Medchem 562 – Fall 2016
Porubek – Anticancer Agents
Problem Set 1 – Introduction and terminology through DNA cross-linkers/alkylators
1. Name and define the two primary classes of anticancer agents.
2. Carcinogenesis is the _______________ growth of _______________ cells. Cancers in
tissues are commonly referred to as __________ tumors, while cancers of the blood or
lymph are referred to as ____________ tumors.
3. Cancer generally arises from mutations in two types of genes. What are these two types
of genes called? For each type, what healthy gene functions are they generally
characterized by? For each type, indicate whether cancer causing mutations result in
gain-of-function (GOF) or loss-of-function (LOF) of the altered gene. Name one example
of each type of gene.
4. Which of the following are true about clonal selection:
a. It can lead to drug resistance
b. It starts very early in the formation of a tumor
c. It directly causes metastases
d. All of the above
e. Only A and B
5. What biological marker is commonly used as a surrogate for cancer aggressiveness/drug
efficacy in cancer treatment? Why is this marker useful (Hint: think about the ultimate
cause of death for most cancer patients)?
6. What are the three important criteria considered for cancer staging and how are they
scored? What are the characteristics of the Stage I-IV classifications?
7. Besides chemotherapy, what other clinical interventions are commonly used to treat
cancer?
8. Name and briefly describe the response criteria used in early clinical trials for anticancer
agents (Hint: there are four of them). What is the current standard measure for
assessing the overall clinical efficacy of anticancer agents (Hint: it’s a single statistic)?
9. Modern cancer care is typically performed by “oncology teams” often consisting of
surgical oncologists, radiation oncologists, hematologic oncologists, medical oncologists,
oncology pharmacists, oncology nurses, oncology histopathologists, and oncology
geneticists. What role does the oncology pharmacist play in this setting?
10. Name the three main types of blood cells and briefly describe the primary functions of
each. What is the (relative) abundance of each type in blood?
11. What condition is characterized by low levels of erythrocytes? High levels?
12. Which of the following are true about neutrophils:
a. They are the most important cells for fighting bacterial infections
b. They are the most abundant type of blood cells
c. They assist with clotting of the blood
d. Only A and B
e. Only B and C
13. Which subtype of agranulocytes contains T-cells, B-cells, and NK-cells? Name four
subtypes of T-cells and briefly describe their primary functions.
14. What is the general mechanism of action of DNA cross-linkers and alkylating agents? Are
they cell-cycle specific, if so what part of the cell cycle do they target? From an organic
chemistry standpoint, what chemical property of these agents (and of DNA) makes them
prone to react with DNA.?
15. What side effect is common to nearly all DNA cross-linker/alkylating agent
chemotherapeutics?
16. Below are structures for the three platinum agents discussed in class (cisplatin,
carboplatin, and oxaliplatin). What is the general mechanism of action of the platinum
agents (draw an arrow-pushing mechanism, you can use DNA-Nu: in place of actual DNA
structure for simplicity)? What is the primary nucleophile in DNA that interacts with
these agents? For carboplatin and oxaliplatin, identify how they differ from the previous
agent (specifically, regarding physical/chemical properties activity and toxicity). Which
of these agents should/should not be administered in saline?
17. Below are the structures for busulfan (left) and treosulfan (right). What is the
mechanism of action of these agents (draw an arrow-pushing mechanism, you can use
DNA-Nu: in place of actual DNA structure for simplicity)? Describe what makes these
agents differ from one another in their mechanisms of action.
18. Fill in the missing structures in the scheme below depicting the mechanism of action of
dacarbazine.
19. What is the primary active moiety in the nitrogen mustards, and how is it activated? In
general, how do the nitrogen mustards illicit their anticancer activity? (Hint: a single
scheme can answer this question)
20. Below are a series of nitrogen mustard agents, listed in order of descending activity. For
each agent (starting with clorambucil), explain why its activity is attenuated relative to
the previous agent (Hint: think about how these compounds become activated).
mechlorethamine
chlorambucil
cyclophosphamide
ifosfamide