Dacarbazine Anticancer Drug

INTRODUCTION: Dacarbazine (brand names DTIC, DTIC-Dome; also known as DIC or imidazole carboxamide) is an antineoplastic chemotherapy drug used in the treatment of various cancers, among them malignant melanoma, Hodgkin's lymphoma, sarcoma, and islet cell carcinoma of the pancreas.

Dacarbazine is a member of the class of alkylating agents, which destroy cancer cells by adding an alkyl group (CnH2n+1) to its DNA.

Dacarbazine is normally administered by intravenous infusion (IV) under the immediate supervision of a doctor or nurse. Dacarbazine is bioactivated in liver by demethylation to "MTIC" and then to diazomethane, which is an alkylating agent.

THERAPEUTIC USES: As of mid-2006, dacarbazine is commonly used as a single agent in the treatment of metastatic melanoma, and as part of the ABVD chemotherapy regimen to treat Hodgkin's lymphoma, and in the MAID regimen for sarcoma. Dacarbazine was proven to be just as efficacious as procarbazine in the German trial for paediatric Hodgkin's lymphoma, without the teratogenic effect. Thus COPDAC has replaced the former COPP regime in children for TG2 & 3 following OEPA

 SIDE EFFECT: Like many chemotherapy drugs, dacarbazine may have numerous serious side effects, because it interferes with normal cell growth as well as cancer cell growth. Among the most serious possible side effects are birth defects to children conceived or carried during treatment; sterility, possibly permanent; or immune suppression (reduced ability to fight infection or disease). Dacarbazine is considered to be highly emetogenic, and most patients will be pre-medicated with dexamethasone and antiemetic drugs like 5-HT3 antagonist (e.g., ondansetron) and/or NK1 receptor antagonist (e.g., aprepitant). Other significant side effects include headache, fatigue and occasionally diarrhea.

• Most people do not experience all of the side effects listed.

• Side effects are often predictable in terms of their onset and duration.

• Side effects are almost always reversible and will go away after treatment is complete.

• There are many options to help minimize or prevent side effects.

• There is no relationship between the presence or severity of side effects and the effectiveness of the medication.

MECHANISM OF ACTION: Dacarbazine works by methylating guanine at the O-6 and N-7 positions. Guanine is one of the four nucleotides that makes up DNA. The alkylated DNA strands stick together such that cell division becomes impossible. This affects cancer cells more than healthy cells because cancer cells divide faster. Unfortunately however, some of the healthy cells will still be damaged.

Cancerous tumors are characterized by cell division, which is no longer controlled as it is in normal tissue. "Normal" cells stop dividing when they come into contact with like cells, a mechanism known as contact inhibition.  Cancerous cells lose this ability. Cancer cells no longer have the normal checks and balances in place that control and limit cell division.  The process of cell division, whether normal or cancerous cells, is through the cell cycle.  The cell cycle goes from the resting phase, through active growing phases, and then to mitosis (division).

The ability of chemotherapy to kill cancer cells depends on its ability to halt cell division.  Usually, the drugs work by damaging the RNA or DNA that tells the cell how to copy itself in division.  If the cells are unable to divide, they die.  The faster the cells are dividing, the more likely it is that chemotherapy will kill the cells, causing the tumor to shrink.  They also induce cell suicide (self-death or apoptosis).

Chemotherapy drugs that affect cells only when they are dividing are called cell-cycle specific.  Chemotherapy drugs that affect cells when they are at rest are called cell-cycle non-specific.  The scheduling of chemotherapy is set based on the type of cells, rate at which they divide, and the time at which a given drug is likely to be effective.  This is why chemotherapy is typically given in cycles.

PHARMACOKINETICS:

• Local pain, burning sensation and irritation at the needle site during the infusion.

• Low blood counts.  Your white and red blood cells and platelets may temporarily decrease.  This can put you at increased risk for infection, anemia and/or bleeding.

• Onset:  5 - 7 days

• Nadir: 7 - 10 days

• Recovery:  21 - 28 days

• Nausea and vomiting.

• Poor appetite.

  Elevation of blood liver enzymes.

PRECAUTIONS:

Before starting dacarbazine treatment, make sure you tell your doctor about any other medications you are taking (including prescription, over-the-counter, vitamins, herbal remedies, etc.). Do not take aspirin, products containing aspirin unless your doctor specifically permits this.

• Do not receive any kind of immunization or vaccination without your doctor's approval while taking dacarbazine.

• Inform your health care professional if you are pregnant or may be pregnant prior to starting this treatment. Pregnancy category C (use in pregnancy only when benefit to mother outweighs risk to fetus).

• For both men and women: Do not conceive a child (get pregnant) while taking dacarbazine. Barrier methods of contraception, such as condoms, are recommended. Discuss with your doctor when you may safely become pregnant or conceive a child after therapy.

• Do not breast feed while taking this medication.

DRUG-DRUG INTERACTIONS:

1. Sometimes interacts with normal cells

2. Metal salts:  Carboplatin, Cisplatin, and Oxaliplatin +  dacarbazine gives synergistic effect

3. Busulfan + drug give synergistic effect

4. Dacarbazine +  DOXOrubicin may increase the side effects of these medications

REFERENCE:  Tripathi K.D; "Essentials of medical pharmacology"; page no-858,861