1 PRINCIPLES OF ONCOLOGIC PRINCIPLES OF ONCOLOGIC PHARMACOTHERAPY PHARMACOTHERAPY Elshami M. Elamin, MD Elshami M. Elamin, MD Medical Oncologist Medical Oncologist Central Care Cancer Center Central Care Cancer Center www.cccancer.com Wichita, KS - USA Wichita, KS - USA
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1 PRINCIPLES OF ONCOLOGIC PHARMACOTHERAPY Elshami M. Elamin, MD Medical Oncologist Central Care Cancer Center Wichita, KS - USA.
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PRINCIPLES OF ONCOLOGIC PRINCIPLES OF ONCOLOGIC PHARMACOTHERAPYPHARMACOTHERAPY
Elshami M. Elamin, MDElshami M. Elamin, MDMedical OncologistMedical Oncologist
Central Care Cancer CenterCentral Care Cancer Center
www.cccancer.com
Wichita, KS - USAWichita, KS - USA
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Neoplastic Cell kinetics
Tumor cells can be subdivided into three general populations: 1- cells: not dividing and terminally differentiated 2- cells: continue to proliferate 3- cells: nondividing, currently quiescent but may be
recruited into the cell cycle.
The kinetic behavior of dividing cells is best described by the concept of the cell cycle.
Cell Cycle G1, or gap, phase,
in which the cell grows and prepares to synthesize DNA
S, or synthesis, phase, in which the cell synthesizes DNA
G2, or second gap, phase, in which the cell prepares to divide
M, or mitosis, phase, in which cell division occurs.
Check points1- As a cell approaches
the end of the G1 phase it is controlled at a vital checkpoint, called G1/S, where the cell determines whether or not to replicate its DNA
Cells with intact DNA continue to S phase; cells with damaged DNA that cannot be repaired are arrested and ‘‘commit suicide’’ through apoptosis
2- A second such checkpoint occurs at the G2 phase following the synthesis of DNA in S phase but before cell division in M phase
Cell cycle regulatory proteins
Cyclin Dependent Kinases, or CDKs, are specific enzymes that use signals to switch on cell cycle mechanisms.
CDKs are activated by forming complexes with cyclins (another group of regulatory proteins only present for short periods in the cell cycle)
Genetic mutations causing the malfunction or absence of one or more of the regulatory proteins at cell cycle checkpoints can result in the ‘‘molecular switch’’ being turned permanently on, permitting uncontrolled multiplication of the cell, leading to carcinogenesis, or tumor development.
Cell Cycle in Cancer
In normal cells, the cell cycle is controlled by a complex series of signaling pathways by which a cell grows, replicates its DNA and divides.
This process also includes mechanisms to ensure errors are corrected, and if not, the cells commit suicide (apoptosis).
In cancer, as a result of genetic mutations, this regulatory process malfunctions, resulting in uncontrolled cell proliferation.
The lipophilic nature of the nitrosoureas enables free passage across membranes; therefore, they rapidly penetrate the blood-brain barrier. used for a variety of brain tumors.
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Alkylating agents Toxicities
Nausea/Vomiting local vesicants skin rashes Bone marrow depression gonadal dysfunction leukemia hyperuricemia pulmonary fibrosis hemorrhagic cystitis (ifex, cytoxan) alopecia
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Alkylating agentsUses
CLL, HD, NHL, AML, ALL M. myeloma ovarian cancer Prostate ca Breast ca Germ-cell testicular lung cancer mycosis fungoides sarcoma Brain tumor: GlioBlastoma Multiforme Pancreatic islet-cell, carcinoid
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Nonclassic alkylators
Altretamine (Hexalen)
Dacarbazine (DTIC)
Procarbazine (Matulane)
Temozolomide (Temodar)
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Nonclassic alkylatorsToxicities
Nausea and vomiting CNS toxicity, Paresthesias Bone marrow depression alopecia
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Nonclassic alkylatorsUses
HD (dacarbazine) Brain (Procarbazine, Temozolomide) cervical cancers Malignant melanoma (DTIC,
Inorganic heavy metal complex cell-cycle phase nonspecific inhibits the synthesis of DNA,
RNA, and proteins have linear dose-response curves
(ie, increasing the dose increases cytotoxicity)
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Platinum complexesToxicities
nausea and vomiting Bone marrow depression Renal toxicity peripheral neuropathy ototoxicity
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PlatinumUses
Ovarian cancer (Cis, carbo) Lung ca (Cis and carbo) Head/Neck acute leukemia NHL Breast bladder uterine cervical Colorectal (oxaliplatin) Gastric and Esophageal ca
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Antimetabolites Antimetabolites are structural analogs
of the naturally occurring metabolites involved in DNA and RNA synthesis.
Exert their cytotoxic activity either by: competing with normal metabolites for the
catalytic or regulatory site of a key enzyme or
substituting for a metabolite that is normally incorporated into DNA and RNA.
Most active when cells are in the S phase and have little effect on cells in the G0 phase.
Most effective against tumors that have a high growth fraction.
Semisynthetic derivatives of extracted precursors from the needles of yew tree. Unlike the vinca alkaloids, which cause
microtubular disassembly, the taxanes promote microtubular assembly and stability
M-phase specific: therefore blocking the cell cycle in mitosis.
Docetaxel is more potent than paclitaxel in enhancing microtubular assembly and also induces apoptosis
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Microtubule agentsToxicities
Bone marrow depression Fluid retention Hypersensitivity Peripheral neuropathy,
Paresthesias Skin changes Nails changes Alopecia Myalgias
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Microtubule agentsUses
Breast (ixempra, Halaven) NSCL Prostate Ovarian head and neck Esophagus Stomach Cervical Kaposi’s sarcoma Uterine bladder
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Vinca alkaloids
Vinblastine Vincristine Vinorelbine
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Vinca alkaloids
Derived from the periwinkle plant Vinca rosea. bind rapidly to the tubulin. M-phase specific The binding occurs in the S phase
polymerization of microtubules is blocked, resulting in impaired mitotic spindle formation in the M phase.
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Vinca alkaloidsToxicities
Bone marrow depression nausea and vomiting ileus Peripheral neuropathy Alopecia Stomatitis myalgias hepatic insufficiency
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Vinca alkaloidsUses
ALL, NHL (Vincristine) HD (Vinblastine) NSCLC (Vinorebine) Gestational trophoblastic tumors Testicular Breast mycosis fungoides Kaposi’s sarcoma bladder and renal cancers
(300-1000 potent than imatinib)(300-1000 potent than imatinib)
Nilotinib, Tasigna, TK inhibitor Nilotinib, Tasigna, TK inhibitor 20-50 potent than imatinib20-50 potent than imatinib not effective in T3151 mutantnot effective in T3151 mutant
PROVENGEPROVENGE Sipuleucel-T (Provenge) is the first Sipuleucel-T (Provenge) is the first
FDA-approved autologous cellular FDA-approved autologous cellular immunotherapy for the treatment of immunotherapy for the treatment of asymptomatic or minimally asymptomatic or minimally symptomatic met HRPCsymptomatic met HRPC
Provenge induces immune response against Provenge induces immune response against PAPPAP
Provenge is produced by taking cells from a Provenge is produced by taking cells from a patient's tumor, and incorporating them into a patient's tumor, and incorporating them into a vaccine consisting of the patient's own blood vaccine consisting of the patient's own blood cells (cells (autologous, with , with dendritic cells thought thought to be the most important) and the Dendreon to be the most important) and the Dendreon PAP--GM-CSF fusion protein