What is chemotherapy?

[Guest guest]

Greetings,

Here's an article I found to be very interesting and provides important concepts

for lymphoma patients to understand. A bit technical, however.

Notable quote: " Lumping all of these treatments under the term 'chemotherapy',

or even 'multi-agent chemotherapy', does the profession and the public a

disservice, by not recognizing the profound differences in mechanism of action,

therapeutic index and treatment outcome from these different types of treatment.

"

Key term:

Apoptosis: programmed cell death - a normal process by which the body rids

itself of old, unneeded, or damaged cells.

http://www.lymphomation.org/about-lay.htm

Many cytotoxic agents trigger apoptosis by damaging DNA - particularly in

dividing cells... This mechanism is similar to how too much sun can trigger

exposed skin cells to peel.

~ Karl

www.lymphomation.org

=

ls of Oncology 13:1697-1698, 2002

© 2002 European Society for Medical Oncology

http://annonc.oxfordjournals.org/cgi/content/full/13/11/1697

Editorial

New paradigms in oncological therapeutics: redefining combination chemotherapy

=Definitions

As oncological therapeutics evolve from cytotoxic-focused treatment to more

mechanism-based interventions, it is time to redefine the terminology to more

precisely reflect the tools being employed.

Nuance counts; the widely used term for systemic cancer treatment with drugs,

'chemotherapy', carries with it well deserved negative connotations to the lay

public.

Among professionals, 'chemotherapy' implies treatment with cytotoxic agents, but

can lead to confusion and miscommunication among healthcare team members, and

from professionals to patients and their families.

Systemic cancer treatments include hormonal, immunological stimulatory,

cytotoxic and molecular-targeted approaches.

The efficacy, toxicities and mechanisms of action of these various modalities

differ substantially.

Lumping all of these treatments under the term 'chemotherapy', or even

'multi-agent chemotherapy', does the profession and the public a disservice, by

not recognizing the profound differences in mechanism of action, therapeutic

index and treatment outcome from these different types of treatment.

Eliminating the term 'chemotherapy' in favor of more accurate terminology will

probably improve the public and professional view of oncology, enhance

recruitment to clinical trials, and permit more selective and beneficial

treatment for cancer patients.

Future role of combined cytotoxic therapeutics

The fundamental concepts of combining cytotoxic therapeutics were conceived over

four decades ago, after the realization that single agents were largely

ineffective in the treatment of cancer.

Cytotoxic agents were combined on the basis of their perceived cytotoxic

mechanism of action, which, more often then not, was found to be nuclear

DNA-based.

While the attention paid to DNA-based mechanisms was scientifically fruitful,

the methodologies employed to discover these mechanisms usually relied on DNA

preparations in vitro. Intracellular trafficking, metabolism, organelle binding

or cellular membrane protein receptor binding mechanisms have not been carefully

investigated.

Thus, insight into multiple mechanisms of cytotoxic agent activity has been

limited. For example, cytotoxic agents have been found to induce apoptosis in

many transformed cells, a mechanism attributed primarily to p53 activation

associated with drug-induced DNA damage [1, 2].

However, cytotoxic agents have effects on multiple, redundant signal

transduction pathways. Many of these pathways ultimately impact Bax

translocation into the mitrochondrial membrane, a common trigger pathway for

apoptosis initiation [3].

Resistance to apoptosis induced by individual cytotoxic agents may be a key

target for future therapeutics or combined systemic anticancer interventions

[3].

Selected cytotoxic agents may inhibit angiogenesis in transformed cells at doses

much lower than those used for known cytotoxic effects [4].

Mechanisms of antiangiogenesis are not well understood, but will provide future

opportunities for novel therapeutic combinations and rethinking the concept of

antineoplastic therapeutic index and targets.

Broad-mechanism non-specific combination 'chemotherapies' with cytotoxins may

have a place in future therapeutics, perhaps in preliminary tumor mass

cytoreduction or, more interestingly, as specific targeting agents at lower less

toxic doses. More might not be better; more might be detrimental to efficacy,

due to enhanced toxicity and loss of antiangiogenic effects at the lower doses-a

Gaussian rather than sigmoidal dose-response curve.

Re-evaluating and rethinking cytotoxin mechanisms of action in the context of

new mechanism-based therapeutics may lead to innovative combinations at doses

that one might not consider if toxicity is used as the dosing end point.

=Targeted therapeutics

Therapeutic agents targeting specific signal transduction pathways are rapidly

moving towards the clinic. Clinical proof of this principle has emerged with the

successful treatment of chronic myelocytic leukemia (CML) with imatinib mesylate

(STI-571, Gleevec) [5, 6] and with the success of trastuzumab (Herceptin), a

humanized mouse monoclonal antibody binding to HER-2/neu [7].

The therapeutic success of imatinib mesylate with CML can be attributed to the

95% incidence of Bcr-Abl translocation in these tumor cells unmasking

constitutively activated tyrosine kinase. All transforming functions of the

Bcr-Abl protein are dependent on this translocation-induced tyrosine kinase

activity [8].

Based on these data, one might predict that selective inhibition of a

disease-related tyrosine kinase that is not transforming in heterogeneous solid

tumor masses should have minimal impact on tumor cell proliferative and

apoptotic control. Imatinib's efficacy in reducing tumor cell mass and inducing

clinical remissions in patients with gastrointestinal stromal tumors is

therefore all the more surprising [9]. Yet not all intestinal stromal tumors

with mutated c-kit respond to imatinib mesylate.

The mechanisms by which these unresponsive tumors subvert inhibition of the

c-kit tyrosine kinase are of major importance. Studies of unresponsive or

resistant tumors will teach us whether redundant pathways may also be targeted

and ultimately therapeutically exploited or whether heterogenous mutations in

the c-kit tyrosine kinase proteins produce stoichiometric changes in the protein

that no longer permit binding of imatinib mesylate to the target [10, 11].

Future therapeutic decisions might employ cost-effective high throughput

proteomic or genomic tools to provide molecular profiles for identifying whether

the targeted protein or related genetic mutations are present in a tumor. Such a

paradigm would allow for individualized therapies for tumors.

=New concepts in combination oncological therapeutics

Will a single agent, chosen on the basis of molecular profiling, be sufficient

to remove the selective advantage enjoyed by cancer cells?

Not according to current thinking. Combined oncological therapeutics will be

defined using many interventions. Potentially, combination non-specific

cytotoxic agents might initially cytoreduce large bulk tumor masses.

Clinical and preclinical synergy of classical DNA-directed non-specific

cytotoxic agents with targeted therapies [12, 13] suggests that classical

cytotoxic agents modulate important cellular signaling pathways so, when

combined with targeted agents, they will lead to enhanced clinical efficacy.

Concepts of dose-response should be considered and exploited to reduce exposure

to toxic agents. Careful phase I biomarker-targeted trials could confirm unique

mechanisms of classical cytotoxic agent action discovered in vitro that may lead

to innovative and unexpected combination therapies.

Combination cancer therapeutics might require identification of mutated upstream

signal transduction genes using high throughput genomic profiles, and

identification of downstream signals with high throughput proteomic profiles

with therapeutic targets individually selected.

New epidermal growth factor receptor tyrosine kinase inhibitors (e.g.

ZD1839/Iressa, cetuximab) will expand the repertoire of signal transduction

targets.

Many angiogenesis inhibitors that variously target vascular endothelial growth

factor receptor tyrosine kinase, fibroblast growth factor receptor tyrosine

kinase and the vß3 integrin may be useful antineoplastic agents.

The challenge of understanding or predicting efficacy with these agents will be

to reproducibly quantify whether drug-induced phosphorylation of other

downstream signal transduction intermediates is translated into the clinical

setting.

Moreover, we are now challenged with redefining the concept of clinical

efficacy-is lack of tumor proliferation and metastatic spread without ablation

sufficient to define efficacy?

Will all of this come to pass?

Only innovative well-designed translational investigations will reveal the

answer. But the future today is far brighter than it was 10 years ago. And

'combination chemotherapy' will take on a totally different nuance and meaning

than it has today.

D. E. Brenner

2150 Cancer Center and Geriatrics Center, University of Michigan Medical Center,

Ann Arbor, MI; and VA Medical Center, Ann Arbor, MI, US

References

1. Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the

cytotoxicity of anticancer agents. Cell 1993; 74: 957-967.[iSI][Medline]

2. Lowe SW, Bodis S, Bardeesy N et al. Apoptosis and the prognostic significance

of p53 mutation. Cold Spring Harb Symp Quant Biol 1994; 59:

419-426.[iSI][Medline]

3. Makin G, Dive C. Apoptosis and cancer chemotherapy. Trends Cell Biol 2001;

11: 522-526.

4. Belotti D, Vergani V, Drudis T et al. The microtubule-affecting drug

paclitaxel has antiangiogenic activity. Clin Cancer Res 1996; 2:

1843-1849.[Abstract]

5. Druker BJ. STI571 (Gleevec) as a paradigm for cancer therapy. Trends Mol Med

2002; 8 (4 Suppl.): S14-S18.[iSI][Medline]

6. Druker BJ. Perspectives on the development of a molecularly targeted agent.

Cancer Cell 2002; 1: 31-36.[iSI][Medline]

7. Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy

and safety of humanized anti-HER2 monoclonal antibody in women who have

HER2-overexpressing metastatic breast cancer that has progressed after

chemotherapy for metastatic disease. J Clin Oncol 1999; 17:

2639-2648.[Abstract/Free Full Text]

8. Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and

transformation potency of bcr-abl oncogene products. Science 1990; 247:

1079-1082.[Abstract/Free Full Text]

9. Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of imatinib

mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347:

472-480.[Abstract/Free Full Text]

10. Barthe C, Cony-Makhoul P, Melo JV, Mahon JR. Roots of clinical resistance to

STI-571 cancer therapy. Science 2001; 293: 2163.[Medline]

11. Gorre ME, Mohammed M, Ellwood K et al. Clinical resistance to STI-571 cancer

therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293:

876-880.[Abstract/Free Full Text]

12. Slamon DJ, Leyland- B, Shak S et al. Use of chemotherapy plus a

monoclonal antibody against HER2 for metastatic breast cancer that overexpresses

HER2. N Engl J Med 2001; 344: 783-792.[Abstract/Free Full Text]

13. Shawver LK, Slamon D, Ullrich A. Smart drugs: tyrosine kinase inhibitors in

cancer therapy. Cancer Cell 2002; 1: 117-123.[iSI][Medline]