Molecular BIology of Cancer Topics             

Cancer Therapy Principles

Cancer prevention includes lifetyle choices and chemoprevention. Lifestyle choices that prevent cancer include not smoking, a diet rich in fruits and vegetables and low in fat, and reduced exposure to physical carcinoges like sunlight or asbestos. Chemoprevention involves the use of drugs to precvvent cancer, for example sunblock.

Treatment of small primary tumors is much more successful than treatment of advance, metastatic cancer. A tumor mass can be detected by palpation, imaging techniques, or detection of tumor antigens (blood test). Computerized tomography (CT) scan and X-ray are common tools used to detect cancer tumors. The use of oncogene or tumor supressor gene mutations as cancer diagnostic markers is under investigation.

The type of tumor is diagnosed by histopathology a a tumor specimen. High mitotic index, invasaion of surrounding tissue, dedifferentiation, and other markers observed during a biopsy are indicative of malignancy.The stage of cancer must be known in order to determine therapy and to follow disease regression or progression. Biopsy markers used to determine staging are the degree of differentiation in the primary tumor, number of lymph node metastases, and the number of metastases to other organs.

Staging and grading schema have been devised for malignant neoplasms, because the stage and/or grade may determine the treatment and the prognosis. In general, the higher the stage, the larger a neoplasm is and the farther it has likely spread. The most common systems for staging employs the TNM classification:

Staging forms have been devised for each organ or site that a malignant neoplasm can occur, although a general scheme is as follows:

Stage Definition
Tis In situ, non-invasive (confined to epithelium)
T1 Small, minimally invasive within primary organ site
T2 Larger, more invasive within the primary organ site
T3 Larger and/or invasive beyond margins of primary organ site
T4 Very large and/or very invasive, spread to adjacent organs
N0 No lymph node involvement
N1 Regional lymph node involvement
N2
Extensive regional lymph node involvement
N3 More distant lymph node involvement
M0 No distant metastases
M1 Distant metastases present

Grading schema are based upon the microscopic appearance of a neoplasm with hematoxylin and eosin (H&E) staining. In general, a higher grade means that there is a lesser degree of differentiation and the worse the biologic behavior of a malignant neoplasm will be. A well-differentiated neoplasm is composed of cells that closely resemble the cell of origin, while poorly differentiated neoplasms have cells that are difficult to recognize as to their cell of origin.

The goals of cancer therapy are to kill stem cells and tumor cells until the tumor mass is no longer detectable (current clinical detection limit is ~ 10,000,000 cells). Until stem cells are eliminated (?) only temporary remission will be attained. The killing of tumor cells must be acomplished with the highest therapeutic ratio possible, i.e. with minimal damage to normal cells.

Cancer therapy includes surgery, radiation and chemotherapy. Surgery is used to remove primary tumors and regional lymph nodes. Radiation treatment kills tumor cells by lethal DNA damage from ionizing radiation. Chemotherapy, i.e. drug treatment, is used primarily against leukemias, lymphomas and metastatic solid tumors.

Chemotherapy

Drugs that induce DNA damage include the alkylating agents, crosslinking agents, antimetabolites

Alkylating agents like the nitrogen mustards melphalan and cyclophosphamide, form covalent bonds with DNA, including crosslinks. Crosslinking agents like cisplatin becomes reactive in the aquous environment of the cell and forms intra- and interstrand crosslinks in DNA.

Cisplatin has been very succesful in treating testicular tumors as part of the BEP (bleomycin/etoposide/cisplatin) or VIP (vinblastine/ifosfamide/cisplatin) combination therapies. After surgery, depending on the response patients may get additional surgery to remove lymph nodes, radiation therapy, and/or BEP or VIP chemotherapy. Before cisp[latin, less than 10% of patients survived metastatic testicular cancer after 5 years. Phase I and Phase II clinical trials demonstrated good activity in refractory advance testicular cancer, with complete and partial remissions. With cisplatin combination therapy, 80% of testicular cancer patients with metastatic disease survive > 5 years.

The antimetabolite 5-fluorouracil is metabolized to 5-fluorodeoxyuridine (5-FdUMP), which inhibits thymidylate synthase, and 5-fluorouridine triphosphate (5-FUTP) which may be incorporated into RNA in place of uridylate (UMP). Cytosine arabinoside is an antimetbolite that differs from cytidine only in the position of an OH. It is a competitive inhibitor of DNA polymerase that may be incorporated into DNA and alters DNA ligation, and is used to treat acute leukemia. Gentamicine is similar to cytosine arabinoside but more potent and active in tumors refractory to standard chemotherapeutic agents. Other antimetabolite chemotherapeutic agents include the purine mimics 6-thioguanine and 6-mercaptopurine.

The antimetabolite methotrexate inhibits dihydrofolate reductase, the enzyme which converts dihydrofolate to tetrahydrofolate. This results in decreased thymidine biosynthesis because thymidylate synthase requires 5,10-CH2-FH4 (5,10-methylenetetrahydrofolate as a cofactor) and reduced purine biosynthesis because 5,10-methenyl-FH4 is required for purine sysnthesis. The net result is decreased DNA replication.

Topoisomerase I is active during S phase, forms and rejoins single strand breaks in DNA which reduce torsion strain ahead of the DNA replication fork. Camptothecin and topotecan inhibit Topoisomerase I and induces DNA strand breaks localized near replication forks.

Topoisomerase II is responsible for cleavage, unwinding and rejoining double stranded DNA during DNA and RNA synthesis. Topoisomerase II inhibitors like doxorubicin and etoposide can intercalate in DNA and form covalent bonds with both DNA and Topoisomerase II leading to double strand breaks in DNA.

Microtubules are partly resposible for the infrastructure of the cell and are particularly important in mitosis, as they form the mitotic spindle. They also play an important role in cell motility. Microtubule formation is reversible, and they are constantly undergoing assembly and dissassembly. Tubulin a and b dimers constiturte the building blocks of microtubules. The vinca alkaloids, vinblastine and vincristine, bind tubulin and inhibit its polymerization to form microtubules. These alkaloids come from the periwinle plant Vinca minor.

Taxol accelerates microtubule formation and stabilizes established microtubules. It comes from the bark of the Pacific yew tree Taxus brevifolia, and is almost imposible to synthesize due to its many stereocenters. There was a low supply for clinical use until a precursor was isolated from the needles of the tree, which are renewable as opposed to the bark (removing it will kill the tree). There is a good response to taxol in patients with melanoma, breast or refractory ovarian cancers. Taxoterene, a more potent anal;og of taxol currently in clinical trials, can also be synthesizzed from the precursor found in needles.

The toxicity of chemotherapeutic agents is important. These agents are toxic to rapidly dividing cells like tumor cells, but also normal tissues like bonemarrow stem cells, intestinal crypt cells, hair follicles. Thus toxic side effects of chemotherapy include decreased white blood cells and platelets, diahrrea, and hair loss.

Drug toxicity is usually dose-limiting for cancer chemotherapeutic agents. It can be serious, even life-threatening, leading to infections, diarrhea and organ failure. The therapeutic index (or therapeutic ratio) is the ratio of the therapeutic effect of a drug to its toxicity to normal cells.

Continue to "Drug Resistance" or take a quiz: [Q1].

Need more practice? Answer the review questions below.

1- List two ways of preventing cancer.
lifestyle choices
preventive chemotherapy

2- List 4 lifechoices that prevent cancer.
not smoking
diet rich in fruits and vegetables, low in fat
reduced exposure to physical carcinogens like sunlight or asbestos

3- What is cancer chemoprevention?
Involves the use of drugs to prevent cancer, for example sunblock.

4- List 5 ways of detecting a tumor.
palpation
computer tomography (CT) imaging
X-ray imaging
detection of tumor antigens in blood
detection of tumor suppressor genes or oncogenes (still under investigation).

5- How is the type of tumor determined?
By histopathology of a tumor specimen.

6- List 3 biopsy markers indicative of malignancy.
high mititic index
invasion of surrounding tissue
dedifferentiation

7- List biopsy markers that define tumor stage.
degree of differentiation of the primary tumor
nukber of lymph node metastases
number of metastases to other organs

8- Why is it important to determine the atage and grade of a tumor?
The stage and grade of the tumor may determine the treatment and prognosis.

9- Describe the TNM cancer clasiffication.
A "T" score is based upon the size and/or extent of invasion
An "N" score indicates extent of lymph node involvement
An "M" score indicates wheather distant metastases asre present.

10- List 5 T scores in a general cancer staging scheme.
Tis: In situ, non-invasive
T1: Small, minimal invasive within primary organ site
T2 Larger, more invasive within original organ site
T3 Larger and/or invasive beyond margins of the original organ
T4: very large and invasive spread to adjacent organs

11- List 4 N scores in a general cancer staging scheme.
N0: no lymph node involvement
N1: regional lymph node involvement
N2: extensive regional lymph node involvement
N3: more distant lymph node involvement

12- List 2 M scores in a general cancer staging scheme.
M0: no distant metastases
M1: distant metastases present.

13- What determines the grading schema of a tumor?
Grading is based upon microscopic apperarance of the neoplasm with H&E staining. A higher grade means there is a lesser degree of differentiation, and the worse biologic behaviour of the malignant neoplasm. A well differentiated neoplsm is composed of cells that closely reseamble the cell of origin, while poorly differentiated neoplasms have cells that are difficult to recognize as to their cell of origin.

14- What is the main goal of chemotherapy? Why?
To kill stem cells and tumor cells until the tumor mass is no longer detectable, whith the highest therapeutic ratio possible. Until stem cells are eliminated, only temporary remission is accomplished.

15- List 3 forms of cancer therapy.
surgery
radiation
chemotherapy

16- How is surgery used in cancer therapy?
To remove primary tumors and regional lymph nodes.

17- How is radiation used in cancer therapy?
To kill tumor cells by lethal DNA damage from ionizing radiation.

18- Which are the applications of chemotherapy in cancer therapy?
Used primarily against leukemias, lymphomas and metastatic solid tumors.

19- List 3 types of drugs that induce DNA damage.
alkylating agents
crosslinking agents
antimetabolites

20- List 2 alkylating agents.
melphalan (a nitrogen mustard)
cyclophosphamide

21- What is the mechanism of action of alkylating agents?
Form covalent bonds with DNA, including cresslinks, thus inducing strand breaks.

22- What is the mechanism of action of cisplatin?
Crosslinking agent, becomes reactive in the aqueous environment of the cell and forms intra and interstrand crosslinks with DNA, leading to single and double strand breaks.

23- List two combiation chemotherapies that use cisplatin.
BEP, blomycin/etoposide/cisplatin
VIP, vinblastine/ifosfamide/cisplatin

24- What is the usuall therapy for testicular cancer?
Depending on the cancer stage and response after surgery, patients may get additional surgery to remove lymph nodes, radiation therapy, and/or eiither BEP or VIP chemotherapy.

25- What is the effectiveness of cisplating to treat testicular cancer?
Before cisplatin was available, less than 10% of patients survived metastatic testicular cancer after 5 years. With cisplatin combination therapy, 80% of testicular cancer patients with metastatic disease survive > 5 years.

26- List 5 antimetabolite chemotherapy drugs.
5-fluorouracil
cytosine arabinoside
gentamicide
6-thiguanine
6-mercaptopurine

27- What is the mechanism of action of 5-fluorouracil?
It is metabolized to 5-FdUMP, which inhibits thymidilate synthase, and to 5-FUTP which may be incorporated into RNA in place of UMP.

28- What is the mechanism of action of cytosine arabinoside?
Antimetabolite that differs from cytidine only by an OH at the ligation position. Acts as a competitive inhibitor of DNA polymerase and inhibits DNA ligation when incorporated into the DNA strand.

29- What is the main use of cytosine arabinoside?
Used to treat acute leukemia.

30- What is the mechanism of action of gentamicine?
Similar to cytosine arabinoside but more potent and active in tumors refractory to standard chemotherapy.

31- What is the mechanism of action of 6-thioguanine and 6-mercaptoguanine?
They are purine mimics.

32- What is the mechanism of action of methotrexate?
Inhibits dihydrofolate reductase, the enzyme that converts dihydrofolate to tetrahydrofolate. Results in decreased thymidine and purine biosynthesis and a net decrease in DNA replication.

33- What is the function of tetrahydrofolate in nucleotide synthesis?
Is a cofactors in the reaction catalyzed by thymidilate synthase and in purine biosynthesis.

34- What is the function of topoisomerase I?
Active during S phase, unwinds DNA by making single strand breaks and rejoining the strands in a way that reduces torsion strain, ahead of the replication fork.

35- List 2 toisomerase I inhibitors.
camptothecin and
topotecan

36- What is the mechanism of action of topoisomerase I inhibitors?
Induce DNA strand breaks localized near replication forks by inhibiting religation of the broken DNA strand.

37- What is the function of topoisomerase II?
Cleavage, unwinding and rejoining double stranded DNA during DNA and RNA synthesis.

38- List 2 topoisomerase II inhibitors?
doxorubicin
etoposide

39- What is the mechanism of action of topoisomerase II inhibitors?
Intercalate in DNA and form covalent bonds with both DNA and topoisomerase II leading to double strand breaks.

40- What is the importance of microtubules in cell proliferation?
Microtubules form the mitotic spindle and play an important role in cell motility.

41- How are microtubules formed?
Microtubules are made of tubulin a and b dimers. Their formation is reversible, and they are constantly undergoing assembly and dissassembly.

42- List 2 vinca alkaloids.
vinblastine
vincristine.

43- What is the source of vinca alkaloids?
the periwinkle plant, Vinca minor.

44- What is the mechanism of action of vinca alkaloids?
Bind tubulin and inhibit polymerization of microtubules.

45- What is the mechanism of action of taxol?
Accelerates microtubule formation and stabilizes established microtubules, resulting in microtubules that are too short.

46- What is the source of taxol?
The bark of the Pacific Yew tree Taxus breviflora. Can also be synthestized from a precursor in the tree's needles.

47- Which cancers are treated with taxol?
melanoma, breast and refractory ovarian cancer.

48- What is taxoterene?
A more potent analog of taxol.

49- What is the importance of chemotherapy toxicity?
Chemotherapeutic agents are toxic to rapidly dividing cells in normal tissues like bone marrow stem cells, intestinal crypt cells and hair follicles. Drg toxicity is usually dose-limiting.

50- List 5 side effects of chemotherapy.
decreased white blood cells and platelets
diarrhea
hair loss
infection
organ failure

51- What is the therapeutic index?
Ratio of the therapeutic effect of a drug to its toxicity to normal cells.

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