adrenal medulla. The tumor often presents in childhood with a flank mass that crosses the midline. Neuroblastoma
    • Carcinoma da tiróide
    • Tumor Tumor Inflammation de Wilms
  • Daunorrubicina:
    • LLA
    • LMA
  • Idarrubicina: LMA
  • Epirrubicina: cancro da mama
  • Mitoxantrona:
    • Cancro da próstata avançado
    • LMA
    • Esclerose múltipla

Efeitos adversos

• Cardiotoxicidade:
  • Agudos: Distúrbios no ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG), pericardite, miocardite, níveis elevados de troponina
  • Crónicos:
    • Cardiomiopatia dilatada (dependente de fose) levando à insuficiência cardíaca
    • Resulta de radicais livres de oxigénio que danificam o miocárdio
    • Dexrazoxano: administrado para prevenir a cardiotoxicidade induzida por antraciclina (cancro da mama metastásico)
  • As formulações lipossomais de antraciclinas têm reduzido a incidência de cardiotoxicidade.
• Mielossupressão
• Malignidade secundária
• Deficiência hepática
• Extravasamento
• Dermatite pós-radiação: Pode desenvolver-se eritema e descamação da pele em áreas tratadas com radiação.
• Síndrome de lise tumoral
• Mucosite

Contraindicações e interações medicamentosas

• Contraindicações:
  • Hipersensibilidade ao fármaco
  • Função cardíaca deficiente ou doença cardíaca grave ou arritmia
  • Função hepática deficiente
  • Mielossupressão grave
  • Infeção ativa
• Interações medicamentosas (particularmente a doxorrubicina):
  • Os seguintes ↑ risco de cardiotoxicidade:
    • Trastuzumab Trastuzumab A humanized monoclonal antibody against the ErbB-2 receptor (HER2). As an antineoplastic agent, it is used to treat breast cancer where HER2 is overexpressed. Targeted and Other Nontraditional Antineoplastic Therapy
    • Taxanos
    • Ciclofosfamida
  • ↓ Efeitos das vacinas inativadas e vivas
  • ↑ Efeitos tóxicos das vacinas vivas

Comparação com outros agentes quimioterápicos