Metastases => generally have faster doubling time than primary lesions
If it is assumed that exponential growth occurs early in a tumor history & that a
tumor starts from a single malignant cell
1mm mass ; undergone 20 doubling times
5mm mass ; undergone 27 doubling times (first visualized an X-ray film)
1cm mass ; undergone 30 doubling times
With current clinical techniques : most tumors recognized late in their growth &
metastasis may well have occurred long before there is evidence of the primary
lesion
In late stages of tumor growth, a very few doubling in tumor mass have a
dramatic impact on the size of the tumor.
E. Cell Cycle
The generation time ; the duration of the cycle form M phase to M phase
variation occurs in all phases of the cell cycle, => greatest during the G1 period
Two major factors affect the rate at which tumors grow : growth fraction & cell
death
The growth fraction ; the number of cells in the tumor mass that are actively
undergoing cell division
Marked variations in growth fraction ; 25 - 90 %
In the past ; human tumors contained billions of cells, all growing slowly
In actuality ; only a small fraction of cells with in a tumor mass are rapidly
proliferating
Factors that alters tumor growth
Cytotoxic chemotherapy
Hormones
X-ray therapy
Alterations in oxygen & vascular supply
Immunologic therapies
II. Chemotherapy
A. Differential Sensitivity
1. Therapeutic Index
Therapeutic index ; a ratio of the doses at which therapeutic effect & toxicity occur
=> The net effect of a chemotherapeutic agent
Most chemotherapeutic agent
=> the window of toxicity is narrow
2. Cell cycle-Specific Versus Cycle non-specific Drugs
·Table. 30.2 - 30.3
3. Log Kill Hypothesis
Chemotherapeutic agents => first order kinetics
; Killing a constant fraction of cells rather than a constant number
Single chemotherapeutic agents => 2 ~ 5 logs or cell kill
1kg ; 1012 cells => single use is unlikely to be curative =>need for intermittent
courses of chemotherapy & multiple drug or combination chemotherapy
Cure rate => significantly improved if small tumors present
101 ~ 104 cell mass => too small for clinical detection;
Basis for using adjuvant chemotherapy in early stages of disease
4. Drug Resistance & Tumor Cell Heterogenicity
A variety of cellular mechanism is involved
a. Increased activation
b. Decreased activation of drugs
c. Increased drug efflux
d. Resist normal drug uptake
e. Altered specificity to an inhibiting enzyme or increased production of the target
enzyme
5. Dose Intensity
Dose intensity = Drug (mg) 1Surface area (M2) / Time (week)
Bone morrow transplantation ; with advanced, refractory ovarian Cancer
Additive ; enhanced anti-tumor activity equivalent to the sum of both agents acting
singly
Antagonize ; producing a lesser therapeutic effects
D. Remission
Complete Remission ; the complete disappearance of all objective evidence of tumor
as well as the resolution of all signs & symptoms referable to the tumor
Partial Remission : > 50% reduction in the size of measurable lesions along with
some degree of subjective improvement & absence of any new lesions during
therapy.
E. Dose Adjustment
Table 30.4 - 30.5
F. Drug Toxicity
1. Hematologic Toxicity
Acute granulocytopenia ; 6 ~ 12 days after administration => recovery, 21 ~ 24days
Acute thrombocytopenia ; 4 ~ 5 days => recovery ; after white cell count returns
to base line
Granulocytopenia
< 500/mm3 => 5days or longer ; at high risk of rapidly fatal sepsis
Prophylactic & empirical use of broad-spectrum antibiotics
=> has significantly decreased the incidence of life-threatening infections
Temperature ; checked every 4 hours
G-CSF, GM-CSF ; shortens duration of granulocytopenia, not thrombocytopenia
Thrombocytopenia
< 20,000/mm3 => at risk of spontaneous hemorrhage
(acute gastrointestinal or intracranial hemorrhage)
6 ~ 10 units transfusion per 2 ~ 3days
> 50,000/mm3 with active bleeding, peptic ulcer disease, surgical procedure
1hr after transfusion => platelet count does not increase
=> HLA-matched platelet is needed
2. Gastrointestinal Toxicity
Mucositis
3 ~ 5 days earlier than the myelosuppression
Can be confused with candidiasis or herpes simplex infection
Candidiasis
Oral candidiasis ; chlorthrimazide (10 mg five times daily)
Prevention : Maintenance of high urine output & high urinary PH(>7.0) prophylactic
use of the xanthine oxidase inhibitor (allopurinal)
G. Anti-neoplastic Drugs
Table 30.6
1. Alkylating Agents
Usually bind to the N-7 position of guanine => interfere with accurate base pairing,
cross-link DNA => single & doable-stranded break => results in DNA & RNA,
protein synthesis
All alkylating agents => similar mechanism => cross-resistance can occur
2. Anti-tumor Anti-biotics
Natural products from fungi
Action mechanism
Inserted between DNA base pairs
Formation of tree radicals => damaging DNA, RNA, proteins
Metal ion chelation & alteration of tumor cell membranes
Anthracyclines, Bleomycin
3. Anti-metabolites
Interacts with vital intracellular enzymes => inactivation or frauclulent products
incapable of normal intracelluar function
More disruptive to actively proliferating cells => cell-cycle specific
Methotrexate ; folate antagonist
Hydroxyurea ; Ribonucleotide reductase inhibitor
5 - FU ; pyrimidine antagonists
4. Plant Alkaloids
Vincristine & Vinblastine
=> binding to microtubular proteins
=> inhibition of microtubular proteins & destruction of the mitotic spindle
=> arrested in mitosis
Paclitaxel
=> binds of microtubules & polymerization & stabilization