Chemotherapy Drugs

Hycamtin ®

Generic Name: Topotecan

Drug type: Hycamtin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug.

Hycamtin is classified as an "topoisomerase 1 inhibitor." (For more detail, see "How this drug
works" section below).

What this drug is used for:

 This medicine is used to treat cancer of the ovaries when other treatments have failed.
 Hycamtinmay also used in certain types of lung cancer (small cell lung cancer).

Note: If a drug has been approved for one use, physicians may elect to use this same drug for
other problems if they believe it may be helpful.

How this drug is given:

 Hycamtin is given through an infusion into a vein (intravenous, IV).

 The amount of Hycamtin that you will receive depends on many factors, including your
height and weight, your general health or other health problems, and the type of cancer or
condition being treated. Your doctor will determine your dose and schedule.

Side effects:
Important things to remember about the side effects of Hycamtin:

 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.

The following side effects are common (occurring in greater than 30%) for patients taking
Hycamtin:

 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.
Nadir: 8 -11 days

Recovery: 14-21 days

 Nausea and vomiting

 Hair loss
 Diarrhea

These side effects are less common side effects (occurring in about 10-29%) of patients
receiving Hycamtin:

 Constipation
 Fatigue
 Fever
 Abdominal pain
 Bone pain
 Weakness
 Mouth sores
 Poor appetite
 Rash (see skin reactions)
 Shortness of breath
 Cough
 Headache

Not all side effects are listed above. Some that are rare (occurring in less than 10% of patients)
are not listed here. However, you should always inform your health care provider if you
experience any unusual symptoms.

When to contact your doctor or health care provider:

Contact your health care provider immediately, day or night, if you should experience any of
the following symptoms:

 Fever of 100.5º F (38º C) or higher, chills (possible signs of infection)

 Shortness of breath, difficulty breathing
 Bleeding that does not stop after a few minutes
The following symptoms require medical attention, but are not an emergency. Contact
your health care provider within 24 hours of noticing any of the following:

 Nausea (interferes with ability to eat and unrelieved with prescribed medication)
 Vomiting (vomiting more than 4-5 times in a 24 hour period)
 Diarrhea (4-6 episodes in a 24-hour period)
 Unusual bleeding or bruising
 Black or tarry stools, or blood in your stools
 Blood in the urine
 Extreme fatigue (unable to carry on self-care activities)
 Mouth sores (painful redness, swelling or ulcers)
 Unable to eat or drink for 24 hours or have signs of dehydration: tiredness, thirst, dry
mouth, dark and decrease amount of urine, or dizziness.

Always inform your health care provider if you experience any unusual symptoms.

Precautions:

 Before starting Hycamtin 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, or 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 Hycamtin.
 Inform your health care professional if you are pregnant or may be pregnant prior to
starting this treatment. Pregnancy category D (Hycamtin may be hazardous to the fetus.
Women who are pregnant or become pregnant must be advised of the potential hazard to
the fetus).
 For both men and women: Do not conceive a child (get pregnant) while taking Hycamtin.
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.

Self-care tips:

 Drink at least two to three quarts of fluid every 24 hours, unless you are instructed
otherwise.
  You may be at risk of infection so try to avoid crowds or people with colds and those not
feeling well, and report fever or any other signs of infection immediately to your health
care provider.
 Wash your hands often.
 To help treat/prevent mouth sores, use a soft toothbrush, and rinse three times a day with
1/2 to 1 teaspoon of baking soda and/or 1/2 to 1 teaspoon of salt mixed with 8 ounces of
water.
 Use an electric razor and a soft toothbrush to minimize bleeding.
 Avoid contact sports or activities that could cause injury.
 To reduce nausea, take anti-nausea medications as prescribed by your doctor, and eat
small, frequent meals.
 Keep your bowels moving. Your health care provider may prescribe a stool softener to
help prevent constipation that may be caused by this medicine.
 You may experience drowsiness or dizziness; avoid driving or engaging in tasks that
require alertness until your response to the drug is known.
 Acetaminophen or ibuprophen may help relieve discomfort from fever, headache and/or
generalized aches and pains. However, be sure to talk with your doctor before taking it.
 In general, drinking alcoholic beverages should be kept to a minimum or avoided
completely. You should discuss this with your doctor.
 Get plenty of rest.
 Maintain good nutrition.
 If you experience symptoms or side effects, be sure to discuss them with your health care
team. They can prescribe medications and/or offer other suggestions that are effective in
managing such problems.

Monitoring and testing:

You will be checked regularly by your health care professional while you are taking Hycamtin, to
monitor side effects and check your response to therapy. Periodic blood work to monitor your
complete blood count (CBC) as well as the function of other organs (such as your kidneys and
liver) will also be ordered by your doctor.

How this drug works:

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.

Chemotherapy is most effective at killing cells that are rapidly dividing. Unfortunately,
chemotherapy does not know the difference between the cancerous cells and the normal cells.
The "normal" cells will grow back and be healthy but in the meantime, side effects occur. The
"normal" cells most commonly affected by chemotherapy are the blood cells, the cells in the
mouth, stomach and bowel, and the hair follicles; resulting in low blood counts, mouth sores,
nausea, diarrhea, and/or hair loss. Different drugs may affect different parts of the body.

Hycamtin is derived from a plant. It is classified as a topoisomerase 1 inhibitor. Camptothecan

analogs are derived from the Asian "Happy Tree" (Camptotheca acuminata). Podophyllotoxins
and camptothecan analogs are also known as topoisomerase inhibitors.

Toposiomerase inhibitors are drugs that interfere with the action of topoisomerase enzymes
(topoisomerase I and II). Topoisomerase enzymes control the manipulation of the structure of
DNA necessary for cell division and replication.

 Topoisomerase I inhibitors: Ironotecan, Hycamtin

 Topoisomerase II inhibitors: Amsacrine, etoposide, etoposide phosphate, teniposide

Note: We strongly encourage you to talk with your health care professional about your specific
medical condition and treatments. The information contained in this website is meant to be
helpful and educational, but is not a substitute for medical advice.

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II) (CDDP) (trade names Platinol

and Platinol-AQ) is a chemotherapy drug. It is used to treat various types of cancers, including
sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas, and
germ cell tumors. It was the first member of a class of platinum-containing anti-cancer drugs,
which now also includes carboplatin and oxaliplatin. These platinum complexes react in vivo,
binding to and causing crosslinking of DNA, which ultimately triggers apoptosis (programmed
cell death).
Contents
[hide]
 1 History
 2 Pharmacology
o 2.1 Usage

o 2.2 Cisplatin resistance

o 2.3 Transplatin

 3 Side effects
 4 Synthesis
 5 References

 6 External links

[edit] History
The compound cis-PtCl2(NH3)2 was first described by M. Peyrone in 1845, and known for a long
time as Peyrone's salt.[1] The structure was deduced by Alfred Werner in 1893.[2] In 1965, Barnett
Rosenberg, van Camp et al. of Michigan State University discovered that electrolysis of
platinum electrodes generated a soluble platinum complex which inhibited binary fission in
Escherichia coli (E. coli) bacteria. Although bacterial cell growth continued, cell division was
arrested, the bacteria growing as filaments up to 300 times their normal length.[3] The octahedral
Pt(IV) complex cis PtCl4(NH3)2, but not the trans isomer, was found to effective at forcing
filamentous growth of E. coli cells. The square planar Pt(II) complex, cis PtCl2(NH3)2 turned out
to be even more effective at forcing filamentous growth.[4][5] This finding led to the finding that
cis PtCl2(NH3)2 was indeed highly effective at regressing the mass of sarcomas in rats.[6]
Confirmation of this finding, and extension of testing to other tumour cell lines launched the
medicinal applications of cisplatin. Cisplatin was approved for use in testicular and ovarian
cancers by the U.S. Food and Drug Administration on December 19, 1978.[7]

[edit] Pharmacology
Following administration, one of the chloride ligands is slowly displaced by water (an aqua
ligand), in a process termed aquation. The aqua ligand in the resulting [PtCl(H2O)(NH3)2]+ is
itself easily displaced, allowing the platinum atom to bind to bases. Of the bases on DNA,
guanine is preferred. Subsequent to formation of [PtCl(guanine-DNA)(NH3)2]+, crosslinking can
occur via displacement of the other chloride ligand, typically by another guanine.[2] Cisplatin
crosslinks DNA in several different ways, interfering with cell division by mitosis. The damaged
DNA elicits DNA repair mechanisms, which in turn activate apoptosis when repair proves
impossible. Recently it was shown that the apoptosis induced by cisplatin on human colon cancer
cells depends on the mitochondrial serine-protease Omi/Htra2.[8] Since this was only
demonstrated for colon carcinoma cells, it remains an open question if the Omi/Htra2 protein
participates in the cisplatin-induced apoptosis in carcinomas from other tissues.

Most notable among the changes in DNA are the 1,2-intrastrand cross-links with purine bases.
These include 1,2-intrastrand d(GpG) adducts which form nearly 90% of the adducts and the less
common 1,2-intrastrand d(ApG) adducts. 1,3-intrastrand d(GpXpG) adducts occur but are
readily excised by the nucleotide excision repair (NER). Other adducts include inter-strand
crosslinks and nonfunctional adducts that have been postulated to contribute to cisplatin's
activity. Interaction with cellular proteins, particularly HMG domain proteins, has also been
advanced as a mechanism of interfering with mitosis, although this is probably not its primary
method of action.

Note that although cisplatin is frequently designated as an alkylating agent, it has no alkyl group
and so cannot carry out alkylating reactions. It is correctly classified as alkylating-like.

[edit] Usage

Cisplatin is administered intravenously as short-term infusion in physiological saline for

treatment of solid malignacies.

[edit] Cisplatin resistance

Cisplatin combination chemotherapy is the cornerstone of treatment of many cancers. Initial

platinum responsiveness is high but the majority of cancer patients will eventually relapse with
cisplatin-resistant disease. Many mechanisms of cisplatin resistance have been proposed
including changes in cellular uptake and efflux of the drug, increased detoxification of the drug,
inhibition of apoptosis and increased DNA repair.[9] Oxaliplatin is active in highly cisplatin-
resistant cancer cells in the laboratory; however, there is little evidence for its activity in the
clinical treatment of patients with cisplatin-resistant cancer.[9] The drug Paclitaxel may be useful
in the treatment of cisplatin-resistant cancer; the mechanism for this activity is unknown.[10]

[edit] Transplatin

Transplatin, the trans stereoisomer of cisplatin, has formula trans-[PtCl2(NH3)2] and does not
exhibit a comparably useful pharmacological effect. Its low activity is generally thought to be
due to rapid deactivation of the drug before it can arrive at the DNA.[citation needed] It is toxic, and it
is desirable to test batches of cis-platin for the absence of the trans isomer. In a procedure by
Woollins et al., which is based on the classic 'Kurnakov test', thiourea reacts with the sample to
give derivatives which can easily be separated and detected by HPLC.[11]

[edit] Side effects

This date March 2010 needs additional citations for verification. Please help improve
this article by adding reliable references. Unsourced material may be challenged and
removed. (April 2010)
Cisplatin has a number of side-effects that can limit its use:

 Nephrotoxicity (kidney damage) is a major concern. The dose is reduced when the
patient's creatinine clearance (a measure of renal function) is reduced. Adequate
hydration and diuresis is used to prevent renal damage. The nephrotoxicity of platinum-
class drugs seems to be related to reactive oxygen species and in animal models can be
ameliorated by free radical scavenging agents (e.g., amifostine). Nephrotoxicity is a dose-
limiting.
 Neurotoxicity (nerve damage) can be anticipated by performing nerve conduction studies
before and after treatment.
 Nausea and vomiting: cisplatin is one of the most emetogenic chemotherapy agents, but
this symptom is managed with prophylactic antiemetics (ondansetron, granisetron, etc.)
in combination with corticosteroids. Aprepitant combined with ondansetron and
dexamethasone has been shown to be better for highly emetogenic chemotherapy than
just ondansetron and dexamethasone.
 Ototoxicity (hearing loss): unfortunately there is at present no effective treatment to
prevent this side effect, which may be severe. Audiometric analysis may be necessary to
assess the severity of ototoxicity. Other drugs (such as the aminoglycoside antibiotic
class) may also cause ototoxicity, and the administration of this class of antibiotics in
patients receiving cisplatin is generally avoided. The ototoxicity of both the
aminoglycosides and cisplatin may be related to their ability to bind to melanin in the
stria vascularis of the inner ear or the generation of reactive oxygen species.
 Electrolyte disturbance: Cisplatin can cause hypomagnesaemia, hypokalaemia and
hypocalcaemia. The hypocalcaemia seems to occur in those with low serum magnesium
secondary to cisplatin, so it is not primarily due to the Cisplatin.

Approved for clinical use by the United States Food and Drug Administration (FDA) in 1978,[2]
[12]
it revolutionized the treatment of certain cancers. Detailed studies on its molecular
mechanism of action, using a variety of spectroscopic methods including X-ray, NMR
spectroscopy, and other physico-chemical methods, revealed its ability to form irreversible
crosslinks with bases in DNA.

[edit] Synthesis
The synthesis of cisplatin is a classic in inorganic chemistry. Starting from potassium
tetrachloroplatinate(II), K2[PtCl4], the first NH3 ligand is added to any of the four equivalent
positions, but the second NH3 could be added cis or trans to the bound amine ligand. Because Cl−
has a larger trans effect than NH3, the second amine preferentially substitutes trans to a chloride
ligand, and therefore cis to the original amine. The trans effect of the halides follows the order I-
>Br->Cl-, therefore the synthesis is conducted using [PtI4]2− to ensure high yield and purity of the
cis isomer, followed by conversion of the PtI2(NH3)2 into PtCl2(NH3)2, as first described by
Dhara.[13][14]