Myelosuppression

Toxicity Amelioration. Cancer researchers traditionally have not focused their attention on the question of toxicity amehoration. This is partiy attributed to the lack of predictive animal models for human toxicities. For example, the preclinical rat model, used as a predictor of myelosuppression, has failed to predict myelosuppression in humans in clinical trials. In addition, reduction of one toxicity may result in the emergence of another, more serious problem. Research efforts to address the problem of toxicity amelioration has progressed in several directions. The three most prominent areas are analogue synthesis, chemoprotection, and dmg targeting. 

Clinical trials showed therapeutic efficacy in a broad spectrum of tumors these include SCLC, testicular tumors, sarcomas, breast cancer, renal cell cancer, pancreatic tumors and lymphomas. Ifosfamide is less myelosuppressive than cyclophosphamide but is more toxic to the bladder. Therefore it is recommended that ifosfamide is coadministered with the thiol compound mesna to avoid hemorrhagic cystitis and to reduce the risk of developing bladder cancer. Other side effects include neurotoxicity and myelosuppression. 

It is used by direct instillation into the bladder for multifocal local bladder carcinoma. Nausea and myelosuppression are the major toxicities of thiotepa. It is not a local vesicant and has been safely injected intramuscularly and even intra-thecally. 

Procarbazine causes myelosuppression, hypnotic and other effects on the central nervous system, e.g., vivid nightmares. Also, procarbazine causes a disulfiram like syndrome on ingestion of ethanol. 

Cisplatin administration requires adequate hydration and forced diuresis to prevent kidney damage. Cisplatin is intensely emetogenic and its use requires adequate antiemetic prophylaxis. Myelosuppression is less evident than with other alkylating agents. 

Carboplatin displays less nephro-, oto- and neurotoxicity. However, myelosuppression is more frequent, and as the drug is exclusively cleared through the kidney, adjustment of dose for creatinine clearance must be accomplished. 

Bendamustine is a useful antineoplastic drug for the treatment of non-Hodgkin s lymphomas, multiple myeloma and as a partner drug in the combination therapy of some solid tumors. The cross-resistance with other alkylating drugs is not complete. Myelosuppression and lymphocytopenia is its main dose-limiting toxicity. 

The plasma half-life of 6-MP after intravenous bolus injection is 21 min in children and is twofold greater in adults. After oral intake peak levels are attained within 2 h. 6-MP is used for the treatment of ALL and has shown certain activity in chronic myelogenous leukemia. The major side effects involve myelosuppression, nausea, vomiting, and hepatic injury. 

The most common adverse effects are myelosuppression, with leukopenia and thrombocytopenia appearing 7-10 days after treatment, as well as mild nausea. Liver toxicity with jaundice has been reported in rare cases. 

Pentostatin is effective in the treatment of hairy cell leukemia, producing 80-90% remissions (with a complete remission rate of more than 50%). The common side effects of pentostatin include myelosuppression, nausea, and skin rashes. Renal failure,... 

Cladribine is highly active against hairy cell leukemia (complete remssions were achieved in more than 60% of patients receiving a single 7-day course). Activity has been recorded in other low-grade lymphoid malignancies. The major side effect is myelosuppression. 

Vinca alkaloids (vincristine, vinblastine, vindesine) are derived from the periwinkle plant (Vinca rosea), they bind to tubulin and inhibit its polymerization into microtubules and spindle formation, thus producing metaphase arrest. They are cell cycle specific and interfere also with other cellular activities that involve microtubules, such as leukocyte phagocytosis, chemotaxis, and axonal transport in neurons. Vincristine is mainly neurotoxic and mildly hematotoxic, vinblastine is myelosuppressive with veiy low neurotoxicity whereas vindesine has both, moderate myelotoxicity and neurotoxicity. 

Epipodophyllotoxins (etoposide, teniposide) are derived from mandrake root (Podophyllum peltatum). They inhibit topoisomerase H thus causing double strand breaks. Cells in S- and G2-phases are most sensitive. Unwanted effects include nausea and vomiting, myelosuppression, and hair loss. 

Common side effects of interferons are flu-like symptoms, fever, myelosuppression, and skin-reactions. 

Myelosuppression is suppression of the production of blood cells by the bone marrow. 

Etoposide (XV) is a semisynthetic gylcoside derivative of podophyllotoxin, which is one of the most extensively used anticancer drugs in the treatment of various types of tumors [64,65]. The anticancer activity of this drug is mainly due to its ability to inhibit an ubiquitous and essential enzyme human DNA topo II [66,67]. Despite its extensive use in the treatment of cancers, it has several limitations, such as poor water solubility, drug resistance, metabolic inactivation, myelosuppression, and toxicity [68]. In order to overcome these... 

The antiproliferatives azathioprine and the mycophenohc acid derivatives inhibit T cell proliferation. Myelosuppression is the most significant adverse event associated with these agents. 

Sirolimus, a target of rapamycin inhibitor, works by decreasing the ability of T cells to respond to IL-2. The major adverse events associated with sirolimus are decreased wound healing, hyperlipidemia, and myelosuppression. This agent appears to have promising effects because it may allow calcineurin inhibitor withdrawal in some patients. 

Mycophenolate mofetil 0.5-1.5 g by mouth twice Myelosuppression, gastrointestinal 250 mg = 3.11... 

Enteric-coated MPA (Myfortic ) 720 mg by mouth twice Myelosuppression, gastrointestinal 180 mg = 2.53... 

After T cell lysis, there is a cytokine release. Owing to this phenomenon, ATG is associated with several adverse reactions.7,8,11 The most common include fever (63%), chills (43%), headache (35%), back pain (43%), nausea (28%), diarrhea (32%), dizziness (25%), malaise (4%), and myelosuppression [leukopenia (30%) and thrombocytopenia (44%)]. Overall incidence of opportunistic infections is 27%, with cytomegalovirus (CMV) disease occurring in 11% of patients.7,8,11... 

The most common adverse events associated with these agents are GI (18% to 54%, namely, diarrhea, nausea, vomiting, and gastritis) and myelosuppression (20% to 40%).7,11,26-28 Despite its enteric coating, to date, mycophenolic acid has shown no significant benefit in terms of reduction in GI adverse events compared with mycophenolate mofetil in renal transplant recipients.26... 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

The use of myelosuppressive agents, such as cotrimoxazole and valganciclovir, also could enhance myelosuppression when combined with azathioprine or the MPA derivatives. 

Anti-Pneumocystis Prophylaxis Sulfamethoxazole-trimethoprim (SMZ-TMP, cotrimoxazole) One SS tablet by mouth once a day3 One DS tablet by mouth once a day3 One DS tablet by mouth every MA/V/F3 Hyperkalemia Myelosuppression Nephrotoxicity Neutropenia Photosensitivity Rash... 

Dapsone 50-1 00-mg tablet by mouth once a day Hepatotoxicity Myelosuppression Nephritis... 

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