Medical Pharmacology Topics   

Cancer Therapy: Natural Anti-Tumor Agents

Several antitumor agents are derived from bacteria or plants. Dactinomycin, plicamycin, the antracyclines, bleomycin and mitomycin are isolated from Streptomyces bacteria, and they all inhibit either DNA synthesis or RNA transcription or both by intercalating into the DNA template or groove binding. A few agents form covalent links with DNA or cause backbone cleavage.

The vinca alkaloids, taxanes, podophyllotoxins and topoisomerase-1 inhibitors are derived from plants.

Streptomyces-Derived Agents

Dactinomycin consists of a 3-ring cdhromophore and two symetrical cyclic peptides. It has a red/yellow color due to the chromophore phenoxazone ring. Dactinomycin intercalates into DNA in G-C rich regions, resulting in depression of RNA transcription at low doses, especially ribosomal RNA since rRNA genes are rich in G-C. There is minimal metabolism of this drug and it is used against rhabdomyosarcoma, Wilm's tumors in children, Erwin's sarcoma and Kaposi's sarcoma.

Plicamycin has a mechanism of action similarto dactinomycin and will competewith it for G-C rich sites. Its primary effect is depression of DNA, RNA and protein synthesis. It also lowers calcium levels in patients with hypercalcemia.

Bleomycin acts by DNA binding, probably by intecalation, and DNA chain excision. Bleomycin binds Fe, which is oxidized to Fe, and the loss of an electron probably forms free radicals that can attack and brak DNA. The resulting DNA breaks can be in close proximity and produce double-strnded breaks, which can lead to chromosomal breaks and fragmentation, as well as translocations. The enzyme bleomycin hydrolase has been detected in most human tissues except lung and skin, were bleomycin is more toxic.

Mitomycin contains an azide ring, a urethane moiety and a quinine group. The molecule can undergo removal of an O-methyl group. The final product is capable of producing DNA inter- nd intrastrand crosslink. Mitomycin is used to treat GI tumors and has temporary benefits against other cancers.

Antracyclines

The antracyclines include daunorubicin, doxorubicin, idarubicin and epirubicin. Although there are marked differences in the clinical uses of daunorubicin and doxorubicin, their chemical structure differs only by a single hydroxyl. They have a four-ring anthracycline chromophore with an attached sugar, daunosamine. The sugar can interact non-covalently with the sugar phosphate backbone of DNA. They act by three potential mechanisms:

• Intercalation into DNA, resulting in complex-stabilizing inhibition of topoisomerase II and thus decreased DNA, RNA and protein synthesis.
• P450 metabolism to a form capable of generating free radicals, which can the produce DNA breks
• Activation of apoptosis signaling

Daunorubicin is primarily metabolized to daunorubicinol in the liver, thus should be avoided in patients with impaired renal function. Renal excretion of the drug and its metabolites may turn the urine red.

Dauorubicin and doxorubicin are used o treat leukemias and lymphomas. Doxorubicin is also good agaist solid tumors. The limiting toxicity of these agents is delayed, cummulative cardiac toxicity, since heart muscle cells are deficient at scavenging free radicals. Doxorubicin may also produce membrane damage and destruction of mitochondrial membrane enzymes.

Other anthracycline derivatives include epirubcin, idarubicin, m-AMSA, ellipticine and mitoxantrone. Mitroxantone is used IV to treat leukemias and breast cancer.

Antimitotic Agents

The vinca alkaloids are derived from the periwinkle shrub (Vinca rosa) and include vincristine, vinblastine, vinorelbine and vindesine. They are all cell cycle specific agents that bock cells at mitosis by binding to tubulin and preventing the polymerization of microtubules. Cell division is arrested at metaphase, and the inhability of chromosomes to segregate correctly presumably leads to apoptosis. The main mechanisms of resistance to the vinca alkaloids are overexpression of P-glycoprotein and MRP1, and decreased binding of the agents to tubulin (?).

Vicristine is a standard component of regimes to treat pediatric leukemias and solid tumors, and is frequently used in adult lymphoma and brest cancer treatment. Vinblastine is used primarily to treat testicular carcinoma and lymphomas. Vinorelbine is a semisynthetic product with less neurotoxicity. Peripheral neurotoxicity is the main side effect of vincristine, and is less common and sever with the othr vinca alkaloids.

The taxanes, paclitaxel and docitaxel, are derived from the bark of the Pacific yew tree (Taxus breviflora). They bind to the b-tubulin subunit of microtubules and appear to antagonize their dissasembly. This results in the formation of bundles of microtubules with aberrant structures, blocking cells in late G2 or M phase. This activates poptosis signaling. Resistance to paclitaxel is associated with increased expression of P-glycoprotein or tubulin mutations.

The yew tree is an endangered species, therefore supply of thetaxanes is a major problem. New semisynthetic and synthetic analogs such as docetaxel (isolated from Taxus baccata) are under development. Taxanes are active against ovarian cancer, brest cancer, non-small cell lung cancer, melanoma, renal cancer and leukemia.

Topoisomerase Inhibitors

The podophylotoxins VP-16 (etoposide) and VM-26 are semisynthetic derivatives of podophyllotoxin, a folk remedy extracted from the roots of the mandrake plant (Mandragora officinarum). While podophylotoxin itself binds to microtubules and causes mitotic arrest, VP-16 and VM-26 do not. Instead, they cause DNA strand breaks and inhibit topoisomerase II by blocking religation of cleaved DNA, trapping and stabilizin the enzyme in a topoisomerase II-DNA intermediate complex.

The podophylotoxins also inhibit nucleotide transport and incorporation into nucleic acids, and activate apoptosis signaling. Mechanisms of resistance to these agents include decreased expression of topoisomerase II and mutations that decrease the activity of the enzyme. VP-16 and VM-26 are active against lymphomas, germ cell neoplasms and small cell lung cancer. They are less active against acute myelogenous leukemia, non-small cell lung cancer and Kaposi's sarcoma.

The topoisomerase I inhibitors include camptothecin, CPT-11 and topotecan. Campthothecin is isolated from the stem wood of the Asian tree Camptotheca accuminata. Despite significant activity in vitro, clinical results are dissapointing. Still, two water soluble analogs of camptothecin, irothecan and topotecan, have been approved for clinical use. These agents trap and stabilize the topoisomerase I-DNA complex and interfere with the movement of DNA replication forks.

Irotecan (CPT-11) is biotransformed by tissue and serum carboxylesterases to the active metabolite SN-38, which has 100-1000-fold the antitumo activity of the parent compound. SN-38 undergoes significant biliary escretion and enterohepatic circulation. It is also glucuronidated in the liver to an inactive metabolite and excreted in the urine or deconjugated in the intestine.

The major side effect of CPT-11 is diarrhea, possibly by direct injury of SN-38 to the intestinal mucosa. Mechanisms of resistance to topoisomerase I inhibitors differ in different fell lines, but include reduction of topoisomerase I activity, mutations in topoisomerase I and loss of Bax.

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